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The exponentially large compositional space of high entropy alloys (HEAs) offers more possibilities for designing alloys with desired properties. However, it also poses challenges to using the traditional “trial and error” approach in alloy design. In this work, an XGBoost model for predicting the elastic properties of the NbTiVZr family across the entire compositional space was established by combining density-functional theory (DFT) calculation results as the dataset with machine learning (ML) algorithms. Furthermore, considerations of charge transfer were incorporated into the solid solution hardening (SSH) model, and the model was further modified. Through comparing plasticity evaluation indices, the parameter D (γSurf/γGSFE) was determined to be suitable for predicting the plasticity of NbTiVZr alloys. A full compositional space model for yield strength and plasticity has been constructed based on the modified SSH model and the parameter D, respectively. Ultimately, an alloy design system combining the full compositional space models for yield strength and plasticity was established, achieving good consistency with experimental results. And a non-equiatomic alloy with a yield strength exceeding that of equiatomic alloys by 32.2 % (1409 MPa), while maintaining 29.27 % compressive strain was discovered. In conclusion, this work provides an efficient design strategy for alloys with desired properties.

Abstract Objective To appraise the quality of guidelines on intravenous iodinated contrast media (ICM) use in patients with kidney disease, and to compare the recommendations among them. Methods We searched four literature databases, eight guideline libraries, and ten homepages of radiological societies to identify English and Chinese guidelines on intravenous ICM use in patients with kidney disease published between January 2018 and June 2023. The quality of the guidelines was assessed with the Scientific, Transparent, and Applicable Rankings (STAR) tool. Results Ten guidelines were included, with a median STAR score of 46.0 (range 28.5–61.5). The guidelines performed well in “Recommendations” domain (31/40, 78%), while poor in “Registry” (0/20, 0%) and “Protocol” domains (0/20, 0%). Nine guidelines recommended estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 as the cutoff for referring patients to discuss the risk-benefit balance of ICM administration. Three guidelines further suggested that patients with an eGFR < 45 mL/min/1.73 m2 and high-risk factors also need referring. Variable recommendations were seen in the acceptable time interval between renal function test and ICM administration, and that between scan and repeated scan. Nine guidelines recommended to use iso-osmolar or low-osmolar ICM, while no consensus has been reached for the dosing of ICM. Nine guidelines supported hydration after ICM use, but their protocols varied. Drugs or blood purification therapy were not recommended as preventative means. Conclusion Guidelines on intravenous ICM use in patients with kidney disease have heterogeneous quality. The scientific societies may consider joint statements on controversial recommendations for variable timing and protocols. Critical relevance statement The heterogeneous quality of guidelines, and their controversial recommendations, leave gaps in workflow timing, dosing, and post-administration hydration protocols of contrast-enhanced CT scans for patients with kidney diseases, calling for more evidence to establish a safer and more practicable workflow. Key points • Guidelines concerning iodinated contrast media use in kidney disease patients vary. • Controversy remains in workflow timing, contrast dosing, and post-administration hydration protocols. • Investigations are encouraged to establish a safer iodinated contrast media use workflow. Graphical Abstract

Purpose The goal of this study was to examine changes in testicular stiffness at various intervals after the induction of testicular torsion, as well as to assess the predictive value of testicular stiffness for testicular spermatogenesis after torsion. Methods Sixty healthy male rabbits were randomly assigned to one of three groups: complete testicular torsion, incomplete testicular torsion, or control. All rabbits underwent preoperative and postoperative scrotal ultrasonography, including shear wave elastography (SWE), at predetermined intervals. Changes in SWE values were analyzed and compared using repeated-measures analysis of variance. To assess the diagnostic performance of SWE in determining the degree of spermatogenic function impairment, the areas under the receiver operating characteristic curves (AUCs) were calculated. Results SWE measurements in both central and peripheral zones of the testicular parenchyma affected by torsion demonstrated significant negative correlations with spermatogenesis, with coefficients of r=-0.759 (P

To maintain the purity of the seeds and rice quality of the high-quality rice varieties, five lines with similar field and yield traits were selected from the Nanjing46 population in Liyang and used as study materials, and the original progeny were used as the control material for comparing rice quality and lipid metabolites in this study. The rice quality of the five lines still differed compared to CKN1. The Badh2-E2 gene was detected in all five lines, but its 2-AP content differed. The C11:0 content in CKN1 and VN1 was significantly greater than that in the other four lines. Most of the differentially abundant metabolites were phospholipids, including PA(16:0/18:2), PC(15:0/16:0) and PG(16:0/16:0). These metabolites can be used as potential metabolic markers for identifying quality variation. This study presents a novel methodology and theoretical framework for investigating varietal degradation and ensuring seed purity authentication.

