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Abstract Chloroplasts are key players in photosynthesis and immunity against microbial pathogens. However, the precise and timely regulatory mechanisms governing the control of photosynthesis-associated nuclear genes (PhANGs) expression in plant immunity remain largely unknown. Here we report that TaPIR1, a Pst-induced RING-finger E3 ubiquitin ligase, negatively regulates Pst resistance by specifically interacting with TaHRP1, an atypical transcription factor histidine-rich protein. TaPIR1 ubiquitinates the lysine residues K131 and K136 in TaHRP1 to regulate its stability. TaHRP1 directly binds to the TaHRP1-binding site elements within the PhANGs promoter to activate their transcription via the histidine-rich domain of TaHRP1. PhANGs expression induces the production of chloroplast-derived ROS. Although knocking out TaHRP1 reduces Pst resistance, TaHRP1 overexpression contributes to photosynthesis, and chloroplast-derived ROS production, and improves disease resistance. TaPIR1 expression inhibits the downstream activation of TaHRP1 and TaHRP1-induced ROS accumulation in chloroplasts. Overall, we show that the TaPIR1-mediated ubiquitination and degradation of TaHRP1 alters PhANGs expression to disrupt chloroplast function, thereby increasing plant susceptibility to Pst.

Abstract Premature Ovarian Insufficiency (POI) is a highly heterogeneous condition characterized by ovarian dysfunction in women occurring before the age of 40, representing a significant cause of female infertility. It manifests through primary or secondary amenorrhea. While more than half of POI cases are idiopathic, genetic factors play a pivotal role in all instances with known causes, contributing to approximately 20–25% of cases. This article comprehensively reviews the genetic factors associated with POI, delineating the primary candidate genes. The discussion delves into the intricate relationship between these genes and ovarian development, elucidating the functional consequences of diverse mutations to underscore the fundamental impact of genetic effects on POI. The identified genetic factors, encompassing gene mutations and chromosomal abnormalities, are systematically classified based on whether the resulting POI is syndromic or non-syndromic. Furthermore, this paper explores the genetic interplay between mitochondrial genes, such as Required for Meiotic Nuclear Division 1 homolog Gene (RMND1), Mitochondrial Ribosomal Protein S22 Gene (MRPS22), Leucine-rich Pentapeptide Repeat Gene (LRPPRC), and non-coding RNAs, including both microRNAs and Long non-coding RNAs, with POI. The insights provided serve to consolidate and enhance our understanding of the etiology of POI, contributing to establishing a theoretical foundation for diagnosing and treating POI patients, as well as for exploring the mechanisms underlying the disease.

Abstract Protein phosphorylation plays an important role in immune signaling transduction in plant resistance to pathogens. Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), severely devastates wheat production. Nonetheless, the molecular mechanism of wheat resistance to stripe rust remains limited. In this study, quantitative phosphoproteomics was employed to investigate the protein phosphorylation changes in wheat challenged by Pst. A total of 1537 and 2470 differentially accumulated phosphoproteins (DAPs) were identified from four early infection stage (6, 12, 18 and 24 h post-inoculation) in incompatible and compatible wheat-Pst interactions respectively. KEGG analysis revealed that Oxidative Phosphorylation, Phosphatidylinositol Signaling, and MAPK signaling processes are distinctively enriched in incompatible interaction, while Biosynthesis of secondary metabolites and RNA degradation process were significantly enriched in compatible interactions. In particular, abundant changes in phosphorylation levels of chloroplast proteins were identified, suggesting the regulatory role of photosynthesis in wheat-Pst interaction, which is further emphasized by protein-protein interaction (PPI) network analysis. Motif-x analysis identified [xxxxSPxxxx] motif, likely phosphorylation sites for defensive response-related kinases, and a new [xxxxSSxxxx] motif significantly enriched in incompatible interaction. The results shed light on the early phosphorylation events contributing to wheat resistance against Pst. Moreover, our study demonstrated that the phosphorylation levels of Nucleoside diphosphate kinase TaNAPK1 are upregulated at 12 hpi with CYR23 and at 24 hpi with CYR31. Transient silencing of TaNAPK1 was able to attenuate wheat resistance to CYR23 and CYR31. Our study provides new insights into the mechanisms underlying Pst-wheat interactions and may provide database to find potential targets for the development of new resistant varieties.

BACKGROUND: Hemorrhagic shock (HS) causes severe organ damage, worsened by high-altitude conditions with lower oxygen and temperatures. Existing research lacks specific insights on brain and heart damage under these conditions. This study hypothesizes that high-altitude and cold (HAC) environments exacerbate HS-induced damage in the brain and heart, aiming to improve treatment strategies. MATERIALS AND METHODS: Twenty-four male Sprague-Dawley (SD) rats (200–250 g of weight) were randomly assigned into sham, HS + normal, HS + HAC (4,000 m), and HS + HAC (6,000 m). The HS model was established in SD rats (35% loss of total blood volume), and histopathological injuries of the brain and heart were detected using hematoxylin and eosin staining, Sirius red staining, and immunohistochemistry. Apoptosis of the brain and heart tissues was detected by terminal transferase-mediated dUTP nick end labeling (TUNEL) immunofluorescence staining. To determine the levels of tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (Mcp-1), BCL2-associated X (BAX), and myeloid cell leukemia-1 (Mcl-1) protein, western blotting assay was used. RESULTS: The HAC environment induced pathological damage to the brain and heart and aggravated the degree of cardiac fibrosis in HS rats. However, it did not cause apoptosis of the brain and heart. In addition, it upregulated TNF-α, IFN-γ, Mcp-1, and BAX protein levels, but downregulated Mcl-1 protein levels (P < 0.05). CONCLUSIONS: The HAC environment aggravated the degree of brain and heart damage in HS rats, which may be related to neuron nucleus pyknosis, myocardial fibrosis, and inflammatory and apoptosis activation.

Semantic Communication (SC) has emerged as a novel communication paradigm that provides a receiver with meaningful information extracted from the source to maximize information transmission throughput in wireless networks, beyond the theoretical capacity limit. Despite the extensive research on SC, there is a lack of comprehensive survey on technologies, solutions, applications, and challenges for SC. In this article, the development of SC is first reviewed and its characteristics, architecture, and advantages are summarized. Next, key technologies such as semantic extraction, semantic encoding, and semantic segmentation are discussed and their corresponding solutions in terms of efficiency, robustness, adaptability, and reliability are summarized. Applications of SC to UAV communication, remote image sensing and fusion, intelligent transportation, and healthcare are also presented and their strategies are summarized. Finally, some challenges and future research directions are presented to provide guidance for further research of SC.

Abstract Domesticated safflower (Carthamus tinctorius L.) is a widely cultivated edible oil crop. However, despite its economic importance, the genetic basis underlying key traits such as oil content, resistance to biotic and abiotic stresses, and flowering time remains poorly understood. Here, we present the genome assembly for C. tinctorius variety Jihong01, which was obtained by integrating Oxford Nanopore Technologies (ONT) and BGI-SEQ500 sequencing results. The assembled genome was 1,061.1 Mb, and consisted of 32,379 protein-coding genes, 97.71% of which were functionally annotated. Safflower had a recent whole genome duplication (WGD) event in evolution history and diverged from sunflower approximately 37.3 million years ago. Through comparative genomic analysis at five seed development stages, we unveiled the pivotal roles of fatty acid desaturase 2 (FAD2) and fatty acid desaturase 6 (FAD6) in linoleic acid (LA) biosynthesis. Similarly, the differential gene expression analysis further reinforced the significance of these genes in regulating LA accumulation. Moreover, our investigation of seed fatty acid composition at different seed developmental stages unveiled the crucial roles of FAD2 and FAD6 in LA biosynthesis. These findings offer important insights into enhancing breeding programs for the improvement of quality traits and provide reference resource for further research on the natural properties of safflower.

