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Abstract Objective To explore the main factors affecting early dental caries among preschool children aged 3–6 years in Xingtai City to formulate effective preventive measures. Methods A cross-sectional study was conducted on 570 preschool children aged 3–6 years in Xingtai City through questionnaire surveys and oral examinations to understand their dental caries situation. Multifactorial logistic regression analysis was used to analyse the main influencing factors for the occurrence of dental caries in preschool children. Results Univariate analysis showed statistically significant differences in age (χ 2 = 2.636, p = 0.008), father’s education level (χ 2 = 4.207, p

Abstract Introduction The management of erythrodermic psoriasis (EP), a rare but severe type of psoriasis, is challenging, especially in patients with concomitant chronic hepatitis B (CHB). We previously demonstrated that oxymatrine treatment alleviated severe plaque psoriasis, but its therapeutic potential in treating EP remains unexplored. This study was to assess the efficacy and safety of oxymatrine for the treatment of EP, with attention to concomitant CHB. Methods In this investigator-initiated clinical trial, four consecutive patients with EP, including two (A and B) with concomitant CHB, were treated with intravenous administration of oxymatrine as monotherapy for 8 weeks, and scheduled to be followed up for a minimum of 24 weeks. The primary outcome was at least 75% improvement in the psoriasis area and severity index (PASI 75) at week 32. Secondary outcomes included the body surface area (BSA) score, dermatology life quality index (DLQI)], and safety. Results Patients A, B, and C achieved PASI 75 at treatment completion and week 32, demonstrating improvements of 77.4%, 97.2%, and 100% in PASI, respectively. Their BSA and DLQI were also improved significantly at week 32 and throughout follow-up of 37, 57, and 105 weeks, respectively. The viral loads in patients A and B with CHB decreased modestly. Patient D discontinued after follow-up for 19 weeks, and the primary outcome could not be analyzed. No adverse events were reported during treatment and follow-up. Conclusion Oxymatrine appears to be efficacious and safe for the treatment of patients with EP, including those with concomitant CHB. Trial Registration This study was registered at the Chinese Clinical Trial Registry ( www.chictr.org.cn ; Registration number ChiCTR-TRC-14004301).

Abstract Dietary salt has been associated with cognitive impairment in mice, possibly related to damaged synapses and tau hyperphosphorylation. However, the mechanism underlying how dietary salt causes cognitive dysfunction remains unclear. In our study, either a high-salt (8%) or normal diet (0.5%) was used to feed C57BL/6 mice for three months, and N2a cells were cultured in normal medium, NaCl medium (80 mM), or NaCl (80 mM) + Liraglutide (200 nM) medium for 48 h. Cognitive function in mice was assessed using the Morris water maze and shuttle box test, while anxiety was evaluated by the open field test (OPT). Western blotting (WB), immunofluorescence, and immunohistochemistry were utilized to assess the level of Glucagon-like Peptide-1 receptor (GLP-1R) and mTOR/p70S6K pathway. Electron microscope and western blotting were used to evaluate synapse function and tau phosphorylation. Our findings revealed that a high salt diet (HSD) reduced the level of synaptophysin (SYP) and postsynaptic density 95 (PSD95), resulting in significant synaptic damage. Additionally, hyperphosphorylation of tau at different sites was detected. The C57BL/6 mice showed significant impairment in learning and memory function compared to the control group, but HSD did not cause anxiety in the mice. In addition, the level of GLP-1R and autophagy flux decreased in the HSD group, while the level of mTOR/p70S6K was upregulated. Furthermore, liraglutide reversed the autophagy inhibition of N2a treated with NaCl. In summary, our study demonstrates that dietary salt inhibits the GLP-1R/mTOR/p70S6K pathway to inhibit autophagy and induces synaptic dysfunction and tau hyperphosphorylation, eventually impairing cognitive dysfunction.

Recent studies have shown that deep neural networks (DNNs) may suffer from some security issues such as backdoor attacks. The triggers of backdoor attacks are dynamic and global. However, existing backdoor attack methods are laborious and time-consuming in hiding global triggers, and most of them focus on single-target attacks, with less research on multitarget backdoor attacks. In this work, we present a multitarget attack strategy using texture features of procedural noise. Specifically, we use the k-LSB steganography algorithm to hide the triggers in the image and use different texture features of procedural noise to trigger multiple targets for attack. Poisoned images can be generated more quickly using the k-LSB steganography algorithm without any training process. Multitarget backdoor attacks apply to more scenarios and are more difficult to defend against. We evaluate the effectiveness of the proposed attack method on GTSRB and ImageNet datasets, and the experiments show that the proposed attack can achieve a high attack success rate (up to 100.00% for GTSRB and up to 98.48% for ImageNet) without compromising the clean data’s categorization performance, and thus is less likely to arouse the suspicion of administrators. In addition, the attack can bypass existing defense methods (STRIP defense and Neural Cleanse defense).

Abstract This study aims to experimentally compare the efficacy of different endodontic materials (iRoot BP Plus, Biodentine, MTA, Rootdent, and Trioxide) in the treatment of pulpitis and perforations on extracted tooth specimens. Additionally, the study aims to investigate the influence of iRoot BP Plus endodontic material on the regenerative processes following pulp amputation in laboratory animals. The secondary goal is to evaluate the effect of iRoot BP Plus on the restoration process in laboratory animals after pulp removal. The study presents a micropermeability analysis of the selected biomaterials performed on a sample of 50 single-rooted apical teeth in 2022. All teeth underwent endodontic treatment. Changes in molar morphology were investigated with eight laboratory animals (rabbits, 3 months old, all males) after simulated pulp removal and subsequent treatment with the iRoot BP Plus biomaterials. iRoot BP Plus appeared to be more effective in retrograde apical root filling than other biomaterials, as evidenced by its higher sealing effect. An experiment involving animal participants revealed the presence of protective adaptive mechanisms, which manifested in the form of an inflammatory process within 6 weeks after the dental pulp was removed. The connective tissue replaced the necrosis, and new capillaries began to form intensively. These dental outcomes suggest that iRoot BP Plus enables hermetical sealing in tooth restoration with good adhesion. Thus, it may have the ability to promote more active tissue regeneration after pulp removal. Graphical Abstract