Abstract Background Laminoplasty (LP), a procedure commonly used to treat cervical spondylotic myelopathy (CSM), often results in the development of axial symptoms (AS) postoperatively. This study aims to analyze the risk factors associated with the occurrence of AS after LP. Methods We collected and evaluated clinical data from 264 patients with CSM who underwent LP treatment at our institution from January 2018 to January 2022 through a single-center retrospective study. Of the patients, 153 were male and 111 were female, with an average age of 58.1 ± 6.7 years. All patients underwent C3-7 posterior laminoplasty. Based on the occurrence of postoperative axial symptoms, the patients were divided into an AS group and a non-AS group. General information, including age, gender, disease duration, Japanese Orthopaedic Association (JOA) score, postoperation early function training, and collar-wearing time, was recorded and compared between the two groups. Surgical-related data, such as operative segments, surgical time, intraoperative blood loss, intraoperative facet joint destruction, and destruction of the C7 spinous process muscle insertion, were also compared. Imaging data, including preoperative cervical curvature, cervical range of motion, preoperative encroachment rate of the anterior spinal canal, and angle of laminar opening, were collected. Univariate and multivariate logistic regression analyses were used to identify risk factors for the development of AS after LP, and receiver operator characteristic (ROC) curves were utilized to explore the optimal preoperative parameters. Results All 264 patients successfully underwent surgery and were followed up for an average of 19.5 ± 6.8 months. At the 6-month follow-up, 117 patients were diagnosed with AS, resulting in an incidence rate of 40.2%. The multivariate logistic regression analysis identified that preoperative encroachment rate of anterior spinal canal (Pre-op ERASC), intraoperative facet joints destruction (Intra-op FJD), intraoperative open-door angle (Intra-op OA), destroy the C7 spinous process muscle insertion (Destroy C7 SPMI), postoperative loss of cervical curvature (Post-op LCC), and postoperative loss of cervical range of motion (Post-op LCROM) were independent risk factors for AS. Conversely, preoperative cervical curvature (Pre-op CC) and postoperation early function training (Post-op EFT) were protective factors against AS. According to the ROC curve, the cutoff values for preoperative anterior spinal canal occupation rate and preoperative cervical curvature were 28.5% and 16.5°, respectively. When the preoperative anterior spinal canal occupation rate was greater than 28.5% or the preoperative cervical curvature was less than 16.5°, AS was more likely to occur after surgery. Conclusion High preoperative anterior spinal canal occupation rate, facet joint damage during surgery, C7 spinous process muscle stop point damage, larger angle of laminar opening, and greater postoperative cervical curvature loss and cervical range of motion loss are associated with an increased risk of developing AS after cervical laminoplasty. Conversely, a larger preoperative cervical curvature and early postoperative functional exercises can help reduce the occurrence of AS.

Abstract Obesity is a metabolic disorder characterized by the hypertrophy expansion of adipose tissue, resulting in dysregulated energy metabolism, and accompanied by chronic low-grade inflammation. Adipose tissue macrophages (ATMs), a principal component of inflammation, respond to microenvironment signals and modulate adipose tissue remodeling and metabolic processes situation-specific. However, the mechanisms governing how the organism maintains equilibrium between its chronic inflammation and metabolism still need to be understood. Here, we describe a novel role of apolipoprotein E (ApoE), which associated with lipid particles, in maintaining fat deposition and system metabolic inflammation. Using human samples and mouse models, we show that ApoE is robustly downregulated in obese individuals, db/db mice, and mice of high-fat diet (HFD) feeding and increased in obese subjects with diabetes. Furthermore, we found that ApoE deficiency mice globally prevented obesity by restraining adipose tissue expansion and improved systemic glucose tolerance and insulin sensitivity. However, macrophage contributed to metabolic inflammation due to increased IL-1β production in adipose tissue from ApoE-/- mice induced by HFD. Our results suggest that the role of ApoE in regulating obesity and obesity-associated glucose dysregulation is inconsistent. Mechanistically, ApoE modulates of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome priming and activation step. Thus, our studies might provide new sights into ApoE, which is required for obesity-induced hyperglycemia, hyperinsulinism, and adaptive inflammation responses but diminishes the tolerance towards a subsequent metabolic inflammatory challenge. Our study shed new light on the integral role of apolipoprotein APOE in immunometabolism and adipose tissue homeostasis.

Texture evolution, microstructure and mechanical properties of an extruded Mg-10Gd-1Zn-0.4Zr alloy during annealing were investigated. A bimodal microstructure containing coarse deformed grains and fine dynamically recrystallized grains is observed when the annealing temperature is lower than 200 °C. Many Mg5(Gd, Zn) phases are formed in the alloy annealed at 200 °C. Further upon increasing the annealing temperature, static recrystallization occurs and lamellar LPSO phase forms within the matrix. When the annealing temperature reaches 500 °C, an obvious grain growth is observed, and Zn2Zr3 phases form. Meanwhile, the dominant texture component transforms from the basal texture ( parallel to extrusion direction) to an abnormal texture ( parallel to extrusion direction), which is attributed to the growth preference of the grains with abnormal texture. The alloy annealed at 200 °C possesses the optimal mechanical properties with the yield strength of 320 MPa, the ultimate strength of 368 MPa and elongation of 18.4 %. The contribution of each strengthening mechanism to the yield strength in annealed alloys is calculated quantitatively. Compared to the as-extruded alloy, the increment of the yield strength in the alloy annealed at 200 °C is mainly due to the increase in secondary phase strengthening, while the decrement of the yield strength in the alloy annealed at 500 °C is attributed to the reduction of grain boundary strengthening. This work sheds light on adjusting the texture and mechanical properties of the extruded Mg alloys via annealing treatment.