Abstract A-to-I mRNA editing in animals is mediated by ADARs, but the mechanism underlying sexual stage-specific A-to-I mRNA editing in fungi remains unknown. Here, we show that the eukaryotic tRNA-specific heterodimeric deaminase FgTad2-FgTad3 is responsible for A-to-I mRNA editing in Fusarium graminearum. This editing capacity relies on the interaction between FgTad3 and a sexual stage-specific protein called Ame1. Although Ame1 orthologs are widely distributed in fungi, the interaction originates in Sordariomycetes. We have identified key residues responsible for the FgTad3-Ame1 interaction. The expression and activity of FgTad2-FgTad3 are regulated through alternative promoters, alternative translation initiation, and post-translational modifications. Our study demonstrates that the FgTad2-FgTad3-Ame1 complex can efficiently edit mRNA in yeasts, bacteria, and human cells, with important implications for the development of base editors in therapy and agriculture. Overall, this study uncovers mechanisms, regulation, and evolution of RNA editing in fungi, highlighting the role of protein-protein interactions in modulating deaminase function.

Based on the differences and correlations of quality and mineral elements content in dried fruit of Lycium barbarum L., a comprehensive evaluation system was established to screen the excellent germplasms, also to provide theoretical basis for high quality breeding of Lycium barbarum L.. The 16 qualities and mineral elements content of dried fruit in 60 germplasms of Lycium barbarum L. were measured. The core evaluation indexes were screened by coefficient of variation, correlation analysis and factor analysis, and the comprehensive evaluation system of dried fruit quality of Lycium barbarum L. was constructed by analytic hierarchy process (AHP), grey correlation analysis (GCA) and cluster analysis (CA). The results showed that there were significant differences in nutritional components, constant element and trace element contents among different germplasms. There were significant positive correlations between total sugar content, betaine content and Zn content, polysaccharide content and Fe content, carotenoids content and Mg, Se content, flavonoids content and B, Zn, Ca content, fat content and Se, Mg content (P

Polyphenols, as subordinate metabolites of plants, have demonstrated significant antibacterial, anti-inflammatory, and antioxidant action in scientific learn. These compounds exert their effects through various mechanisms, containing interference with microbial cell structures, rule of host immune responses, and neutralization of free radicals. This multifaceted activity positions polyphenols as promising candidates for maintaining human health and treating related diseases. Notably, in the context of escalating antibiotic resistance, the antibacterial properties of polyphenols offer innovative avenues for the development of new therapeutic agents. Additionally, their anti-inflammatory and antioxidant effects hold substantial potential for treating inflammatory diseases and mitigating the aging process. This review aims to summarize the latest findings on the biological activities of polyphenols, highlighting their mechanisms of action and potential applications in health and disease management. Furthermore, optimizing polyphenol extraction methods aligns with the goals of sustainable and green processing, reducing environmental impact while enhancing food safety and extending shelf life. Employing advanced analytical techniques, such as spectroscopy and chromatography, can ensure the accurate evaluation of polyphenol content and efficacy. These efforts collectively contribute to the ongoing improvement of food processing practices and product quality, promoting a healthier and more sustainable future in the food industry.

Abstract Continued emergence of SARS-CoV-2 variants of concern that are capable of escaping vaccine-induced immunity highlights the urgency of developing new COVID-19 therapeutics. An essential mechanism for SARS-CoV-2 infection begins with the viral spike protein binding to the human ACE2. Consequently, inhibiting this interaction becomes a highly promising therapeutic strategy against COVID-19. Herein, we demonstrate that ACE2-expressing human lung spheroid cells (LSC)-derived exosomes (LSC-Exo) could function as a prophylactic agent to bind and neutralize SARS-CoV-2, protecting the host against SARS-CoV-2 infection. Inhalation of LSC-Exo facilitates its deposition and biodistribution throughout the whole lung in a female mouse model. We show that LSC-Exo blocks the interaction of SARS-CoV-2 with host cells in vitro and in vivo by neutralizing the virus. LSC-Exo treatment protects hamsters from SARS-CoV-2-induced disease and reduced viral loads. Furthermore, LSC-Exo intercepts the entry of multiple SARS-CoV-2 variant pseudoviruses in female mice and shows comparable or equal potency against the wild-type strain, demonstrating that LSC-Exo may act as a broad-spectrum protectant against existing and emerging virus variants.

Abstract Prenatal cannabis use is associated with adverse offspring neurodevelopmental outcomes, however the underlying mechanisms are relatively unknown. We sought to determine the impact of chronic delta-9-tetrahydrocannabinol (THC) exposure on fetal neurodevelopment in a rhesus macaque model using advanced imaging combined with molecular and tissue studies. Animals were divided into two groups, control (n = 5) and THC-exposed (n = 5), which received a daily THC edible pre-conception and throughout pregnancy. Fetal T2-weighted MRI was performed at gestational days 85 (G85), G110, G135 and G155 to assess volumetric brain development. At G155, animals underwent cesarean delivery with collection of fetal cerebrospinal fluid (CSF) for microRNA (miRNA) studies and fetal tissue for histologic analysis. THC exposure was associated with significant age by sex interactions in brain growth, and differences in fetal brain histology suggestive of brain dysregulation. Two extracellular vesicle associated-miRNAs were identified in THC-exposed fetal CSF; pathway analysis suggests that these miRNAs are associated with dysregulated axonal guidance and netrin signaling. This data is indicative of subtle molecular changes consistent with the observed histological data, suggesting a potential role for fetal miRNA regulation by THC. Further studies are needed to determine whether these adverse findings correlate with long-term offspring neurodevelopmental health.

Abstract Early and accurate diagnosis of focal liver lesions is crucial for effective treatment and prognosis. We developed and validated a fully automated diagnostic system named Liver Artificial Intelligence Diagnosis System (LiAIDS) based on a diverse sample of 12,610 patients from 18 hospitals, both retrospectively and prospectively. In this study, LiAIDS achieved an F1-score of 0.940 for benign and 0.692 for malignant lesions, outperforming junior radiologists (benign: 0.830-0.890, malignant: 0.230-0.360) and being on par with senior radiologists (benign: 0.920-0.950, malignant: 0.550-0.650). Furthermore, with the assistance of LiAIDS, the diagnostic accuracy of all radiologists improved. For benign and malignant lesions, junior radiologists’ F1-scores improved to 0.936-0.946 and 0.667-0.680 respectively, while seniors improved to 0.950-0.961 and 0.679-0.753. Additionally, in a triage study of 13,192 consecutive patients, LiAIDS automatically classified 76.46% of patients as low risk with a high NPV of 99.0%. The evidence suggests that LiAIDS can serve as a routine diagnostic tool and enhance the diagnostic capabilities of radiologists for liver lesions.

In order to optimize the operational safety and reliability of the upper launcher for the CFETR ECRH system, a design of the launcher based on the remote steering concept is currently being carried out for comparison with the front steering equivalent. This paper presents the remote steering system's conceptual design and simulation analysis. A Square Corrugated Waveguide (SCW) of 65 × 65 mm has been designed with an optimized length of 9.35 m. By changing the relative length of the waveguide, the transmission efficiency of the SCW is optimized within the range of steering angles ±12°. Different error factors are investigated in detail, and corresponding acceptable error ranges are provided. Considering these error factors and ignoring ohmic losses and thermal effects, the relative transmission efficiency of the SCW is estimated to be >98 % within the steering angle range. A matching steering unit for the SCW is designed, which consists of an ellipsoidal focusing mirror and a steerable flat mirror. The detailed design of the steerable mirror motion trajectory is presented. Also, the influence of the possible beam incident errors caused by the steering unit on the transmission efficiency is analyzed in detail.