Abstract Many meteorological centers have operationally implemented global model‐based ensemble prediction systems (GEPSs), making tropical cyclone (TC) forecasts from these systems available. The relatively low resolution of these GEPSs means that limits previous studies primarily focused on TC track forecasting. However, recent GEPS upgrades mean that TC intensity predictions from GEPSs are now also becoming of interest. This study focuses on the verification and comparison of the latest generation of GEPSs for TC intensity forecasts, particularly during the rapid intensification (RI) period over the western North Pacific (WP), eastern North Pacific (EP), and North Atlantic (NA) basins in 2021–2022. On average, the National Centers for Environmental Prediction (NCEP) GEPS performed best in predicting both TC intensity and RI across all three basins. Nevertheless, the exact timing of RI remains highly uncertain for these GEPS, indicating significant limitations in using GEPSs to forecast RI.

The development of fluorine-free foaming extinguishing agent, abbreviation FFEA, has become an urgent scientific challenge in the field of fire protection engineering due to the fact that the key component of existing aqueous film-forming foams is listed as a persistent organic pollutant. A study was conducted on foam performance and fire extinguishing efficiency of FFEA prepared by hydrocarbon and silicone surfactants with low-carbon alcohol modulation, using three selected silicone surfactants. The results show that the FFEA, including low-carbon alcohol-modulated Silok8141/SDS and Silok8008/SDS, exhibit low surface tension, good foam stabilization coefficient and long foam drainage time. Laboratory foam extinguishing experiments demonstrate that the FFEA produced by Silok8141/SDS/Isobutanol ternary system has better cooling effect and fire extinguishing performance. And the study of FFEA mechanism reveals that the addition of isobutanol blocks the foam liquid channel and increases the foam stability. The wide applicability of the design route for FFEA prepared by low-carbon alcohol-regulated hydrocarbon and silicone surfactants has been demonstrated.

Age-related cognitive impairment represents a significant health concern, with the understanding of its underlying mechanisms and potential interventions being of paramount importance. This study aimed to investigate the effects of hyperbaric oxygen therapy (HBOT) on cognitive function and neuronal integrity in aged (22-month-old) C57BL/6 mice. Male mice were exposed to HBOT for 2 weeks, and spatial learning and memory abilities were assessed using the Morris water maze. We employed transcriptome sequencing and Gene Ontology (GO) term enrichment analysis to examine the effects of HBOT on gene expression profiles, with particular attention given to synapse-related genes. Our data indicated a significant upregulation of postsynapse organization, synapse organization, and axonogenesis GO terms, likely contributing to improved cognitive performance. Moreover, the hyperphosphorylation of tau, a hallmark of many neurodegenerative diseases, was significantly reduced in the HBO-treated group, both in vivo and in vitro. Transmission electron microscopy revealed significant ultrastructural alterations in the hippocampus of the HBOT group, including an increase in the number of synapses and the size of the active zone, a reduction in demyelinated lesions, and a decreased number of “PANTHOS.” Furthermore, Western blot analyses confirmed the upregulation of PSD95, BDNF, and Syn proteins, suggesting enhanced synaptic plasticity and neurotrophic support. Moreover, HBOT increased autophagy, as evidenced by the elevated levels of Beclin-1 and LC3 proteins and the reduced level of p62 protein. Finally, we demonstrated that HBOT activated the AMPK-mTOR signaling pathway, a critical regulator of autophagy. Notably, our findings provide novel insights into the mechanisms by which HBOT ameliorates age-related cognitive impairment, suggesting the potential therapeutic value of this approach.

Objective: Pre-treatment enhanced CT image data were used to train and build models to predict the efficacy of non-small cell lung cancer after conventional radiotherapy and chemotherapy using two classification algorithms, Logistic Regression (LR) and Gaussian Naive Baye (GNB). Methods: In this study, we used pre-treatment enhanced CT image data for region of interest (ROI) sketching and feature extraction. We utilized the least absolute shrinkage and selection operator (LASSO) mutual confidence method for feature screening. We pre-screened logistic regression (LR) and Gaussian naive Bayes (GNB) classification algorithms and trained and modeled the screened features. We plotted 5-fold and 10-fold cross-validated receiver operating characteristic (ROC) curves to calculate the area under the curve (AUC). We performed DeLong's test for validation and plotted calibration curves and decision curves to assess model performance. Results: A total of 102 patients were included in this study, and after a comparative analysis of the two models, LR had only slightly lower specificity than GNB, and higher sensitivity, accuracy, AUC value, precision, and F1 value than GNB (training set accuracy: 0.787, AUC value: 0.851; test set accuracy: 0.772, AUC value: 0.849), and the LR model has better performance in both the decision curve and the calibration curve. Conclusion: CT can be used for efficacy prediction after radiotherapy and chemotherapy in NSCLC patients. LR is more suitable for predicting whether NSCLC prognosis is in remission without considering the computing speed.

Abstract Bacteria abundance alternation in the feces or mucosa of Crohn’s disease (CD) patients has long been applied to identify potential biomarkers for this disease, while the taxa occurrence frequency and their correlations with clinical traits were understudied. A total of 97 samples from the feces and gut mucosa were collected from CD patients and healthy controls (HCs), 16S rRNA-based analyses were performed to determine the changes in taxa abundance and occurrence frequency along CD and to correlate them with clinical traits. The results showed that bacteria communities were divergent between feces and mucosa, while the taxa abundance and occurrence frequency in both partitions showed similar exponential correlations. The decrease of specific fecal bacteria was much more effective in classifying the CD and HCs than that of the mucosal bacteria. Among them, Christensenellaceae_R-7_group and Ruminococcus were predicted as biomarkers by using random forest algorithm, which were persistently presented (> 71.40% in frequency) in the feces of the HCs with high abundance, whereas transiently presented in the feces (