Diabetes causes a loss of sensation in the skin, so diabetics are prone to burns when using heating devices. Diabetic scalded skin is often difficult to heal due to the microenvironment of high glucose, high oxidation, and low blood perfusion. The treatment of diabetic scald mainly focuses on three aspects: 1) promote the formation of the epithelium; 2) promote angiogenesis; and 3) maintain intracellular homeostasis. In response to these three major repair factors, we developed a cadherin-responsive hydrogel combined with FGF21 and dental pulp stem cells (DPSCs) to accelerate epithelial formation by recruiting cadherin to the epidermis and promoting the transformation of N cadherin to E cadherin; promoting angiogenesis to increase wound blood perfusion; regulating the stability of lysosomal and activating autophagy to maintain intracellular homeostasis in order to comprehensively advance the recovery of diabetic scald.

Abstract Background Ewing sarcoma (ES) is an aggressive childhood bone and soft tissue cancer. KIAA1429 is one type of N6-methyladenosine (m6A) writer that plays a tumor-progressive role in various cancers, but the role of KIAA1429 in ES remains to be elucidated. The aim of the study was to investigate the role of KIAA1429 in ES. Methods We performed a multi-omic screen including CRISPR-Cas9 functional genomic and transcriptomic approaches, and identified that KIAA1429 played a significant role in ES progression. Gene knockdown, quantitative real-time PCR (Q-RT-PCR), immunoblotting, CellTiter-Glo assays, clonogenic assays, a subcutaneous xenograft model and immunohistochemistry were used to assess the functional role of KIAA1429 in ES. We mainly conducted RNA sequencing (RNA-seq) in ES cells to analyze the downstream regulatory mechanism of KIAA1429. An integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-seq indicated the upstream regulatory mechanism of KIAA1429. Results In vitro and in vivo CRISPR-Cas9 knockout screening identified KIAA1429 as an ES-dependent gene. Genetic suppression of KIAA1429 inhibited ES cell proliferation and tumorigenicity both in vitro and in vivo. Further studies revealed that KIAA1429 promotes ES tumorigenesis by regulating the ribosome-associated cell cycle and cancer-related inflammation. Interestingly, we found that STAT3 was a target of KIAA1429 and that a STAT3 inhibitor reduced KIAA1429 transcript levels, indicating positive feedback between KIAA1429 and STAT3. Finally, we found that NKX2-2 bound to the KIAA1429 promoter and transactivated KIAA1429. Conclusion Our study systematically analyzed ES-dependent epigenetic/transcriptional regulatory genes and identified KIAA1429 as a biomarker of tumor progression in ES, providing a potential therapeutic target for treating ES.

Abstract Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.

Abstract Purpose Non-specific low back pain (NLBP) is a common clinical condition that affects approximately 60–80% of adults worldwide. However, there is currently a lack of scientific prediction and evaluation systems in clinical practice. The purpose of this study was to analyze the risk factors of NLBP and construct a risk prediction model. Methods We collected baseline data from 707 patients who met the inclusion criteria and were treated at the Sixth Hospital of Ningbo from December 2020 to December 2022. Logistic regression and LASSO regression were used to screen independent risk factors that influence the onset of NLBP and to construct a risk prediction model. The sensitivity and specificity of the model were evaluated by tenfold cross-validation, and internal validation was performed in the validation set. Results Age, gender, BMI, education level, marital status, exercise frequency, history of low back pain, labor intensity, working posture, exposure to vibration sources, and psychological status were found to be significantly associated with the onset of NLBP. Using these 11 predictive factors, a nomogram was constructed, and the area under the ROC curve of the training set was 0.835 (95% CI 0.756–0.914), with a sensitivity of 0.771 and a specificity of 0.800. The area under the ROC curve of the validation set was 0.762 (95% CI 0.665–0.858), with a sensitivity of 0.800 and a specificity of 0.600, indicating that the predictive value of the model for the diagnosis of NLBP was high. In addition, the calibration curve showed a high degree of consistency between the predicted and actual survival probabilities. Conclusion We have developed a preliminary predictive model for NLBP and constructed a nomogram to predict the onset of NLBP. The model demonstrated good performance and may be useful for the prevention and treatment of NLBP in clinical practice.