Abstract Background Satellite repeats are one of the most rapidly evolving components in eukaryotic genomes and play vital roles in genome regulation, genome evolution, and speciation. As a consequence, the composition, abundance and chromosome distribution of satellite repeats often exhibit variability across various species, genome, and even individual chromosomes. However, we know little about the satellite repeat evolution in allopolyploid genomes. Results In this study, we investigated the satellite repeat signature in five okra (Abelmoschus esculentus) accessions using genomic and cytogenetic methods. In each of the five accessions, we identified eight satellite repeats, which exhibited a significant level of intraspecific conservation. Through fluorescence in situ hybridization (FISH) experiments, we observed that the satellite repeats generated multiple signals and exhibited variations in copy number across chromosomes. Intriguingly, we found that five satellite repeats were interspersed with centromeric retrotransposons, signifying their involvement in centromeric satellite repeat identity. We confirmed subgenome-biased amplification patterns of these satellite repeats through existing genome assemblies or dual-color FISH, indicating their distinct dynamic evolution in the allotetraploid okra subgenome. Moreover, we observed the presence of multiple chromosomes harboring the 35 S rDNA loci, alongside another chromosomal pair carrying the 5 S rDNA loci in okra using FISH assay. Remarkably, the intensity of 35 S rDNA hybridization signals varied among chromosomes, with the signals predominantly localized within regions of relatively weak DAPI staining, associated with GC-rich heterochromatin regions. Finally, we observed a similar localization pattern between 35 S rDNA and three satellite repeats with high GC content and confirmed their origin in the intergenic spacer region of the 35 S rDNA. Conclusions Our findings uncover a unique satellite repeat signature in the allotetraploid okra, contributing to our understanding of the composition, abundance, and chromosomal distribution of satellite repeats in allopolyploid genomes, further enriching our understanding of their evolutionary dynamics in complex allopolyploid genomes.

Abstract Background This study used a bidirectional 2-sample Mendelian randomization study to investigate the potential causal links between mtDNA copy number and cardiometabolic disease (obesity, hypertension, hyperlipidaemia, type 2 diabetes [T2DM], coronary artery disease [CAD], stroke, ischemic stroke, and heart failure). Methods Genetic associations with mtDNA copy number were obtained from a genome-wide association study (GWAS) summary statistics from the UK biobank (n = 395,718) and cardio-metabolic disease were from largest available GWAS summary statistics. Inverse variance weighting (IVW) was conducted, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. We repeated this in the opposite direction using instruments for cardio-metabolic disease. Results Genetically predicted mtDNA copy number was not associated with risk of obesity (P = 0.148), hypertension (P = 0.515), dyslipidemia (P = 0.684), T2DM (P = 0.631), CAD (P = 0.199), stroke (P = 0.314), ischemic stroke (P = 0.633), and heart failure (P = 0.708). Regarding the reverse directions, we only found that genetically predicted dyslipidemia was associated with decreased levels of mtDNA copy number in the IVW analysis (β= − 0.060, 95% CI − 0.044 to − 0.076; P = 2.416e−14) and there was suggestive of evidence for a potential causal association between CAD and mtDNA copy number (β= − 0.021, 95% CI − 0.003 to − 0.039; P = 0.025). Sensitivity and replication analyses showed the stable findings. Conclusions Findings of this Mendelian randomization study did not support a causal effect of mtDNA copy number in the development of cardiometabolic disease, but found dyslipidemia and CAD can lead to reduced mtDNA copy number. These findings have implications for mtDNA copy number as a biomarker of dyslipidemia and CAD in clinical practice.

The soaking process of glutinous rice allows the growth and reproduction of microorganisms, which can easily cause food safety problems. In this work, the effects of different ultrasonic powers (150 W, 300 W, 450 W, and 600 W) on the bactericidal effect of glutinous rice, the physicochemical properties of starch and the quality characteristics of sweet dumplings were studied. Compared with soaking for 0 and 2 h, sonication of glutinous rice after soaking for 4 h was more effective at reducing the number of microorganisms in soaked glutinous rice, and the bactericidal effect increased with increasing ultrasound intensity. After 30 min, the total number of bacteria decreased by 2.04 log CFU/g. Moreover, ultrasonic treatment destroys the grain structure of glutinous rice starch, resulting in the formation of dents and cracks on the starch surface, increasing the amylose content, improving its expansion, reducing its short-range order and relative crystallinity, and altering its gelatinization characteristics. In addition, ultrasonic treatment increased the soup transparency of sweet dumplings from 51.8 % to 63.95 %, reducing their hardness, chewiness and adhesiveness. In summary, ultrasonic treatment can not only effectively kill microorganisms in soaked glutinous rice but also improve the quality of glutinous rice dumplings by changing the physicochemical properties of glutinous rice starch. The results of this study provide theoretical support for the application of ultrasonic technology in glutinous rice food production.

Nuclear progesterone receptor (nPR) is a member of the nuclear receptor family known to play a critical role in gonad development, gametogenesis, and ovulation in vertebrates, and also important in pregnancy maintenance and parturition in mammals. However, its biological functions in ovoviviparity teleosts are less clear. This study aimed to determine the possible role of nPR in fish oogenesis, pregnancy and parturition using black rockfish as a model. The npr, which consists of 2076 bp and codes for a 691 amino acids protein, was cloned. Phylogenetic analysis revealed that the nPR of black rockfish is more conserved in teleosts. Quantitative real-time PCR analyses in various tissues showed that npr was mainly detected in the pituitary followed by the ovary, testis and brain, while it was very low or undetectable in the spleen, head kidney, intestine and gill. During the gonadal development process, the npr level showed no variation in the ovary. In testis, the mRNA level of npr showed varied expression in different developmental stages with the highest level in the maturation stage. Detection of npr expression during fertilization and the perinatal period further showed that nPR may play important roles in the regulation of pregnancy and the parturition. In situ hybridization further revealed that npr mRNA was observed in the follicular cell layer during the perinatal period. The results from in vitro experiments showed that npr level was significantly downregulated when the primary cultured follicular cells during vitellogenesis (stage Ⅳ) were exposed to hCG. Studies using primary culture of black rockfish ovarian cells during the perinatal period, treated in vitro revealed that genes related to PGs synthesis (pla2g4a, cox2) and matrix metalloproteinases (mmp2, mmp9) were upregulated in response to 17,20β-P. However, treatment with 17,20β-P downregulated npr expression. In conclusion, these data suggest that nPR plays an essential role in fertilization, pregnancy maintenance and parturition in black rockfish.

Adopting drought-tolerant (DT) cultivars is an effective strategy to sustain maize (Zea mays L.) production under water shortage. Optimizing plant density is an important management practice for improving maize yield. In a two-year field trial, the response of yield, actual evapotranspiration (ETc act), and water productivity (WP) to plant density (6, 7.5, 9 plants m−2) was assessed under irrigated and rainfed conditions using a DT (ZD958) and a drought-susceptible (DS, ZY309) maize cultivar, and additionally, the comparison of soil water depletion will be conducted among soils growing different DT maize varieties. Under rainfed, average yield, ETc act, and WP were 24.7%, 8.6% and 14.8% greater in ZD958 than ZY309, respectively. When density increased from 6 to 9 plants m−2, for ZD958 and ZY309 ETc act remained relatively constant, whereas their yield and WP first increased and then decreased and ultimately reached their maximum at 7.5 plants m−2. Under irrigation, increasing density (6–9 plants m−2) significantly increased yield and WP for ZD958, but for ZY309, yield and WP were not significantly impacted. Yield across seasons did not differ between cultivars at 6 and 7.5 plants m−2, and ZD958 had a 10.2% yield advantage over ZY309 at 9 plants m−2. The findings imply that DT cultivar showed greater high density tolerance than DS cultivar and thus higher optimal density under irrigation. Under rainfed, both cultivars had similar density tolerance and optimum density, whereas DT cultivar had stronger drought tolerance than DS cultivar, which could explain DT cultivar’s greater yield and WP. This study indicate that DT cultivar showed higher and more stable yields than DS cultivar across rainfed and irrigated conditions when grown at optimal densities. Thus, sustainable maize production could be achieved by adopting DT cultivars and optimizing density for different conditions in the study region.