Cost-effective bismuth (Bi) boasts a high theoretical capacity and exceptional selectivity towards Cl- ion storage, making it a promising material for desalination batteries (DBs). However, the substantial volume expansion and low conductivity severely hinder the cycling performance of Bi-based DBs. In this study, a carbon-layer-coated Bi nanocomposite (Bi@C) was synthesized by pyrolyzing a metal–organic framework (Bi-MOF) containing Bi using a straightforward method. The results show that the Bi@C synthesized under the condition of annealing at 700 °C for 2 h has the optimum properties. The Bi@C has good multiplication performance, and the desalination capacity is 106.1 mg/g at a high current density of 1000 mA/g. And the material exhibited a high desalination capacity of 141.9 mg/g at a current density of 500 mA/g and retained 66.9% of its capacity after 200 cycles. In addition, the Bi@C can operate at a wide range of NaCl concentrations from 0.05 to 2 mol/L. The desalination mechanism analysis of the Bi@C revealed that the carbon coating provides space for Bi particles to expand in volume, thereby mitigating the issues of electrode material powdering and shedding. Meanwhile, the porous carbon skeleton establishes electron and ion channels to enhance the electrode material’s conductivity. This research offers a promising strategy for the application of chloride-storage electrode materials in electrochemical desalination systems.

Abstract In nature, some semiaquatic arthropods evolve biomechanics for jumping on the water surface with the controlled burst of kinetic energy. Emulating these creatures, miniature jumping robots deployable on the water surface have been developed, but few of them achieve the controllability comparable to biological systems. The limited controllability and agility of miniature robots constrain their applications, especially in the biomedical field where dexterous and precise manipulation is required. Herein, an insect‐scale magnetoelastic robot with improved controllability is designed. The robot can adaptively regulate its energy output to generate controllable jumping motion by tuning magnetic and elastic strain energy. Dynamic and kinematic models are developed to predict the jumping trajectories of the robot. On‐demand actuation can thus be applied to precisely control the pose and motion of the robot during the flight phase. The robot is also capable of making adaptive amphibious locomotion and performing various tasks with integrated functional modules.

With the development of endoscopic technology, an increasing number of patients with esophageal disease are being diagnosed, although the underlying pathogenesis of many esophageal diseases remains unclear. In recent years, a large number of studies have demonstrated that the occurrence and development of various intestinal diseases were related to intestinal flora. As a result, researchers have shifted their focus towards investigating esophageal flora to better understand the pathogenesis, early diagnosis, and treatment of esophageal diseases. This paper reviewed the normal esophageal flora and the changes of esophageal flora under different esophageal disease states. It was observed that there are distinct differences in the composition of esophageal microflora among Gastroesophageal Reflux, Barrett’s esophagus, eosinophilic esophagitis and normal esophagus. The normal esophageal flora was dominated by gram-positive bacteria, particularly Streptococcus, while the esophageal flora under esophagitis was dominated by gram-negative bacteria. Furthermore, the diversity of esophageal flora is significantly decreased in patients with esophageal cancer. Several potential microbial biomarkers for esophageal cancer have been identified, among which Fusobacterium nucleatum showed a close association with esophageal squamous cell carcinoma’s pathological stage and clinical stage.

Background Previous research has found that multi-drug resistant (MDR) bacteria can be transmitted between ICU patients, and the infections caused by MDR bacteria may negatively affect the efficacy of current treatment. As the speed of diagnostic testing to identify MDR bacteria is relatively slow in clinical practice, the research regarding the prediction of MDR bacteria infections has developed. Objective To develop an evidence-based risk prediction model for MDR bacterial infections in ICU patients, and to verify it using the real-world clinical data collected retrospectively. Methods Potential risk factors for MDR bacterial infections in ICU patients were identified by a meta-analysis of studies regarding MDR bacterial infections in ICU patients included in databases of PubMed, EMBase, the Cochrane Library, CNKI, Wanfang, China Science and Technology Journal Database, Ace Base of CMA during January 2012 to June 2020 using Stata/SE 12.0 software, and were used to develop a risk prediction model by transforming effect size to the standardized regression (β) coefficient. Next the model was fully established and externally verified using the clinical data of adult ICU patients (n=3 908) recruited from Shanghai General Hospital from January 2018 to June 2021. ROC analysis was used to describe the predictive accuracy of the prediction model. Results Seventeen potential risk factors of MDR bacterial infections in ICU patients were identified through the meta-analysis of 31 included studies. The MDR bacterial infection risk prediction model incorporating these 17 factors with corresponding β value as coefficient (derived from converting the risk effect size of each factor) was developed: Logit (P) =-2.476 3 +0.086X1〔gender (male) 〕+0.191X2 (history of hospitalization) +0.392X3 (being transferred from another hospital) +1.723X4 (length of ICU stay) +0.315X5 (other infections) +0.385X6 (chronic obstructive pulmonary disease) +0.131X7 (diabetes) +0.536X8 (renal disease) +0.285X9 (renal failure) +0.565X10 (dialysis) +0.148X11 (mechanical ventilation) +0.742X12 (central venous catheter) +0.336X13 (urinary catheter) +3.483X14 (types of used antimicrobial drugs) +0.174X15 (history of antimicrobial use) +0.975X16 (history of carbapenems use) +1.151X17 (history of aminoglycosides use) . External verification of the model revealed that the model had 64.36% sensitivity, 80.39% specificity, and 0.447 4 Youden index, and an AUC of 0.724. Conclusion Our model has been proved to have good performance in predicting the MDR bacterial infection risk in ICU patients, as well as relatively good applicability, scientificity, and practicability. The development regimen may be used as a reference for developing a risk prediction model for other diseases.

Abstract Prediction of the rapid intensification (RI) of tropical cyclones (TCs) remains challenging. In this paper, by using information from the early period following TC formation, the rapid intensification warning index (RIWI) is developed based on the analog method. A 10‐year cross‐validation and data from Hurricane Ida (2021) are used to verify its potential application. Results show that the RIWI can efficiently discriminate between RI and non‐RI storms and has a significant positive correlation with the lifetime maximum intensity (LMI) of the TCs. By using this index, an early warning can be issued ∼30 hr before the onset of RI, which is much earlier than the predictions made using the probabilistic Statistical Hurricane Intensity Prediction System RI index. In addition, by using the RIWI as a predictor, the prediction of LMI provides an early estimate of TC severity.