Numerous post-translational modifications are involved in oocyte maturation and embryo development. Recently, lactylation has emerged as a novel epigenetic modification implicated in the regulation of diverse cellular processes. However, it remains unclear whether lactylation occurs during oocyte maturation and embryo development processes. Herein, the lysine lactylation (Kla) modifications were determined during mouse oocyte maturation and early embryo development by immunofluorescence staining. Exogenous lactate was supplemented to explore the consequences of modulating histone lactylation levels on oocyte maturation and embryo development processes by transcriptomics. Results demonstrated that lactylated proteins are widely present in mice with tissue- and cell-specific distribution. During mouse oocyte maturation, immunofluorescence for H3K9la, H3K14la, H4K8la, and H4K12la was most intense at the germinal vesicle (GV) stage and subsequently weakened or disappeared. Further, supplementing the culture medium with 10 mM sodium lactate elevated both the oocyte maturation rate and the histone Kla levels in GV oocytes, and there were substantial increases in Kla levels in metaphase II (MII) oocytes. It altered the transcription of molecules involved in oxidative phosphorylation. Moreover, histone lactylation levels changed dynamically during mouse early embryogenesis. Sodium lactate at 10 mM enhanced early embryo development and significantly increased lactylation, while impacting glycolytic gene transcription. This study reveals the roles of lactylation during oocyte maturation and embryo development, providing new insights to improving oocyte maturation and embryo quality.

In this research, our objective was to investigate the combined impact of microbial extracts and chemical fungicides on Northern corn leaf blight (NCLB), which is induced by Exserohilum turcicum, and the growth-promoting effect of the crude extracts was also determined. NCLB poses a serious threat to global maize production, necessitating sustainable and environmentally friendly solutions. Mycelial growth rate assays were used to assess the single or synergistic effects of microbial crude extracts and chemical fungicides, and the seed-soaking and root irrigation method was used to detect the growth-promoting effect of the crude extracts on maize seedlings. The results revealed an 84.60% inhibition rate of B. amyloliquefaciens gfj-4 against E. turcicum, and with an EC50 of 49.01 mg·L−1 for the crude extracts. Chemical fungicides demonstrated varying toxicity levels, with fludioxonil exhibiting the highest potency. The mixture of the crude extracts and pyraclostrobin at an 8:2 volume ratio displayed the highest toxicity ratio of 1.24, indicating a synergistic effect. The selected combinations exhibited strong synergistic effects. Soaking maize seeds with 80 mg·L−1 of the crude extracts followed by root irrigation with 40 mg·L−1 produced the most significant growth-promoting effect on maize seedlings. This study highlights the potential of microbial crude extracts to enhance the control of NCLB when combined with pyraclostrobin, along with its growth-promoting effects on maize seedlings.

Abstract Purpose To evaluate the correlation between the degree of preoperative contralateral foraminal stenosis(CFS) and the incidence of contralateral root symptoms after unilateral transforaminal lumbar interbody fusion(TLIF) and to evaluate the appropriate candidate of preventive decompression according to the degree of preoperative contralateral foraminal stenosis. Methods An ambispective cohort study was conducted to investigate the incidence of contralateral root symptoms after unilateral transforaminal lumbar interbody fusion (TLIF) and the effectiveness of preventive decompression. A total of 411 patients were included in the study, all of whom met the inclusion and exclusion criteria and underwent surgery at the Department of Spinal Surgery, Ningbo Sixth Hospital, between January 2017 and February 2021. The study was divided into two groups: retrospective cohort study A and prospective cohort study B. The 187 patients included in study A from January 2017 to January 2019 did not receive preventive decompression. They were divided into four groups based on the degree of preoperative contralateral intervertebral foramen stenosis: no stenosis group A1, mild stenosis group A2, moderate stenosis group A3, and severe stenosis group A4. A Spearman rank correlation analysis was used to evaluate the correlation between the preoperative contralateral foramen stenosis degree and the incidence of contralateral root symptoms after unilateral TLIF. From February 2019 to February 2021, 224 patients were included in the prospective cohort group B. The decision to perform preventive decompression during the operation was based on the degree of preoperative contralateral foramen stenosis. Severe intervertebral foramen stenosis was treated with preventive decompression as group B1, while the rest were not treated with preventive decompression as group B2. The baseline data, surgical-related indicators, the incidence of contralateral root symptoms, clinical efficacy, imaging results, and other complications were compared between group A4 and group B1. Results All 411 patients completed the operation and were followed up for an average of 13.5 ± 2.8 months. In the retrospective study, there was no significant difference in baseline data among the four groups (P > 0.05). The incidence of postoperative contralateral root symptoms increased gradually, and a weak positive correlation was found between the degree of preoperative intervertebral foramen stenosis and the incidence of postoperative root symptoms (rs = 0.304, P 0.05). There was no significant difference in cage position, intervertebral fusion rate, and lumbar stability between the two groups (P > 0.05). No incisional infection occurred after the operation. No pedicle screw loosening, displacement, fracture, or interbody fusion cage displacement occurred during follow-up. Conclusion This study found a weak positive correlation between the degree of preoperative contralateral foramen stenosis and the incidence of contralateral root symptoms after unilateral TLIF. Intraoperative preventive decompression of the contralateral side may prolong the operation time and increase intraoperative blood loss to some extent. However, when the contralateral intervertebral foramen stenosis reaches the severe level, it is recommended to perform preventive decompression during the operation. This approach can reduce the incidence of postoperative contralateral root symptoms while ensuring clinical efficacy.