BackgroundEndoscopic obstruction (eOB) is associated with a poor prognosis in colorectal cancer (CRC). Our study aimed to investigate the association between tumor location and eOB, as well as the prognostic differences among non-endoscopic obstruction (N-eOB), eOB with tumor size ≤ 5 cm, and eOB with tumor size > 5 cm in non-elderly patients.MethodsWe retrospectively reviewed the clinicopathological variables of 230 patients with CRC who underwent curative surgery. The multivariable logistic regression model was used to identify risk factors for eOB. The association between eOB with tumor size ≤ 5 cm and disease-free survival (DFS) was evaluated using multivariate cox regression analysis.ResultsA total of 87 patients had eOB while 143 had N-eOB. In multivariate analysis, preoperative carcinoembryonic antigen (p = 0.014), tumor size (p = 0.010), tumor location (left-side colon; p = 0.033; rectum; p < 0.001), and pT stage (T3, p = 0.009; T4, p < 0.001) were significant factors of eOB. The DFS rate for eOB with tumor size ≤ 5 cm was significantly lower (p < 0.001) in survival analysis. The eOB with tumor size ≤ 5 cm (p = 0.012) was an unfavorable independent factor for DFS.ConclusionsThe patients with eOB were significantly associated with right-side colon cancer as opposed to left-side colon cancer and rectal cancer. The eOB with tumor size ≤ 5 cm was an independent poor prognostic factor. Further studies are needed to target these high-risk groups.

PurposeThe aim to assess treatment failure in patients with stage III colon cancer who underwent radical surgery and was analyzed using the nomogram.MethodsClinical factors and survival outcomes for stage III colon cancer patients registered in the SEER database from 2018 to 2019 were analyzed, with patients split into training and testing cohorts (7:3 ratio). A total of 360 patients from the First Affiliated Hospital of Longyan served as an external validation cohort. Independent predictors of treatment failure were identified using logistic regression analyses. The nomograms was evaluated by concordance index (C-index), calibration curves, and the area under the curve (AUC), decision curve analysis (DCA) and clinical impact curves (CIC) assessed the clinical utility of nomograms versus TNM staging.ResultsThe study included 4,115 patients with stage III colon cancer. Multivariate logistic analysis age, tumor site, pT stage, pN stage, chemotherapy, pretreatment CEA levels, number of harvested lymph nodes, perineural invasion and marital status were identified as independent risk factors for treatment failure. The C-indices for the training and testing sets were 0.853 and 0.841. Validation by ROC and calibration curves confirmed the stability and reliability of the model. DCA showed that the net clinical effect of the histogram was superior to that of the TNM staging system, while CIC highlighted the potentially large clinical impact of the model.ConclusionsThe developed Nomogram provides a powerful and accurate tool for clinicians to assess the risk of treatment failure after radical surgery in patients with stage III colon cancer.

Gyrotrons are vacuum electronic devices capable of generating high-power, high-frequency THz radiation. With the increasing utilization of gyrotrons in thermonuclear fusion experimental devices, achieving higher output performance and ensuring stable and reliable operation have become key development goals. However, occasional radio frequency (RF) oscillation faults inside the gyrotron during long-pulse operation hinder its stable and reliable operation. Due to the difficulty in directly observing abnormal changes within the gyrotron resonator during operation, this paper explores a data-driven approach to diagnose RF oscillation faults in the gyrotron for the first time and proposes a classification model that combines K-Nearest Neighbors and Random Forest (KNN-RForest) algorithms for fault identification. Compared with seven baseline models, the results show that our proposed KNN-RForest model has a better classification performance. It is verified that data-driven methods can effectively identify RF oscillation faults in gyrotrons. Finally, the state probabilities of the gyrotron under different power levels were predicted using the KNN-RForest model, demonstrating the application of the KNN-RForest model in identifying gyrotron RF oscillation faults, which may be helpful for setting stable operating parameters for the gyrotron to reduce the likelihood of RF oscillation faults.

Abstract HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor used for treating hyperuricemia. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of HP501 in male Chinese patients. Patients with hyperuricemia were sequentially assigned to receive oral doses of HP501 (30, 50, 60, 90, and 120 mg) as a single dose on Day 1 and as once-daily doses from Days 4 to 13. Safety, pharmacokinetic, and pharmacodynamic data were collected. Multiple oral doses of HP501 were well-tolerated in all the cohorts. The most common adverse events (≥ 10% of patients) of any grade regardless of drug relationship were gout flare (14 patients, 25.93%), diarrhea (12 patients, 22.22%), elevated ALT (8 patients, 14.81%), hypertriglyceridemia (7 patients, 12.96%), dry mouth (7 patients, 12.96%) and oral ulcer (7 patients, 12.96%). All adverse events were mild or moderate. The Cmax and exposure (AUC) of HP501 was approximately dose-proportional between 30 and 120 mg. A dose-dependent serum uric acid (UA)-lowering effect was observed in the dose range of 30 to 60 mg and the serum UA lowering effect was similar between 90 and 120 mg on day 13, indicating that the maximal serum UA lowering effect of HP501 was achieved at 90 mg in the patients with hyperuricemia. In conclusion, the tolerability, pharmacokinetics, and pharmacodynamics supported 90 mg HP501 for subsequent clinical studies of this highly selective URAT1 inhibitor. Clinical Trial registration: No. CTR20212259 ( http://www.chinadrugtrials.org.cn/ ) was registered in September 2021, and No. CTR20222257 was registered in September 2022.

Abstract Due to the high population density and economic property in urban environments, urban flooding can result in substantial economic losses. However, accurate urban flood modeling and assessing the associated damages are challenging due to complex urban layouts and rugged topography. Furthermore, the rapid development of urban underground spaces has introduced additional complexities. To address the demanding need for accurate flood modeling and damage assessment in cities, a fine‐scale flood damage assessment method was proposed in this study, based on the 1D/2D coupled hydrodynamic model, which can not only assess the flood damage on the ground surface but also evaluate the flood loss in underground spaces. Taking the Gangxi drainage area in Wuhan City, China as a case, this study extensively discussed the flood inundation processes on the ground surface as well as in the buildings and underground spaces, under different rainfall scenarios with the return period ranging from 2 to 200 years. Based on the high spatial‐temporal hydrodynamic simulations, the flood damage degrees were evaluated for the buildings and underground spaces with different industry types. The results indicated that the inundation of buildings and underground spaces in densely built cities cannot be neglected in urban flood modeling. Buildings with public service attributes can have a higher flood damage degree, as compared with other types of buildings and underground spaces.

Abstract Background After the eradication of smallpox in China in 1979, vaccination with the vaccinia virus (VACV) Tiantan strain for the general population was stopped in 1980. As the monkeypox virus (MPXV) is rapidly spreading in the world, we would like to investigate whether the individuals with historic VACV Tiantan strain vaccination, even after more than 40 years, could still provide ELISA reactivity and neutralizing protection; and whether the unvaccinated individuals have no antibody reactivity against MPXV at all. Results We established serologic ELISA to measure the serum anti-MPXV titer by using immunodominant MPXV surface proteins, A35R, B6R, A29L, and M1R. A small proportion of individuals (born before 1980) with historic VACV Tiantan strain vaccination exhibited serum ELISA cross-reactivity against these MPXV surface proteins. Consistently, these donors also showed ELISA seropositivity and serum neutralization against VACV Tiantan strain. However, surprisingly, some unvaccinated young adults (born after 1980) also showed potent serum ELISA activity against MPXV proteins, possibly due to their past infection by some self-limiting Orthopoxvirus (OPXV). Conclusions We report the serum ELISA cross-reactivity against MPXV surface protein in a small proportion of individuals both with and without VACV Tiantan strain vaccination history. Combined with our serum neutralization assay against VACV and the recent literature about mice vaccinated with VACV Tiantan strain, our study confirmed the anti-MPXV cross-reactivity and cross-neutralization of smallpox vaccine using VACV Tiantan strain. Therefore, it is necessary to restart the smallpox vaccination program in high risk populations.