BackgroundDue to the aging of society, the average age of LC (lung cancer) patients has increased in recent years. The purpose of this study was to determine the risk factors and develop nomograms to predict the probability of early death (dead in three months) for elderly (≥ 75 years old) LC patients.MethodsData of elderly LC patients were obtained from the SEER database by using the SEER stat software. All patients were randomly divided into a training cohort and a validation cohort in a ratio of 7:3. The risk factors of all-cause early and cancer-specific early death were identified by univariate logistic regression and backward stepwise multivariable logistic regression in the training cohort. Then, risk factors were used to construct nomograms. The performance of nomograms was validated by receiver operating curves (ROC), calibration curves, and decision curve analysis (DCA) in the training cohort and validation cohort.ResultsA total of 15,057 elderly LC patients in the SEER database were included in this research and randomly divided into a training cohort (n = 10,541) and a validation cohort (n = 4516). The multivariable logistic regression models found that there were 12 independent risk factors for the all-cause early death and 11 independent risk factors for the cancer-specific early death of the elderly LC patients, which were then integrated into the nomograms. The ROC indicated that the nomograms exhibited high discriminative ability in predicting all-cause early (AUC in training cohort = 0.817, AUC in validation cohort = 0.821) and cancer-specific early death (AUC in training cohort = 0.824, AUC in validation cohort = 0.827). The calibration plots of the nomograms were close to the diagonal line revealing that there was good concordance between the predicted and practical early death probability in the training and validation cohort. Moreover, the results of DCA analysis indicated that the nomograms had good clinical utility in predicting early death probability.ConclusionThe nomograms were constructed and validated to predict the early death probability of elderly LC patients based on the SEER database. The nomograms were expected to have high predictive ability and good clinical utility, which may help oncologists develop better treatment strategies.

This study aimed to investigate the nutritional value of five commercial meal-replacement shakes, and mainly focused on the lipid digestion fates and fat-soluble vitamin bioavailability. Four out of five samples exhibited a low lipolysis level (37.33–61.42%), aligning with the intended objectives of these products. Although the remaining sample rich in diacylglycerol (DAG) had a higher lipolysis level (80.83%), the inherent low-calorie nature of DAG might compensate for this drawback. The release level of individual fatty acid was largely determined by the glycerolipid composition. Moreover, the strong positive correlation between lipid hydrolyzed products amounts and the fat-soluble vitamin bioavailability was observed. Surprisingly, one out of five samples can provide enough vitamin A and vitamin E for consumers as a total replacement of one or two regular meals. Consequently, the meal-replacement shakes hold the potential to emerge as healthy products for this fast-paced era if the composition and structure were carefully designed and calculated.

Hydrogenases catalyze the simple yet important redox reaction between protons and electrons and H2, thus mediating symbiotic interactions. The contribution of hydrogenase to this symbiosis and anti-oxidative damage was investigated using the M. huakuii hypE (encoding hydrogenase maturation protein) mutant. The hypE mutant grew a little faster than its parental 7653R and displayed decreased antioxidative capacity under H2O2-induced oxidative damage. Real-time quantitative PCR showed that hypE gene expression is significantly up-regulated in all the detected stages of nodule development. Although the hypE mutant can form nodules, the symbiotic ability was severely impaired, which led to an abnormal nodulation phenotype coupled to a 47% reduction in nitrogen fixation capacity. This phenotype was linked to the formation of smaller abnormal nodules containing disintegrating and prematurely senescent bacteroids. Proteomics analysis allowed a total of ninety differentially expressed proteins (fold change > 1.5 or p < 0.05) to be identified. Of these proteins, 21 are related to stress response and virulence, 21 are involved in transporter activity, and 18 are involved in energy and nitrogen metabolism. Overall, the HypE protein is essential for symbiotic nitrogen fixation, playing independent roles in supplying energy and electrons, in bacterial detoxification, and in the control of bacteroid differentiation and senescence.

Background: To explore the safety and feasibility of transumbilical single-hole laparoscopic treatment of cesarean scar pregnancy (CSP) by uterine artery pre-ligation. Methods: Four cases with type II or III CSP were collected. Under transumbilical single-hole laparoscope, an active knot was first made around the uterine artery. If excessive bleeding occurred, the active knot was tightened to control intraoperative bleeding. Excessive bleeding was defined as more than 50 mL of bleeding within 2 min that failed to respond to electrocoagulation. Results: The active knot was tightened in two of the four cases. Overall, the mean intraoperative bleeding was 175.00 ± 155.456 mL, mean operation duration was 171.00 ± 17.455 min, mean postoperative hospitalization was 4.50 ± 0.577 days, and the mean time required for postoperative serum β-HCG to return to normal level was 27.50 ± 5.196 days. Menstruation recovered in 40.25 ± 16.112 days after operation, while postoperative menstrual volume was less in one case and otherwise normal. Conclusions: For the treatment of type II or III CSP, transumbilical single-hole laparoscope combined with uterine artery pre-ligation can accurately control and reduce intraoperative bleeding in place of uterine artery embolization. This treatment regimen is safe and may obtain better abdominal appearance.

PurposeWe performed this study to determine the relationship between serum vitamin D levels and refractive status in adolescents aged 12–19 years.MethodsCross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database from 2001 to 2006. We used weighted multivariate linear regression models to assess the association between serum vitamin levels and adolescent refractive status and then built a smooth curve fitting to investigate their internal non-linear relationships. Finally, subgroup analysis was performed according to gender, and the threshold effect of serum vitamin D levels on spherical equivalent degree was analyzed using a two-piecewise linear regression model.ResultA total of 5,901 adolescents aged 12 to 19 years were included in this study. After adjusting for all confounding factors, the multiple linear regression model showed no significant correlation between adolescent spherical equivalent degree and serum vitamin D [0.0019 (−0.0018, 0.0046)]. However, smooth curve fitting analysis showed an inverted U-shaped curve relationship between spherical equivalent degree and serum vitamin D levels in adolescents (turning point: 58.1 nmol/L). In analyses by gender subgroup, this inverted U-shaped relationship was found to be more pronounced in female adolescents (turning point: 61.6 nmol/L).ConclusionOur results suggest that the correlation between refractive status and serum vitamin D in adolescents differs by gender. When serum vitamin D concentrations were