During the independent process of evolution in plants, photosynthesis appears to have been under convergent evolution to adapt to specific selection pressure in their geographical regions. However, it is unclear how lncRNA regulation and DNA methylation are involved in the phenotypic convergence in distinct lineages. Here, we present a large-scale comparative study of lncRNA transcription profile and whole-genome bisulfite sequencing (WGBS) data in two unrelated Populus species, selected from three relatively overlapping geographical regions. The results indicated that 39.75% lncRNAs of Populus tomentosa were shown to have homologous sequences in the 46.99% lncRNA of Populus simonii. Evolutionary analysis revealed that lncRNAs showed a rapid gain rate in the Populus lineage. Furthermore, co-expression networks in two Populus species identified eight lncRNAs that have the potential to simultaneously cis- or trans-regulate eight photosynthetic-related genes. These photosynthetic lncRNAs and genes were predominantly expressed in accessions from the southern region, indicating a conserved spatial expression in photosynthetic pathways in Populus. We also detected that most lncRNA targeted photosynthetic genes hypomethylated in promoter regions of Southern accessions compared with Northern accessions. Geographical DMRs correlated with genetic SNP variations in photosynthetic genes among Populus from the three geographic regions, indicating that DNA methylation coordinated with lncRNAs in convergent evolution of photosynthesis in Populus. Our results shed light on the evolutionary forces acting on patterns of lncRNA and DNA methylation, and provide a better understanding of the genetic and epigenetic mechanism in photosynthetic convergence evolution.

In recent years, the semi-glutinous japonica rice variety has been extensively utilized in Jiangsu Province to greatly increase rice quality. Nevertheless, the increasing occurrence of seed variation presented a major threat to rice quality. Enhancing the quality of rice grains has emerged as a critical factor in guaranteeing consumer acceptance. Throughout this investigation, five lines (VJ1, VJ2, VJ3, VJ4, and VJ5) selected from the Nanjing9108 population in Liyang were used as research materials, and original cultivars of Nanjing9108 (CKJ1) provided by the original breeder were utilized as control materials to compare rice quality and differential metabolites. VJ4 and VJ3 demonstrated a significant reduction in milled rice rate and head milled rice rate when contrasted to CKJ1. Compared with CKJ1, the amylose content of the five strains was significantly increased. Only VJ3 amplified the 106 bp target band, and its 2-AP content was 0 ng/g. Most metabolites are mainly enriched in cutin, suberine, wax biosynthesis, histidine, and tryptophan metabolism. The primary metabolites throughout the metabolic pathway involve lipids and lipid-like molecules (mono palmitin, alpha-eleostearic, and palmitic acid) and amino acid metabolites (L-glutamate, L-tryptophan, and L-serine). The identification of these key metabolites helps in the discovery of prospective biomarkers for screening seed variation throughout seed production.

Abstract The molecular mechanisms underlying uric acid (UA)‐induced mitochondrial dysfunction and apoptosis have not yet been elucidated. Herein, we investigated underlying mechanisms of UA in the development of mitochondrial dysfunction and apoptosis. We analyzed blood samples of individuals with normal UA levels and patients with hyperuricemia. Results showed that patients with hyperuricemia had significantly elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, which may indicate liver or mitochondrial damage in patients with hyperuricemia. Subsequently, lipidomic analysis of mouse liver tissue mitochondria and human liver L02 cell mitochondria was performed. Compared with control group levels, high UA increased mitochondrial phosphatidylserine (PS) and decreased mitochondrial phosphatidylethanolamine (PE) levels, whereas the expression of mitochondrial phosphatidylserine decarboxylase (PISD) that mediates PS and PE conversion was downregulated. High UA levels also inhibited signal transducer and activator of transcription 3 （STAT3） phosphorylation as well as mitochondrial respiration, while inducing apoptosis both in vivo and in vitro. Treatment with allopurinol, overexpression of PISD, and lyso‐PE (LPE) administration significantly attenuated the three above‐described effects in vitro. In conclusion, UA may induce mitochondrial dysfunction and apoptosis through mitochondrial PISD downregulation. This study provides a new perspective on liver damage caused by hyperuricemia.

Abstract Background With the deepening of social aging, the incidence rate of osteoporosis and diabetes continues to rise. More and more clinical studies show that diabetes is highly correlated with osteoporosis. Diabetes osteoporosis is considered as a metabolic bone disease of diabetes patients. This study aims to explore the role and mechanism of metformin (Met) in diabetic osteoporosis. Methods Mouse MC3T3-E1 cells were treated with Met (0.5 mM) and exposed to high glucose (HG, 35 mM). The cells were cultured in an osteogenic medium for osteogenic differentiation, and the cell proliferation ability was determined using Cell Counting Kit-8; Alkaline phosphatase (ALP) activity detection and alizarin red staining were utilized to evaluate the effect of Met on MC3T3-E1 osteogenic differentiation. Western blot was used to detect the expressions of osteogenesis-related proteins (Runx2 and OCN) as well as Wnt/β-catenin signaling pathway-related proteins in MC3T3-E1 cells. Results HG inhibited proliferation and calcification of MC3T3-E1 cells, down-regulated ALP activity, and the expression of Runx2 and OCN in MC3T3-E1 cells. Meanwhile, the activity of the Wnt/β-catenin signaling pathway was inhibited. Met treatment was found to significantly stimulate the proliferation and calcification of MC3T3-E1 cells under HG conditions, as well as increase the ALP activity and the protein expression level of Runx2 and OCN in the cells. As a result, osteogenic differentiation was promoted and osteoporosis was alleviated. Apart from this, Met also increased the protein expression level of Wnt1, β-catenin, and C-myc to activate the Wnt/β-catenin signaling pathway. Conclusion Met can stimulate the proliferation and osteogenic differentiation of MC3T3-E1 cells under HG conditions. Met may also treat diabetic osteoporosis through Wnt/β-catenin activation.