Chronic stress has become a major problem that endangers people’s physical and mental health. Studies have shown that chronic stress impairs female reproduction. However, the related mechanism is not fully understood. P2X7 receptor (P2X7R) is involved in a variety of pathological changes induced by chronic stress. Whether P2X7R is involved in the effect of chronic stress on female reproduction has not been studied. In this study, we established a chronic restraint stress mouse model and chronic cold stress mouse model. We found that the number of corpora lutea was significantly reduced in the two chronic stress models. The number of corpora lutea indirectly reflects the ovulation, suggesting that chronic stress influences ovulation. P2X7R expression was significantly increased in ovaries of the two chronic stress models. A superovulation experiment showed that P2X7R inhibitor A-438079 HCL partially rescued the ovulation rate of the two chronic stress models. Further studies showed that activation of P2X7R signaling inhibited the cumulus expansion and promoted the expression of NPPC in granulosa cells, one key negative factor of cumulus expansion. Moreover, sirius red staining showed that the ovarian fibrosis was increased in the two chronic stress models. For the fibrosis-related factors, TGF-β1 was increased and MMP2 was decreased. In vitro studies also showed that activation of P2X7R signaling upregulated the expression of TGF-β1 and downregulated the expression of MMP2 in granulosa cells. In conclusion, P2X7R expression was increased in the ovaries of the chronic restraint-stress and chronic cold-stress mouse models. Activation of P2X7R signaling promoted NPPC expression and cumulus expansion disorder, which contributed to the abnormal ovulation of the chronic stress model. Activation of P2X7R signaling is also associated with the ovarian fibrosis changes in the chronic stress model.

Vacuolar (H+)-ATPases (V-ATPases) are ATP-driven proton pumps that play multifaceted roles across various organisms. Despite their widespread significance, the functional implications of V-ATPase genes in Hyphantria cunea, an invasive forest pest with a global presence, have yet to be elucidated. In this study, two specific V-ATPase genes from H. cunea were identified and analyzed, namely HcV-ATPase A (accession number: OR217451) and HcV-ATPase C (accession number: OR217452). Phylogenetic analysis and multiple sequence alignment reveal that HcV-ATPase A shares the highest amino acid sequence similarity with SfV-ATPase A, while HcV-ATPase C is most similar to HaV-ATPase C. Spatiotemporal expression profiles, determined via RT-qPCR, demonstrate that both HcV-ATPase A and HcV-ATPase C are expressed throughout all larval developmental stages, with HcV-ATPase A predominantly expressed in the midgut and HcV-ATPase C showing high expression in the epidermis. RNA interference (RNAi) targeting of these genes significantly suppressed their expression by 62.7% and 71.0% 120 h post-injection, leading to halted larval growth and increased mortality rates of 61.7% and 46.7%, respectively. Further investigations using immunohistochemistry, hematoxylin and eosin (HE) staining, and transmission electron microscopy (TEM) revealed that gene silencing induced vesiculation and subsequent losses or sloughing of intestinal parietal cells, alongside an increase in the number of autophagic cells. Additionally, the silencing of HcV-ATPase A and C genes resulted in a reduced gut epidermal cell layer thickness and further increases in goblet cell numbers. Importantly, RNAi of HcV-ATPase A and C did not affect the expression levels of one another, suggesting independent functional pathways. This study provides foundational insights into the role of V-ATPase in H. cunea and identifies potential targets for the biocontrol of its larvae, contributing to the understanding of V-ATPase mechanisms and their application in pest management strategies.

Introduction: Human basic fibroblast growth factor (hbFGF) is a highly valuable multifunctional protein that plays a crucial role in various biological processes. In this study, we aim to accomplish the scaling-up production of mature hbFGF (146aa) by implementing a high cell-density fermentation and purification process on a 500-L scale, thereby satisfying the escalating demands for both experimental research and clinical applications.Methods: The hbFGF DNA fragment was cloned into a mpET-3c vector containing a kanamycin resistance gene and then inserted into Escherichia coli BL21 (DE3) plysS strain. To optimize the yield of hbFGF protein, various fermentation parameters were systematically optimized using BOX-Behnken design and further validated in large-scale fermentation (500-L). Additionally, a three-step purification protocol involving CM-Sepharose, heparin affinity, and SP-Sepharose column chromatography was developed to separate and purify the hbFGF protein. Isoelectric focusing electrophoresis, MALDI-TOF/MS analysis, amino acid sequencing, CD spectroscopy, and Western blotting were performed to authenticate its identity. The biological efficacy of purified hbFGF was evaluated using an MTT assay as well as in a diabetic deep second-degree scald model.Results: The engineered strain was successfully constructed, exhibiting high expression of hbFGF and excellent stability. Under the optimized fermentation conditions, an impressive bacterial yield of 46.8 ± 0.3 g/L culture with an expression level of hbFGF reaching 28.2% ± 0.2% was achieved in 500-L scale fermentation. Subsequently, during pilot-scale purification, the final yield of purified hbFGF protein was 114.6 ± 5.9 mg/L culture with RP-HPLC, SEC-HPLC, and SDS-PAGE purity exceeding 98%. The properties of purified hbFGF including its molecular weight, isoelectric point (pI), amino sequence, and secondary structure were found to be consistent with theoretical values. Furthermore, the purified hbFGF exhibited potent mitogenic activity with a specific value of 1.05 ± 0.94 × 106 AU/mg and significantly enhanced wound healing in a deep second-degree scald wound diabetic rat model.Conclusion: This study successfully established a stable and efficient large-scale production process of hbFGF, providing a solid foundation for future industrial production.

Saltmarsh is widely recognized as a blue carbon ecosystem with great carbon storage potential. Yet soil respiration with a major contributor of atmospheric CO2 can offset its carbon sink function. Up to date, mechanisms ruling CO2 emissions from saltmarsh soil remain unclear. In particular, the effect of precipitation on soil CO2 emissions is unclear in coastal wetlands, due the lack of outdoor data in real situations. We conducted a 7-year field manipulation experiment in a saltmarsh in the Yellow River Delta, China. Soil respiration in five treatments (−60%, −40%, +0%, +40%, and + 60% of precipitation) was measured in the field. Topsoils from the last 3 years (2019–2021) were analyzed for CO2 production potential by microcosm experiments. Furthermore, quality and quantity of soil organic carbon and microbial function were tested. Results show that only the moderate precipitation rise of +40% induced a 66.2% increase of CO2 production potential for the microcosm experiments, whereas other data showed a weak impact. Consistently, soil respiration was also found to be strongest at +40%. The CO2 production potential is positively correlated with soil organic carbon, including carbon quantity and quality. But microbial diversity did not show any positive response to precipitation sizes. r-/K-strategy seemed to be a plausible explanation for biological factors. Overall, our finding reveal that a moderate precipitation increase, not decrease or a robust increase, in a saltmarsh is likely to improve soil organic carbon quality and quantity, and bacterial oligotroph:copiotroph ratio, ultimately leading to an enhanced CO2 production.