Abstract Background Bacterial abortive infection (Abi) systems are type IV toxin–antitoxin (TA) system, which could elicit programmed cell death and constitute a native survival strategy of pathogenic bacteria under various stress conditions. However, no rhizobial AbiE family TA system has been reported so far. Here, a M. huakuii AbiE TA system was identified and characterized. Results A mutation in M. huakuii abiEi gene, encoding an adjacent GntR-type transcriptional regulator, was generated by homologous recombination. The abiEi mutant strain grew less well in rich TY medium, and displayed increased antioxidative capacity and enhanced gentamicin resistance, indicating the abiEi operon was negatively regulated by the antitoxin AbiEi in response to the oxidative stress and a particular antibiotic. The mRNA expression of abiEi gene was significantly up-regulated during Astragalus sinicus nodule development. The abiEi mutant was severely impaired in its competitive ability in rhizosphere colonization, and was defective in nodulation with 97% reduction in nitrogen-fixing capacity. The mutant infected nodule cells contained vacuolation and a small number of abnormal bacteroids with senescence character. RNA-seq experiment revealed it had 5 up-regulated and 111 down-regulated genes relative to wild type. Of these down-regulated genes, 21 are related to symbiosis nitrogen fixation and nitrogen mechanism, 16 are involved in the electron transport chain and antioxidant responses, and 12 belong to type VI secretion system (T6SS). Conclusions M. huakuii AbiEi behaves as a key transcriptional regulator mediating root nodule symbiosis.

Abstract Background Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. Methods Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9–39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1β and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. Results The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1β and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1β and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. Conclusions These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway.

High-fat diets (HFDs) are related to the incidence of obesity and diabetes, but the effect of high-fat diet-induced brain damage remains to be clarified. In our study, we found that 24 weeks of a HFD effectively induced obesity and a change in fur color in mice. In addition, the mice also exhibited deficits in learning and memory. We further found that autophagic flux was impaired in mice after HFD feeding. Hypoxia-inducible factor 1α (HIF-1α) expression was significantly increased in HFD-fed mice, and HFD feeding inhibited adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and induced mechanistic target of rapamycin (mTOR) phosphorylation and p70S6K expression. Treatment of HFD-induced BV2 cell model with palmitic acid (PA) was used to further verify a similar result. We concluded that improving tissue hypoxia or enhancing autophagy through the AMPK/mTOR/p70S6K pathway may be a relevant strategy for improving obesity- and ageing-related disorders.

Plenty of factors affect the oncogenesis and progression of colorectal cancer in the tumor microenvironment, including various immune cells, stromal cells, cytokines, and other factors. Chemokine is a member of the cytokine superfamily. It is an indispensable component in the tumor microenvironment. Chemokines play an antitumor or pro-tumor role by recruitment or polarization of recruiting immune cells. Meanwhile, chemokines, as signal molecules, participate in the formation of a cross talk among signaling pathways and non-coding RNAs, which may be involved in promoting tumor progression. In addition, they also function in immune escape. Chemokines are related to drug resistance of tumor cells and may even provide reference for the diagnosis, therapy, and prognosis of patients with colorectal cancer.

α-Tocopherol has been widely used in medicine, cosmetics, and food industry as a nutritional supplement and antioxidant. However, α-tocopherol showed low bioaccessibility, and there is a widespread α-tocopherol deficiency in society today. The preparation of oil-in-water emulsions with high safety and low-calorie property is necessary. The aim of this research was to investigate the effects of different protein emulsifiers (whey protein isolate (WPI), soy protein isolate (SPI), and sodium casein (SC)) on the properties of emulsions delivery system, and diacylglycerol (DAG) was picked as a low-accumulated lipid. The interfacial changes, microstructural alterations, and possible interactions of the protein-stabilized DAG emulsions were investigated during the in vitro digestion. The results show that different proteins affect the degree of digestibility and α-tocopherol bioaccessibility of the emulsions. Both WPI- and SPI-coated emulsions showed good digestibility and α-tocopherol bioaccessibility (77.64 ± 2.93%). This might be due to the strong hydrolysis resistance of WPI (β-lactoglobulin) and the good emulsification ability of SPI. The SC-coated emulsion showed the lowest digestibility and α-tocopherol bioaccessibility, this might be due to the emulsification property of hydrolysis products of SC and the potential interaction with calcium ions. This study provides new possibilities for the application of DAG emulsions in delivery systems.

Abstract Background RNA binding protein (RBP) is an active factor involved in the occurrence and development of colorectal cancer (CRC). Therefore, the potential mechanism of RBP in CRC needs to be clarified by dry-lab analyses or wet-lab experiments. Methods The differential RBP gene obtained from the GEPIA 2 (Gene Expression Profiling Interactive Analysis 2) were performed functional enrichment analysis. Then, the alternative splicing (AS) events related to survival were acquired by univariate regression analysis, and the correlation between RBP and AS was analyzed by R software. The online databases were conducted to analyze the mutation and methylation of RBPs in CRC. Moreover, 5 key RBP signatures were obtained through univariate and multivariate Cox regression analysis and established as RBP prognosis model. Subsequently, the above model was verified through another randomized group of TCGA CRC cohorts. Finally, multiple online databases and qRT-PCR analysis were carried to further confirm the expression of the above 5 RBP signatures in CRC. Results Through a comprehensive bioinformatics analysis, it was revealed that RBPs had genetic and epigenetic changes in CRC. We obtained 300 differentially expressed RBPs in CRC samples. The functional analysis suggested that they mainly participated in spliceosome. Then, a regulatory network for RBP was established to participate in AS and DDX39B was detected to act as a potentially essential factor in the regulation of AS in CRC. Our analysis discovered that 11 differentially expressed RBPs with a mutation frequency higher than 5%. Furthermore, we found that 10 differentially expressed RBPs had methylation sites related to the prognosis of CRC, and a prognostic model was constructed by the 5 RBP signatures. In another randomized group of TCGA CRC cohorts, the prognostic performance of the 5 RBP signatures was verified. Conclusion The potential mechanisms that regulate the aberrant expression of RBPs in the development of CRC was explored, a network that regulated AS was established, and the RBP-related prognosis model was constructed and verified, which could improve the individualized prognosis prediction of CRC.