BackgroundCoronary artery calcification (CAC) is associated with high rates of restenosis and adverse clinical events after percutaneous coronary intervention (PCI) with drug-eluting stents (DES).ObjectivesThe aim of this study was to evaluate the long-term clinical outcomes of drug-coated balloon (DCB)-only treatment for de novo lesions with and without CAC.MethodsPatients with de novo coronary disease treated with the DCB-only strategy were retrospectively enrolled from three centers and categorized into a CAC group and a non-CAC group. The primary endpoint was the target lesion failure (TLF) rate during the 3-year follow-up. Secondary endpoints included the occurrence of major adverse cardiac events (MACEs), target lesion revascularization (TLR), cardiac death, myocardial infarction (MI) and any revascularization. Propensity score matching (PSM) was conducted to assemble a cohort of patients with similar baseline characteristics.ResultsA total of 1,263 patients with 1,392 lesions were included, and 243 patients were included in each group after PSM. Compared with the non-CAC group, the incidence rates of TLF (9.52% vs. 4.94%, odds ratio [OR]: 2.080; 95% confidence interval [CI]: 1.083–3.998, P = 0.034) and TLR (7.41% vs. 2.88%, OR: 2.642; 95% CI: 1.206–5.787, P = 0.020) in the CAC group were higher. The incidence rates of MACE (12.35% vs. 7.82%, OR: 1.665; 95% CI: 0.951–2.916, P = 0.079), cardiac death (2.06% vs. 2.06%, OR: 0.995; 95% CI: 0.288–3.436, P = 0.993), MI (1.23% vs. 0.82%, OR: 2.505; 95% CI: 0.261–8.689, P = 0.652) and any revascularization (12.76% vs. 9.67%, OR: 1.256; 95% CI: 0.747–2.111, P = 0.738) were similar between groups.ConclusionsCAC increased the incidence of TLF and TLR without a substantial increase in the risk of MACE, cardiac death, MI, or any revascularization in patients treated with DCB-only angioplasty during the 3-year follow-up.

BackgroundImmune checkpoint inhibition holds promise as a novel treatment for pancreatic ductal adenocarcinoma (PDAC). The clinical significance of soluble immune checkpoint (ICK) related proteins have not yet fully explored in PDAC.MethodsWe comprehensively profiled 14 soluble ICK-related proteins in plasma in 70 PDAC patients and 70 matched healthy controls. Epidemiological data of all subjects were obtained through structured interviews, and patients’ clinical data were retrieved from electronical health records. We evaluated the associations between the biomarkers with the risk of PDAC using unconditional multivariate logistic regression. Consensus clustering (k-means algorithm) with significant biomarkers was performed to identify immune subtypes in PDAC patients. Prediction models for overall survival (OS) in PDAC patients were developed using multivariate Cox proportional hazards regression. Harrell’s concordance index (C-index), time-dependent receiver operating characteristic (ROC) curve and calibration curve were utilized to evaluate performance of prediction models. Gene expressions of the identified ICK-related proteins in tumors from TCGA were analyzed to provide insight into underlying mechanisms.ResultsSoluble BTLA, CD28, CD137, GITR and LAG-3 were significantly upregulated in PDAC patients (all q < 0.05), and elevation of each of them was correlated with PDAC increased risk (all p < 0.05). PDAC patients were classified into soluble immune-high and soluble immune-low subtypes, using these 5 biomarkers. Patients in soluble immune-high subtype had significantly poorer OS than those in soluble immune-low subtype (log-rank p = 9.7E-03). The model with clinical variables and soluble immune subtypes had excellent predictive power (C-index = 0.809) for the OS of PDAC patients. Furthermore, the immune subtypes identified with corresponding genes’ expression in PDAC tumor samples in TCGA showed an opposite correlation with OS to that of immune subtypes based on blood soluble ICK-related proteins (log-rank p =0.02). The immune-high subtype tumors displayed higher cytolytic activity (CYT) score than immune-low subtype tumors (p < 2E-16).ConclusionFive soluble ICK-related proteins were identified to be significantly associated with the risk and prognosis of PDAC. Patients who were classified as soluble immune-low subtype based on these biomarkers had better overall survival than those of the soluble immune-high subtype.