IntroductionHeavy ion beam is a novel approach for crop mutagenesis with the advantage of high energy transfer line density and low repair effect after injury, however, little investigation on the biological effect on plant was performed. 50 Gy irradiation significantly stimulated the growth of Arabidopsis seedlings, as indicated by an increase in root and biomass, while 200 Gy irradiation significantly inhibited the growth of seedlings, causing a visible decrease in plant growth.MethodsThe Arabidopsis seeds were irradiated by 12C6+. Monte Carlo simulations were used to calculate the damage to seeds and particle trajectories by ion implantation. The seed epidermis received SEM detection and changes in its organic composition were detected using FTIR. Evidence of ROS and antioxidant systems were analyzed. RNA-seq and qPCR were used to detect changes in seedling transcript levels.Results and discussionMonte Carlo simulations revealed that high-dose irradiation causes various damage. Evidence of ROS and antioxidant systems implies that the emergence of phenotypes in plant cells may be associated with oxidative stress. Transcriptomic analysis of the seedlings demonstrated that 170 DEGs were present in the 50 Gy and 200 Gy groups and GO enrichment indicated that they were mainly associated with stress resistance and cell wall homeostasis. Further GO enrichment of DEGs unique to 50 Gy and 200 Gy revealed 58 50Gy-exclusive DEGs were enriched in response to oxidative stress and jasmonic acid entries, while 435 200 Gy-exclusive DEGs were enriched in relation to oxidative stress, organic cyclic compounds, and salicylic acid. This investigation advances our insight into the biological effects of heavy ion irradiation and the underlying mechanisms.

Excessive biofluid around wounds can cause infection and prevent healing. In this study, an anisotropic quaternized chitosan (QC)/sodium alginate (AL)-based aerogel wound dressing was prepared via a directional freeze-drying technique inspired by the channel structure used for water transport in trees. The aligned channels provided the dressing with self-pumping ability, allowing it to rapidly and completely remove biofluids and absorb biofluids up to 1292.5 % of its own weight. To enhance the strength of the dressing, a double cross-linked network was constructed based on the QC-AL electrostatic attraction and AL-Ca2+ chelation interaction. The axial compressive strength of the double cross-linked dressing reached 207.3 kPa (ε = 50 %). In addition, the dressing exhibited strong conductive properties (conductivity = 13.0 S/m), antioxidant activities [reactive oxygen species (ROS) scavenging ability = 88.0 %], and hemostatic characteristics (blood coagulation index = 1.8 %). The dressing also exhibited powerful antibacterial performance, exhibiting over 98.0 % inhibition of E. coli and S. aureus. Experiments on diabetic mouse models revealed that the dressing considerably promoted wound healing. On day 3, the wound healing rate was 96.7 % faster in the QAC group than in the gauze group. Therefore, the developed dressing may have great potential for chronic wound care.

Abstract Background The recommended operation for cecum cancer (CC) is right hemicolectomy (RH) in some Western countries while the principle of D3 lymphadenectomy in Japan recommends resecting approximately 10 cm from the tumor edge. Therefore, the optimal surgical approach for cecum cancer (CC) remains controversial. We conducted this retrospective study to explore the pattern of lymph node metastasis and better surgical procedures for CC. Methods A total of 224 cecum cancer patients from January 1, 2014, to December 31, 2021, were retrospectively included in the final study. The pattern of lymph node metastasis (LNM) was investigated. Results A total of 113 (50.4%, 113/224) patients had pathologically confirmed LNM. The most frequent metastatic site was no. 201 lymph node (46%, 103/224), while 20 (8.9%, 20/224) patients had LNM in no. 202 lymph node, and 8 (3.6%, 8/224) patients had LNM in no. 203 lymph node. Only 1 (0.4%, 1/224) patient had LNM in no. 221 lymph node, four (1.8, 4/224%) patients had LNM in no. 223 lymph node, and no patients had LNM in no. 222 lymph node. LNM in no. 223 lymph node was significantly associated with a poor prognosis. Multivariate analysis indicated that LNM in no. 223 lymph node (HR = 4.59, 95% CI 1.18–17.86, P = 0.028) was the only independent risk factor associated with worse disease-free survival (DFS). Conclusions The LNM in no. 223 lymph node for cecum cancer was rare. Therefore, standard right hemicolectomy excision is too extensive for most CC cases.

Abstract Background Recent insights suggest that remnant cholesterol (RC) plays a role in cellular senescence, yet its specific contribution to frailty remains indeterminate. Through the integration of observational and mendelian randomization (MR) studies, this research explores the impact of elevated serum RC levels on frailty susceptibility. Methods A dual-method approach, combining an observational study with an MR study, was employed to investigate the connection between RC and frailty. The observational study included 11,838 participants from the National Health and Nutrition Examination Survey. Multivariable logistic regression and propensity score matching were employed to control for potential confounders. The non-linear relationship was assessed using restricted cubic splines. To circumvent observational study limitations, a two-sample MR analysis was conducted using the inverse-variance weighted method, leveraging genome-wide association studies (GWAS) data. Results After adjusting for potential confounding variables, the observational study identified a significant association between high serum RC levels and frailty in middle-aged and older adults (odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.20 to 2.33, P = 0.003), exhibiting a non-linear dose–response correlation (non-linear P = 0.011). This association persisted after propensity score matching (OR = 1.53, 95% CI = 1.14 to 2.06, P = 0.005). The MR study echoed these results, demonstrating a causal association of RC with the frailty index (β = 0.059, 95% CI = 0.033 to 0.085, P = 1.05E-05), consistent with the observational findings (β = 0.017, 95% CI = 0.008 to 0.026, P = 4.51E-04). Conclusion This study provides evidence that higher RC levels amplify frailty risk in middle-aged and older adults, implying that the reduction of RC levels may present a promising strategy for frailty prevention and management.

Abstract Background Evidence has linked self-reported sedentary behavior (SB) and physical activity (PA) with cognitive impairment; however, the underlying mechanisms are poorly understood. We examined the associations of the accelerometer-measured movement behaviors with plasma neurofilament light chain (NfL) among older adults and the role of systemic low-grade inflammation in the associations. Results This population-based study included 1,029 dementia-free older adults (age ≥ 60 years, range 60–88 years; 59.48% women) who undertook the ActiGraph substudy (March 2018-December 2020) in MIND-China. There were nonlinear relationships of daily SB and PA time with plasma NfL concentration, such that more daily SB time or less time spent in daily light-intensity physical activity (LPA) and moderate-to-vigorous-intensity physical activity (MVPA) was significantly associated with increased plasma NfL only when SB time ≥ 8.00 h/day or LPA time

Prediction of water inflow of a sub-sea tunnel under the blasting vibration effect is still a difficult subject. This paper takes the sub-sea tunnel between the Wawuzhuang Station and Guizhou Road Station of the Qingdao Metro Line 1 as the engineering background. Based on the equivalent continuum model, the mirror image method is used to deduce the calculation formula for the water inflow of the sub-sea tunnel considering the damage area factor. Through forward modeling and inversion, combined with numerical simulation results and actual engineering monitoring results, the correctness of the formula is comprehensively verified, and the influence mechanism of damage area factors on water inflow is analyzed. The results show that the squeezing effect caused by blasting vibration makes the pore water pressure of surrounding rock around the tunnel rise rapidly in a short time. After reaching the peak value, it began to decline slowly with the weakening and disappearance of blasting vibration. Under the influence of damage zone factors, the water inflow of the tunnel increases gradually with the increasing thickness of the damage zone, but it will not increase continuously with the increase of the coefficient of permeability in the damaged area. Through numerical simulation calculation, the ratio of tunnel water inflow considering blasting damage area is 1.4, and the error is only 4.1% compared with the calculation result of 1.342 deduced in this paper. The calculated results in this study are only 0.53 m3/(d·m) less than the field measured results, and are closer to the measured results than those with the traditional calculation formula, indicating that the calculation formula in this paper is suitable for the calculation of tunnel water inflow considering the factor of damage zone, and are of high engineering application value.