Mitochondrial dysfunction is considered an early event of Alzheimer disease (AD). D-ribose is a natural monosaccharide that exists in cells, especially in mitochondria, and can lead to cognitive dysfunction. However, the reason for this is unclear. Berberine (BBR) is an isoquinoline alkaloid that can target mitochondria and has great prospect in the treatment of AD. The methylation of PINK1 reinforces the burden of Alzheimer’s pathology. This study explores the role of BBR and D-ribose in the mitophagy and cognitive function of AD related to DNA methylation. APP/PS1 mice and N2a cells were treated with D-ribose, BBR, and mitophagy inhibitor Mdivi-1 to observe their effects on mitochondrial morphology, mitophagy, neuron histology, AD pathology, animal behavior, and PINK1 methylation. The results showed that D-ribose induced mitochondrial dysfunction, mitophagy damage, and cognitive impairment. However, BBR inhibition of PINK1 promoter methylation can reverse the above effects caused by D-ribose, improve mitochondrial function, and restore mitophagy through the PINK1–Parkin pathway, thus reducing cognitive deficits and the burden of AD pathology. This experiment puts a new light on the mechanism of action of D-ribose in cognitive impairment and reveals new insights in the use of BBR for AD treatment.

This research presents an experimental study on the tribological behavior and plastic deformation layer response of quenched-tempered AISI 6150 steel and austempered AISI 6150 steel under sliding with a ball-on-disk type apparatus. Worn surfaces were analyzed by micro-hardness, 3D profilometer, microscopy and scanning electron microscope (SEM). The results showed that the disk surfaces were hardened after tribo-tests due to fresh-martensite formation caused by frictional heating/self-quenching during the sliding tests. The wear loss of the disk specimens was due to smearing plastic deformation resulting in material pile-up along the wear track and debris inside the wear track. The quenched-tempered disk specimens generated more debris than the austempered specimens. The greater amount of wear debris in the quench-tempered samples led to more severe contact stresses between the ball and disk samples which accelerated the smearing of material. As the tempering temperature increases, more cracks were observed for all quenched-tempered disk specimens. More voids and cracks was developed in the near surface region of tempered martensite leading to accelerated material loss through smearing and delamination. Also, more plate-like wear particles were observed on the disks of tempered martensite due to greater surface and subsurface crack fomation and propagation.

Abstract Background Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity in children and adolescents which presents as complex three-dimensional (3D) deformity of the spine and rib cage. This study aimed to estimate the effectiveness and safety of surgical interventions for AIS using Bayesian meta-analysis. Methods The PubMed, EMBASE, and Cochrane Controlled Register of Trials were searched through Oct 1, 2019, without language restrictions. Relevant studies evaluating combined effectiveness and safety of surgical interventions for AIS were included according to eligibility criteria. The primary outcome measures included pulmonary function (change of absolute forced vital capacity and forced expiratory volume in 1 second from pre-operation to post-operation) and incidence of complications. The secondary outcome measure was change of Cobb angle from pre-operation to post-operation. Data was pooled using a random effects model in pairwise meta-analysis. Bayesian meta-analysis combined direct and indirect evidence using a Bayesian framework. Results Twenty-eight case-controlled studies with totally 1970 participants were included. This Bayesian meta-analysis combining direct and indirect evidences indicated that posterior fusion with instrumentation without thoracoplasty (PSF) had the highest probability to achieve better pulmonary function and lower complication rate; video assisted anterior fusion with instrumentation without thoracoplasty (VAT) had the highest probability to obtain better Cobb angle correction based on analysis of rank probability. Conclusion This Bayesian meta-analysis demonstrated that PSF had the highest probability to achieve better post-surgical pulmonary function and lower complication rate, which gives a practical recommendation of PSF as a primary surgical treatment for AIS. The results also support statistics that current surgeries adopted more PSF but less open anterior approach surgery and thoracoplasty. More research work is required to address the effectiveness and safety of VAT for treating AIS more convincingly.

Austempered ductile iron (ADI) is a type of graphite cast iron produced by an isothermal heat treatment process. It is an alternative to traditional steel castings and forgings and even aluminum due to the exceptional mechanical properties such as high strength, good toughness and excellent machinability. In the matrix, the unique ausferritic structure consists of graphite nodules uniformly surrounded by acicular ferrite and carbon saturated austenite. In the automotive industry, ADI has been commonly applied in the manufacturing of camshafts, crankshafts, gears and engine valves. These components are frequently subjected to surface contact with relative motion and external load. Therefore, it is necessary to understand the wear behavior of ADI in order to solve the tribological issues in existing ADI applications and utilize ADI into future designs appropriately. This paper was aimed at reviewing the fabrication processes of single-step and dual-step ADIs. The corresponding microstructure and mechanical properties were also briefly discussed. The studies on wear performance of ADI and potential mechanisms have been systemically reviewed. Keywords: Austempered ductile iron, Single-step austempering, Dual-step austempering, Stress-induced transformation, Wear resistance

In situ TiC/Al-Cu3.7-Mg1.3 nanocomposites containing 5–20 vol. % nano-TiC with nacre-like structures were prepared via combustion synthesis and hot pressing assisted by hot extrusion. Dry sliding friction and wear tests of the prepared in situ TiC/Al-Cu3.7-Mg1.3 nanocomposites and Al-Cu3.7-Mg1.3 alloy was carried out by a pin-on-disc apparatus under various applied loads and at different sliding velocities at room temperature. The nanocomposites showed much better friction and wear performance than the Al-Cu3.7-Mg1.3 alloy. SEM and EDS analyses were conducted to identify the wear mechanisms. The enhanced wear resistance of the nanocomposites was attributed to the formation of a protective mechanically mixed layer reinforced by nano-TiC particles. Keywords: Nanocomposites, Nano-sized TiC particles, Nacre-like structures, Wear resistance