Diseases of grass carps often occur in juveniles but not in adults that may have established disease resistance during development. We performed both DNA bisulfite and transcriptome sequencing on liver libraries of 1- and 3-year-old grass carps. Differential DNA-methylation analysis exhibited a declined methylation level through development. Functional annotation revealed that identified differentially methylated genes (DMGs) and differentially expressed genes were enriched in immune-related pathways such as PI3K-Akt signaling pathway and its related pathways. Both differentially methylated and differentially expressed genes were clustered into the growth- and immune-related function networks. Subcellular localization analysis indicated that the DMGs localized on cell membrane were significantly enriched in calcium signaling pathway and neuroactive ligand-receptor interaction pathway, implying the importance of G protein-coupled receptors to development. These findings will broaden our understanding of the key genes and pathways that affect the immune system at different development stages and the developing protective strategies in grass carp.

Liver function indicators are often impaired in patients with type 2 diabetes mellitus (T2DM), who present higher concentrations of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase than individuals without diabetes. However, the mechanism of liver injury in patients with T2DM has not been clearly elucidated. In this study, we performed a lipidomics analysis on the liver of T2DM mice, and we found that phosphatidylethanolamine (PE) levels were low in T2DM, along with an increase in diglyceride, which may be due to a decrease in the levels of phosphoethanolamine cytidylyltransferase (Pcyt2), thus likely affecting the de novo synthesis of PE. The phosphatidylserine decarboxylase pathway did not change significantly in the T2DM model, although both pathways are critical sources of PE. Supplementation with CDP-ethanolamine (CDP-etn) to increase the production of PE from the CDP-etn pathway reversed high glucose and FFA (HG&FFA)-induced mitochondrial damage including increased apoptosis, decreased ATP synthesis, decreased mitochondrial membrane potential, and increased reactive oxygen species, whereas supplementation with lysophosphatidylethanolamine, which can increase PE production in the phosphatidylserine decarboxylase pathway, did not. Additionally, we found that overexpression of PCYT2 significantly ameliorated ATP synthesis and abnormal mitochondrial morphology induced by HG&FFA. Finally, the BAX/Bcl-2/caspase3 apoptosis pathway was activated in hepatocytes of the T2DM model, which could also be reversed by CDP-etn supplements and PCYT2 overexpression. In summary, in the liver of T2DM mice, Pcyt2 reduction may lead to a decrease in the levels of PE, whereas CDP-etn supplementation and PCYT2 overexpression ameliorate partial mitochondrial function and apoptosis in HG&FFA-stimulated L02 cells.

BackgroundAs a device for percutaneous coronary intervention, drug-coated balloon (DCB) is widely used to treat in-stent restenosis. However, data regarding the use of DCB in treating de novo saphenous vein graft (SVG) lesions are limited. This study aimed to explore the outcomes of using the DCB in the treatment of de novo SVG lesions of coronary heart disease (CHD).MethodsThis retrospective and observational study analyzed CHD patients with de novo SVG lesions treated with DCB or the new-generation drug-eluting stent (DES) between January 2018 and December 2020. Restenosis was the primary endpoint, whereas target lesion revascularization (TLR), major adverse cardiac events, restenosis, cardiac death, target vessel revascularization, and myocardial infarction were the secondary outcomes.ResultsWe enrolled 31 and 23 patients treated with DCB and DES, respectively. The baseline clinical data, lesion characteristics, and procedural characteristics were similar between the two groups. Twenty-eight (90.3%) patients in the DCB group and 21 (91.3%) in the DES group completed follow-up angiography after 1 year. The quantitative coronary angiography measurements at angiographic follow-up showing late lumen loss were −0.07 ± 0.95 mm for the DCB group and 0.86 ± 0.71 mm for the DES group (P = 0.039), and the rates of restenosis were 13.3% and 21.7% for the DCB and DES groups, respectively (P = 0.470). No significant differences were observed in the rates of MACE (16.7% vs. 26.1%, P = 0.402) and TLR (13.3% vs. 4.3%, P = 0.374) during clinical follow-up.ConclusionOur findings suggest that when pre-dilatation was successful, DCB might be safe and effective in treating de novo SVG lesions.

BackgroundData on drug-coated balloons (DCB) for de novo coronary chronic total occlusion (CTO) are limited. We aimed to investigate the long-term outcomes of substitution of drug-eluting stents (DES) by DCB.MethodsWe compared the outcomes of less DES strategy (DCB alone or combined with DES) and DES-only strategy in treating de novo coronary CTO in this prospective, observational, multicenter study. The primary endpoints were major adverse cardiovascular events (MACE), target vessel revascularization, myocardial infarction, and death during 3-year follow-up. The secondary endpoints were late lumen loss (LLL) and restenosis until 1-year after operation.ResultsOf the 591 eligible patients consecutively enrolled between January 2015 and December 2019, 281 (290 lesions) were treated with DCB (DCB-only or combined with DES) and 310 (319 lesions) with DES only. In the DCB group, 147 (50.7%) lesions were treated using DCB-only, and the bailout stenting rate was relatively low (3.1%). The average stent length per lesion in the DCB group was significantly shorter compared with the DES-only group (21.5 ± 25.5 mm vs. 54.5 ± 26.0 mm, p 0.999). The Kaplan–Meier estimates of MACE at 3-year (11.8% vs. 12.0%, log-rank p = 0.688) was similar between the groups.ConclusionPercutaneous coronary intervention with DCB is a potential “stent-less” therapy for de novo CTO lesions with satisfactory long-term clinical results compared to the DES-only approach.