Task-oriented dialogue systems (TODs) enable users to complete specific goals and are widely used in practice. Although existing models have achieved delightful performance for single-domain dialogues, scalability to new domains is far from well explored. Traditional dialogue systems rely on domain-specific information like dialogue state and database (DB), which limits the scalability of such systems. In this paper, we propose a Scalable Task-Oriented Dialogue modeling framework (STOD). Instead of labeling multiple dialogue components, which have been adopted by previous work, we only predict structured API queries to interact with DB and generate responses based on the complete DB results. Further, we construct a new API-schema-based TOD dataset MultiWOZ-API with API query and DB result annotation based on MultiWOZ 2.1. We then propose MSTOD and CSTOD for multi-domain and cross-domain TOD systems, respectively. We perform extensive qualitative experiments to verify the effectiveness of our proposed framework. We find the following. (1) Scalability across multiple domains: MSTOD achieves 2% improvements than the previous state-of-the-art in the multi-domain TOD. (2) Scalability to new domains: our framework enables satisfying generalization capability to new domains, a significant margin of 10% to existing baselines.

Context modeling has always been the groundwork for the dialogue response generation task, yet it presents challenges due to the loose context relations among open-domain dialogue sentences. Introducing simulated dialogue futures has been proposed as a solution to mitigate the problem of low history–response relevance. However, these approaches simply assume that the history and future of a dialogue have the same effect on response generation. In reality, the coherence between dialogue sentences varies, and thus, history and the future are not uniformly helpful in response prediction. Consequently, determining and leveraging the relevance between history–response and response–future to aid in response prediction emerges as a pivotal concern. This paper addresses this concern by initially establishing three context relations of response and its context (history and future), reflecting the relevance between the response and preceding and following sentences. Subsequently, we annotate response contextual relation labels on a large-scale dataset, DailyDialog (DD). Leveraging these relation labels, we propose a response generation model that adaptively integrates contributions from preceding and succeeding sentences guided by explicit relation labels. This approach mitigates the impact in cases of lower relevance and amplifies contributions in cases of higher relevance, thus improving the capability of context modeling. Experimental results on public dataset DD demonstrate that our response generation model significantly enhances coherence by 3.02% in long sequences (4-gram) and augments bi-gram diversity by 17.67%, surpassing the performance of previous models.

The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops, and were further validated for changed expression. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.

Abstract Background This study aimed to develop and validate an AI (artificial intelligence)-aid method in myocardial perfusion imaging (MPI) to differentiate ischemia in coronary artery disease. Methods We retrospectively selected 599 patients who had received gated-MPI protocol. Images were acquired using hybrid SPECT-CT systems. A training set was used to train and develop the neural network and a validation set was used to test the predictive ability of the neural network. We used a learning technique named “YOLO” to carry out the training process. We compared the predictive accuracy of AI with that of physician interpreters (beginner, inexperienced, and experienced interpreters). Results Training performance showed that the accuracy ranged from 66.20% to 94.64%, the recall rate ranged from 76.96% to 98.76%, and the average precision ranged from 80.17% to 98.15%. In the ROC analysis of the validation set, the sensitivity range was 88.9 ~ 93.8%, the specificity range was 93.0 ~ 97.6%, and the AUC range was 94.1 ~ 96.1%. In the comparison between AI and different interpreters, AI outperformed the other interpreters (most P-value

Abstract Renal tubular epithelial cells (TECs) play a key role in kidney fibrosis by mediating cycle arrest at G2/M. However, the key HDAC isoforms and the underlying mechanism that are involved in G2/M arrest of TECs remain unclear. Here, we find that Hdac9 expression is significantly induced in the mouse fibrotic kidneys, especially in proximal tubules, induced by aristolochic acid nephropathy (AAN) or unilateral ureter obstruction (UUO). Tubule-specific deletion of HDAC9 or pharmacological inhibition by TMP195 attenuates epithelial cell cycle arrest in G2/M, then reduces production of profibrotic cytokine and alleviates tubulointerstitial fibrosis in male mice. In vitro, knockdown or inhibition of HDAC9 alleviates the loss of epithelial phenotype in TECs and attenuates fibroblasts activation through inhibiting epithelial cell cycle arrest in G2/M. Mechanistically, HDAC9 deacetylates STAT1 and promotes its reactivation, followed by inducing G2/M arrest of TECs, finally leading to tubulointerstitial fibrosis. Collectively, our studies indicate that HDAC9 may be an attractive therapeutic target for kidney fibrosis.

Abstract Female subfertility is an increasing reproductive issue worldwide, which is partially related to abnormal ovarian follicular development. Granulosa cells (GCs), by providing the necessary physical support and microenvironment for follicular development, play critical roles in maintaining female fertility. We previously showed that ectopic expression of four and a half LIM domains 2 (FHL2) promoted ovarian granulosa cell tumor progression. However, its function in follicular development and fertility remains unknown. Here, we confirmed that FHL2 is highly expressed in human and mouse ovaries. FHL2 immunosignals were predominantly expressed in ovarian GCs. A Fhl2 knockout (KO) mouse model was generated to examine its roles in follicular development and fertility. Compared with wildtype, knockout of Fhl2 significantly decreased female litter size and offspring number. Furthermore, Fhl2 deficiency reduced ovarian size and impaired follicular development. RNA-sequencing analysis of GCs isolated from either KO or WT mice revealed that, Fhl2 deletion impaired multiple biological functions and signaling pathways, such as Ovarian Putative Early Atresia Granulosa Cell, ErbB, Hippo/YAP, etc. In vitro studies confirmed that FHL2 silencing suppressed GCs growth and EGF-induced GCs proliferation, while its overexpression promoted GC proliferation and decreased apoptosis. Mechanistic studies indicated that FHL2, via forming complexes with transcriptional factors AP-1 or NF-κB, regulated Egf and Egfr expression, respectively. Besides, FHL2 depletion decreased YAP1 expression, especially the active form of YAP1 (nuclear YAP1) in GCs of growing follicles. EGF, serving as an autocrine/paracrine factor, not only induced FHL2 expression and nuclear accumulation, but also stimulated YAP1 expression and activation. Collectively, our study suggests that FHL2 interacts with EGFR and Hippo/YAP signaling to regulate follicular development and maintain fertility. This study illuminates a novel mechanism for follicular development and a potential therapeutic target to address subfertility.

Although Blufensins (Bln) have important functions in the response of plants to biotic stress the precise functioning of Bln in wheat remains largely unknown. Here we isolated a Bln gene (TaBln4) from Suwon 11 infected by Puccinia striiformis f. sp. tritici (Pst). Expression of TaBln4 increased in host plants at the early stage of infection with a virulent Pst race (CYR31) but was unchanged in response to infection by an avirulent race (CYR23). Transcription levels of TaBln4 were also regulated by hormone and abiotic stresses. Expression of TaBln4 in tobacco leaves suppressed Bax-induced programmed cell death. Knockdown of TaBln4 by virus-induced gene silencing inhibited colonization of race CYR31 by increasing the accumulation of H2O2 and formation of hypersensitive responses (HR). Transient overexpression of TaBln4 by a transient overexpression system (BSMV-VOX) increased the susceptibility of wheat to CYR31. Results from bimolecular fluorescence complementation and pull-down assays demonstrated that TaBLN4 interacted with calmodulin. Taken together, our results suggest that TaBln4 negatively regulates resistance in wheat to Pst in a reactive oxygen species (ROS)- and HR-dependent manner.

Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the in vivo study of human thrombopoiesis.

Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering pathogenic actions of hHcys are not fully understood. The present study was mainly designed to investigate the role of HDACs in renal injury induced by hHcys. Firstly, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC9 was preferentially upregulated in the kidney from mice with hHcys. Deficiency or pharmacological inhibition of HDAC9 ameliorated renal injury in mice with hHcys. Moreover, podocyte-specific deletion of HDAC9 significantly attenuated podocyte injury and proteinuria. In vitro, gene silencing of HDAC9 attenuated podocyte injury by inhibiting apoptosis, reducing oxidative stress and maintaining the expressions of podocyte slit diaphragm proteins. Mechanically, we proved for the first time that HDAC9 reduced the acetylation level of H3K9 in the promoter of Klotho, then inhibited gene transcription of Klotho, finally aggravating podocyte injury in hHcys. In conclusion, our results indicated that targeting of HDAC9 might be an attractive therapeutic strategy for the treatment of renal injury induced by hHcys.

The CFETR is the next generation magnetic confinement tokamak, its increasing heating needs and stringent shielding requirements present new challenges for the ECRH launcher. In an effort to evaluate the viability of the equatorial launcher, a port plug prototype is designed and its performance under steady state or some interrupted events is assessed. The well-configured steel/water ratio is beneficial to improve its shielding capability and effectively mitigate the 493 kW heat. The maximum temperature of the port plug is less than 300 °C when the inlet temperature is 70 °C, and the average outlet water temperature reaches 142 °C. The worst EM case is a major disruption of the plasma, which would induce about 200 kN force on the port plug at the end of the plasma current linear decay. The combined heat and EM force loads on the port plug would result in a total deformation of 1.7 mm and a maximum equivalent stress of 320 MPa, with little impacts on the port plug or the surrounding vacuum vessel. As the installation of the port plug, the H and He generation rates of the surrounding vacuum vessel have increased by about 2 % and 1 % separately, but remain lower than the limit of 1 appm/FPY, and the nuclear heat density of the toroidal field coils has increased by about 5%.

Background: The 10-item Connor-Davidson Resilience Scale (CD-RISC-10) is a scale widely used to assess resilience among various clinical and nonclinical populations. Measurement invariance of a scale is essential for group comparison. However, to our knowledge, the psychometric properties, including the measurement invariance, validity and reliability, of the CD-RISC-10 in male military personnel with posttraumatic stress disorder (PTSD) are unknown. The current study aimed to determine the measurement invariance of the CD-RISC-10 and its validity and reliability in male military personnel with and without PTSD. Methods: A total of 8089 male military personnel were enrolled in the study, 370 of whom were screened as having PTSD based on the screening criteria of a Posttraumatic Stress Disorder Checklist-Civilian score ≥38 and 7719 of whom did not have PTSD. Confirmatory factor analysis (CFA) was conducted to evaluate whether the scale had a single factor and to determine the measurement invariance in PTSD and non-PTSD samples. Results: The results showed that the CD-RISC-10 had satisfactory and reliable internal consistency and criterion-related validity among the PTSD (α = 0.91; r = -0.54, -0.44, -0.55, P

Background Gastric cancer consists of solid tumors with a tendency for disseminated intravascular coagulation (DIC). DIC is rare in patients with stomach cancer, and there have been few studies on this condition. We aimed to perform comprehensive analyses of the prognosis and clinicopathologic characteristics of stomach cancer patients with DIC. Methods Between June 2006 and March 2020, 14,016 patients at Fujian Cancer Hospital were diagnosed with stomach cancer. We reviewed their medical records and found that 105 of these patients were diagnosed with DIC. After excluding patients who were lost to follow-up, 71 patients with DIC remained. The clinical data were retrospectively analyzed to observe clinical characteristics and prognostic factors, and the Kaplan–Meier survival analysis was performed. Prognostic variables were investigated by the Cox proportional hazards method. Results The median age was 54 (range, 21–83) years, and 38 patients (53.5%) were male. The histological category was poorly differentiated gastric cancer in 58 patients (81.7%). Eleven patients (15.5%) developed DIC after curative gastric resection. Sixty patients (84.5%) had DIC at the initial presentation of gastric cancer or developed DIC when the tumor progressed during treatment. Fifty-one patients (71.8%) had bleeding symptoms, and 43 (60.6%) patients had comorbidities at the time of DIC diagnosis. Among the 71 patients, 42 (59.2%) had multiple metastatic patterns. Twenty-one (29.6%) patients received chemotherapy. The median overall survival (OS) was 57.0 days (95% confidence interval [CI] [33.1–80.9] days). Tumor status (P = 0.000) and treatment (P = 0.003) were found to be significant variables associated with OS by univariate analysis. Multivariate analysis showed that tumor status (P = 0.000) and treatment (P = 0.000) had independent effects on OS. Conclusions Gastrointestinal bleeding, multiple metastatic patterns and comorbidities at diagnosis with DIC are common in patients with gastric cancer complicated with DIC. Patients with poorly differentiated gastric cancer are more likely to develop DIC. Treatment and tumor status are separate risk variables for the survival of gastric cancer patients with DIC.DIC patients without tumors have a good prognosis and can be cured by appropriate etiological correction and symptomatic treatment. Chemotherapy can improve the prognosis of DIC patients with tumors.

Background/aimHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with a higher risk of metastasis and poorer overall survival (OS) due to HER2 gene overexpression/amplification. Although anti-HER2 targeted therapy has shown survival benefits in HER2-positive advanced breast cancer (ABC) patients, long-term treatment often leads to drug resistance, complicating further treatment options. RC48, an antibody-drug conjugate (ADC), combines the benefits of antibody targeting with the cytotoxic effects of a small molecule drug.Case reportWe present a case involving a female patient with HER2-positive ABC who developed drug resistance and disease progression following multi-line anti-HER2 targeted therapy. In this instance, RC48 exhibited anti-tumor activity in an ABC patient resistant to HER2-targeted therapy. After eight treatment cycles with 120 mg of RC48, the tumor size decreased and stabilized.ConclusionThis case report underscores the potential clinical value of RC48 as a promising treatment alternative for patients resistant to HER2 targeted therapies.

The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription. The N-terminal domain of CAP2 bound to the WD5 to WD7 domains of receptor for activated C kinase 1 (RACK1) and induced M2 macrophage polarization by activating the SRC/focal adhesion kinase (FAK)/ERK signaling pathway, which resulted in IL-4 and IL-10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting TGFB1, which created a TGFB1/JUN/CAP2 positive-feedback loop to activate CAP2 expression continuously. Furthermore, we identified salvianolic acid B as an inhibitor of CAP2, which effectively inhibited GC cell invasion capabilities by suppressing the SRC/FAK/ERK signaling pathway. Our data suggest that CAP2, a key molecule mediating the interaction between GC cells and tumor-associated macrophages, may be a promising therapeutic target for suppressing tumor metastasis in GC.

This paper presents a new gripping technique that merges the variable stiffness characteristics of conventional magnet-controlled and negative-pressure spherical grippers to produce a spherical gripper capable of securely grasping large and structurally diverse objects. The proposed method incorporates the smart rheological material from magnet-controlled grippers with the particle-jamming smart structure used in negative-pressure grippers. The gripper comprises a magnetic control device and a spherical variable stiffness body. Simulation analysis was used to optimize its structure and enhance the efficiency ratio of the magnetic control device. The flexible variable stiffness body was initially designed to be cylindrical to increase interlocking with objects. Experiments were conducted to evaluate the gripping efficiency and adaptability of the magnetron spherical gripper, which were designed to simulate real-world application requirements. These results suggest that the magnetically controlled spherical gripper can achieve a gripping efficiency of approximately five and securely grasp objects with a relative bladder diameter ranging from 20 % to 130 %. Furthermore, it can stably grip objects up to an offset distance of 15 mm without requiring sensor assistance. The enhanced magnetic field-powered spherical gripper exhibits superior adaptability and efficiency in gripping compared to its counterpart. In addition, it boasts robust resistance against environmental interference.