Abstract Using an optical interferometric technique, the grease film distribution under a pure rolling reciprocating motion is observed on a ball-disk test rig, to explore the transient response of grease, which is expected to fill the contact with thickener fiber and run for a long time under steady-state conditions. It is found that the reciprocating motion reduces the accumulation of the thickener fiber gradually with time. The maximum film thickness forms around the stroke ends. After 1,000 working cycles, very severe starvation occurs so that either the central or minimum film thickness becomes nearly constant over one working period. Thus, the life of grease lubrication under a transient condition is far below that under steady-state conditions. However, it is also found that by selecting a smaller stroke length, the thickener fiber spreads out in the contact instead of being removed from the contact at the 1,000th working period. When increasing the maximum entraining speed of the reciprocating motion to a certain value, during which the thickener fiber is not expected to accumulate under a steady-state condition, severe starvation occurs very quickly, causing surface damage.

Psoriasis is a chronic inflammatory skin disease that affects millions of people worldwide. There is still no effective approach for the clinical treatment of psoriasis. This is largely due to the lack of understanding of the pathological mechanism. Here, we comprehensively characterized the skin microbiome and plasma metabolome alterations of psoriasis patients. We observed that some pathogenic bacteria, including Vibrio, were significantly increased in psoriasis patients. The metabolomics results showed alterations in some metabolic pathways, especially pathways for lipid metabolism. In addition, microbiome-specific metabolites, including bile acids and kynurenine, were significantly changed. Correlation analysis revealed the interplay between the skin microbiota and plasma metabolites, especially between Vibrio and several lipids. Our results provide new evidence for the interplay between the skin microbiome and plasma metabolites, which is dramatically disrupted in psoriasis patients. This study also revealed the mechanism underlying the pathogenesis of psoriasis.

Objective To determine the association between serum visfatin levels and psoriasis and to evaluate the correlation between serum visfatin levels and the severity of psoriasis. Methods The electronic databases PubMed®, Embase® and the Cochrane Library were searched for articles published from inception to 1 May 2020. Data were extracted and then standard mean differences (SMDs) and 95% confidence intervals (CIs) were calculated for pooled estimates. Results A total of 11 studies met the inclusion criteria and were included (448 patients diagnosed with psoriasis and 377 controls). This meta-analysis demonstrated that patients with psoriasis had significantly higher levels of visfatin than the controls (SMD = 0.90, 95% CI 0.52, 1.28). Subgroup analyses showed that differences in serum visfatin levels between the patient group and the control group were associated with ethnicity, Psoriasis Area and Severity Index (PASI) and body mass index. Additionally, a meta-analysis of correlations showed that visfatin levels in patients with psoriasis were positively correlated with PASI ( r = 0.51, 95% CI 0.14, 0.75). Conclusions This meta-analysis showed that serum visfatin levels in patients with psoriasis were significantly higher than those in the controls and a positive correlation between serum visfatin levels and psoriasis severity was observed.

Glutathione (GSH) plays a key role in regulating the cellular Redox Homeostasis, and appears to be essential for initiation and development of root nodules. Glutathione peroxidase (Gpx) catalyzes the reduction of H2O2 and organic hydroperoxides by oxidation of GSH to oxidized GSH (GSSG), which in turn is reduced by glutathione reductase (GR). However, it has not been determined whether the Rhizobium leguminosarum Gpx or GR is required during symbiotic interactions with pea. To characterize the role of glutathione-dependent enzymes in the symbiotic process, single and double mutants were made in gpxA (encoding glutathione peroxidase) and gshR (encoding glutathione reductase) genes. All the mutations did not affect the rhizobial growth, but they increased the sensitivity of R. leguminosarum strains to H2O2. Mutant in GpxA had no effect on intracellular GSH levels, but can increase the expression of the catalase genes. The gshR mutant can induce the formation of normal nodules, while the gpxA single and double mutants exhibited a nodulation phenotype coupled to more than 50% reduction in the nitrogen fixation capacity, these defects in nodulation were characterized by the formation of ineffective nodules. In addition, the gpxA and gshR double mutant was severely impaired in rhizosphere colonization and competition. Quantitative proteomics using the TMT labeling method was applied to study the differential expression of proteins in bacteroids isolated from pea root nodules. A total of 27 differentially expressed proteins were identified in these root bacteroids including twenty down-regulated and seven up-regulated proteins. By sorting the down-regulated proteins, eight are transporter proteins, seven are dehydrogenase, deoxygenase, oxidase, and hydrolase. Moreover, three down-regulating proteins are directly involved in nodule process.

GmcA is a FAD-containing enzyme belonging to the GMC (glucose-methanol-choline oxidase) family of oxidoreductases. A mutation in the Rhizobium leguminosarum gmcA gene was generated by homologous recombination. The mutation in gmcA did not affect the growth of R. leguminosarum, but it displayed decreased antioxidative capacity at H2O2 conditions higher than 5 mM. The gmcA mutant strain displayed no difference of glutathione reductase activity, but significantly lower level of the glutathione peroxidase activity than the wild type. Although the gmcA mutant was able to induce the formation of nodules, the symbiotic ability was severely impaired, which led to an abnormal nodulation phenotype coupled to a 30% reduction in the nitrogen fixation capacity. The observation on ultrastructure of 4-week pea nodules showed that the mutant bacteroids tended to start senescence earlier and accumulate poly-β-hydroxybutyrate (PHB) granules. In addition, the gmcA mutant was severely impaired in rhizosphere colonization. Real-time quantitative PCR showed that the gmcA gene expression was significantly up-regulated in all the detected stages of nodule development, and statistically significant decreases in the expression of the redoxin genes katG, katE, and ohrB were found in gmcA mutant bacteroids. LC-MS/MS analysis quantitative proteomics techniques were employed to compare differential gmcA mutant root bacteroids in response to the wild type infection. Sixty differentially expressed proteins were identified including 33 up-regulated and 27 down-regulated proteins. By sorting the identified proteins according to metabolic function, 15 proteins were transporter protein, 12 proteins were related to stress response and virulence, and 9 proteins were related to transcription factor activity. Moreover, nine proteins related to amino acid metabolism were over-expressed.