In present work, a novel γ′′-strengthened Nb-alloyed medium-entropy alloy (MEA) was successfully fabricated and systematically investigated. Our results evidence that the γ′′ phase brings out significant precipitation hardening effect (∼10.2 %volume fraction contributes ∼ 685 MPa strength enhancement). The metastable γ′′ phase could abnormally transform to ε phase, and the morphology and distribution of ε phase shows great impacts on mechanical properties. A hetero-lamellae grain coupling with dual-precipitation (HLG + dual-P) structure was successfully constructed in this Nb-alloyed MEA, which could effectively combine precipitation hardening and hetero-deformation induced (HDI) hardening effects. Deformation characters investigations reveals that the absence of mechanical twinning in γ′′-strengthened MEA originates from the improved critical twinning stress related to the fine dislocation source size and the difficulty of high-energy complex SFs reordering. The combination of massive stacking-faults, Lomer-Cottrell locks and dynamically reinforced HDI hardening contribute to the excellent ductility and work-hardening capacity at high-level strength in the HLG + dual-P structural alloy. Our work provides a useful insight and helpful guidance for developing high-performance precipitation-hardened multi-principal element alloys.

Objective: No new U-net (nnU-Net) is a newly-developed deep learning neural network, whose advantages in medical image segmentation have been noticed recently. This study aimed to investigate the value of the nnU-Net-based model for computed tomography angiography (CTA) imaging in assisting the evaluation of carotid artery stenosis (CAS) and atherosclerotic plaque.Methods: This study retrospectively enrolled 93 CAS-suspected patients who underwent head and neck CTA examination, then randomly divided them into the training set (N = 70) and the validation set (N = 23) in a 3:1 ratio. The radiologist-marked images in the training set were used for the development of the nnU-Net model, which was subsequently tested in the validation set.Results: In the training set, the nnU-Net had already displayed a good performance for CAS diagnosis and atherosclerotic plaque segmentation. Then, its utility was further confirmed in the validation set: the Dice similarity coefficient value of the nnU-Net model in segmenting background, blood vessels, calcification plaques, and dark spots reached 0.975, 0.974 0.795, and 0.498, accordingly. Besides, the nnU-Net model displayed a good consistency with physicians in assessing CAS (Kappa = 0.893), stenosis degree (Kappa = 0.930), the number of calcification plaque (Kappa = 0.922), non-calcification (Kappa = 0.768) and mixed plaque (Kappa = 0.793), as well as the max thickness of calcification plaque (intraclass correlation coefficient = 0.972). Additionally, the evaluation time of the nnU-Net model was shortened compared with the physicians (27.3 ± 4.4 s vs. 296.8 ± 81.1 s, p < 0.001).Conclusion: The automatic segmentation model based on nnU-Net shows good accuracy, reliability, and efficiency in assisting CTA to evaluate CAS and carotid atherosclerotic plaques.

AimsAn increasing body of evidence suggests that drug-coated balloon (DCB) angioplasty represents a valuable option for revascularization in selected patients with coronary bifurcation disease. However, there remains a paucity of real-world observational evidence on the efficacy of DCB in left main (LM) true bifurcation lesion. We compared clinical and angiographic outcomes of hybrid [DCB + drug-eluting stent (DES)] versus DES-only strategy (provisional stenting or two-stent strategies) in de novo LM true bifurcated lesions.MethodsThe primary endpoint was the 2-year composite rate of target lesion failure (TLF): cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target lesion revascularization (CD-TLR). A routine 1-year angiographic follow-up was scheduled. Propensity-score matching was utilized to assemble a cohort of patients with similar baseline characteristics.ResultsAmong 1077 eligible patients, 199 who received DCB treatment and 398 who were assigned to DES therapy had similar propensity scores and were included in the analysis. TLF within 2 years occurred in 13 patients (7.56%) assigned to DCB group, and 52 patients (14.36%) assigned to DES group (odds ratio: 0.487; 95% confidence interval: 0.258–0.922; P = 0.025; Log-rank P = 0.024). Compared with the DES group, the DCB group resulted in a lower rate of CD-TLR (2.91% vs. 9.42%; P = 0.007). Cardiac death, TVMI, all-cause mortality, and stent thrombosis were comparable between both groups. Patients treated with DES-only were associated with a higher late lumen loss (0.42 ± 0.62 mm vs. 0.13 ± 0.42 mm, P < 0.001) compared with the DCB group at 1 year. In sensitivity analysis, the DCB group also presented a lower incidence of TLF, CD-TLR and stent thrombosis both compared to the two-stent strategy and compared to provisional stenting (Ps < 0.05).ConclusionThe 2-year results of PCI utilizing DCB for LM true bifurcation lesions are superior to employing DES alone in terms of safety and effectiveness.