The complete mitochondrial genome of Penicillium sp. D1806 isolated from Oryza sativa seeds is reported on the basis of the Illumina sequencing data. Its circular mitogenome is 27,461 bp in length, containing 15 protein-coding genes (PCGs), 1 ORFs, 2 ribosomal RNA (rns and rnl) genes, and 24 transfer RNA (tRNA) genes. The overall base composition is as follows: 36.2% A, 37.1% T(U), 11.8% C, 14.9% G, with a low GC content of 26.7%. Phylogenetic analysis shows that Penicillium sp. D1806 is clustered in the genus Penicillium of Aspergillaceae and forms a separate clade with strong statistical support. This study contributes to our understanding of systematics and evolutionary biology of the filamentous fungi in Aspergillaceae (Eurotiomycetes, Ascomycota).

The multisource impact signal of rolling bearings often represents nonlinear and nonstationary characteristics, and quantitative description of the complexity of the signal with traditional spectrum analysis methods is difficult to be obtained. In this study, firstly, a novel concept of local frequency is defined to develop the limitation of traditional frequency. Then, an adaptive waveform decomposition method is proposed to extract the time-frequency features of nonstationary signals with multicomponents. Finally, the normalized Lempel–Ziv complexity method is applied to quantitatively measure the time-frequency features of vibration signals of rolling bearings. The results indicate that the time-frequency features extracted by the proposed method have clear physical meanings and can accurately distinguish the different fault states of rolling bearings. Furthermore, the normalized Lempel–Ziv complexity method can quantitatively measure the nonlinearity of the multisource impact signal. So, it supplies an effective basis for fault diagnosis of rolling bearings.

Cochliobolus miyabeanus is known as a significant causal agent in relation to brown spot disease of rice and causes significant yield losses. In the present study, the complete mitochondrial genome was determined using next-generation sequencing technology. This complete mitogenome is a circular molecule of 124,887 bp in length. It contains 13 conserved protein-coding genes, 21 transfer RNA genes, 2 ribosomal RNA genes and 9 open reading frames. The overall base composition of C. miyabeanus is 35.4% A, 34.4% T, 14.4% C, 15.8% G, with a CG content of 30.2%. Phylogenetic analysis based on concatenated protein genes from 15 taxa within Pezizomycotina showed that C. miyabeanus is closely related to Bipolaris cookei in the family Pleosporaceae (Dothideomycetes, Pleosporales). This work would facilitate the understanding of systematics and evolutionary biology of phytopathogenic fungi.

Combination chemotherapy is a common clinical practice in cancer treatment. Here, cyclic RGD (arginylglycylaspartic acid) peptide was introduced to the surface of lipid/calcium/phosphate (LCP) asymmetric lipid layer nanoparticles for the co-delivery of paclitaxel (PTX) and gemcitabine monophosphate (GMP) (P/G-NPs). The sphere-like morphology of P/G-NPs displays a well-distributed particle size, and high entrapment efficiency and drug loading for both PTX and GMP, with a positive zeta potential. P/G-NPs were stable for up to 15 days. The cellular uptake of these cyclic RGD-modified nanoparticles was significantly higher than that of unmodified nanoparticles over 2 h incubation. Compared with the combination of free PTX and GMP (P/G-Free), P/G-NPs exhibited a longer circulation lifetime and improved absorption for PTX and GMP. Polyethylene glycol was responsible for a higher plasma concentration and a decreased apparent volume of distribution (Vz). Nanoparticles enhanced the drug accumulation in tumors compared with other major organs after 24 h. P/G-NPs nearly halted tumor growth, with little evidence of general toxicity, whereas P/G-Free had only a modest inhibitory effect at 16 mg/kg of GMP and 2.0 mg/kg of PTX. Increased levels of apoptosis within tumors were detected in P/G-NPs group by approximately 43.6% (TUNEL assay). When compared with GMP NPs, PTX NPs, and P/G-Free, P/G-NPs decreased expression of B-cell lymphoma-2 and B-cell lymphoma-extra large proteins, and increased expression of cleaved poly-ADP-ribose polymerase-1. Calreticulin expression in tumors also increased upon the co-delivery of PTX and GMP. The antitumor effect of P/G-NPs is more powerful than P/G-Free, GMP NP, or PTX NP alone, without obvious toxicity.

Bimodal hybrid in-situ nano-/micro-size TiC/Al composites were prepared with combustion synthesis of Al-Ti-C system and hot press consolidation. Attempt was made to obtain in-situ bimodal-size TiC particle reinforced dense Al matrix composites by using different carbon sources in the reaction process of hot pressing forming. Microstructure showed that the obtained composites exhibited reasonable bimodal-sized TiC distribution in the matrix and low porosity. With the increasing of the carbon nano tube (CNT) content from 0 to 100 wt. %, the average size of the TiC particles decreases and the compressive strength of the composite increase; while the fracture strain increases first and then decreases. The compressive properties of the bimodal-sized TiC/Al composites, especially the bimodal-sized composite synthesized by Al-Ti-C with 50 wt. % CNTs as carbon source, were improved compared with the composites reinforced with single sized TiC. The strengthening mechanism of the in-situ bimodal-sized particle reinforced aluminum matrix composites was revealed.

A multiphase nanostructured ZrCu-base bulk alloy which showed a unique microstructure consisting of sub-micrometer scale Zr2Cu solid solution, nano-sized twinned plate-like ZrCu martensite (ZrCu (M)), and retained ZrCu (B2) austenite was fabricated by copper mold casting. The observation of periodic morphology evolution on the fracture surface of the multiphase nanostructured ZrCu-base alloys has been reported, which suggested a fluctuant local stress intensity along the crack propagation. It is necessary to investigate the compressive deformation behavior and the fracture mechanism of the multiphase alloy and the relation to the unique microstructures. The results obtained in this study provide a better understanding of the deformation and fracture mechanisms of multiphase hybrid nanostructured ZrCu-based alloys and give guidance on how to improve the ductility/toughness of bulk ZrCu-based alloys.