A combined AIMD and DFT study of the low-energy radiation responses of GaN.

Although GaN is a promising candidate for semiconductor devices, degradation of GaN-based device performance may occur when the device is bombarded by high-energy charged particles during its application in aerospace, astronomy, and nuclear-related areas. It is thus of great significance to explore the influence of irradiation on the microstructure and electronic properties of GaN and to reveal the internal relationship between the damage mechanisms and physical characteristics. Using a combined density functional theory (DFT) and ab initio molecular dynamics (AIMD) study, we explored the low-energy recoil events in GaN and the effects of point defects on GaN. The threshold displacement energies (Eds) significantly depend on the recoil directions and the primary knock-on atoms. Moreover, the Ed values for nitrogen atoms are smaller than those for gallium atoms, indicating that the displacement of nitrogen dominates under electron irradiation and the created defects are mainly nitrogen vacancies and interstitials. The formation energy of nitrogen vacancies and interstitials is smaller than that for gallium vacancies and interstitials, which is consistent with the AIMD results. Although the created defects improve the elastic compliance of GaN, these radiation damage states deteriorate its ability to resist external compression. Meanwhile, these point defects lead the Debye temperature to decrease and thus increase the thermal expansion coefficients of GaN. As for the electronic properties of defective GaN, the point defects have various effects, i.e., VN (N vacancy), Gaint (Ga interstitial), Nint (N interstitial), and GaN (Ga occupying the N lattice site) defects induce the metallicity, and NGa (N occupying the Ga lattice site) defects decrease the band gap. The presented results provide underlying mechanisms for defect generation in GaN, and advance the fundamental understanding of the radiation resistances of semiconductor materials.

Prediction of the bioaccessibility and accumulation of cadmium in the soil-rice-human system based on optimized DGT and BCR coupled models.

Cadmium, as a typical heavy metal, has the potential to induce soil pollution and threaten human health through the soil-plant-human pathway. The conventional evaluation method based on the total content in soil cannot accurately represent the content migrated from the food chain to plants and the human body. Previous studies focused on the process of plant enrichment of heavy metals in soil, and very few studies directly predicted human exposure or risk through the labile state of Cd in soil. Hence, a relatively accurate and convenient prediction model of Cd release and translocation in the soil-rice-human system was developed. This model utilizes available Cd and soil parameters to predict the bioavailability of Cd in soil, as well as the in vitro bioaccessibility of Cd in cooked rice. The bioavailability of Cd was determined by the Diffusive Gradients in Thin-films technology and BCR sequential extraction procedure, offering in-situ quantification, which presents a significant advantage over traditional monitoring methods and aligns closely with the actual uptake of heavy metals by plants. The experimental results show that the prediction model based on the concentration of heavy metal forms measured by BCR sequential extraction procedure and diffusive gradients in thin-films technique can accurately predict the Cd uptake in rice grains, gastric and gastrointestinal phase (R2=0.712, 0.600 and 0.629). This model accurately predicts Cd bioavailability and bioaccessibility across the soil-rice-human pathway, informing actual human Cd intake, offering scientific support for developing more effective risk assessment methods.

NADPHnet: a novel strategy to predict compounds for regulation of NADPH metabolism via network-based methods.

Identification of compounds to modulate NADPH metabolism is crucial for understanding complex diseases and developing effective therapies. However, the complex nature of NADPH metabolism poses challenges in achieving this goal. In this study, we proposed a novel strategy named NADPHnet to predict key proteins and drug-target interactions related to NADPH metabolism via network-based methods. Different from traditional approaches only focusing on one single protein, NADPHnet could screen compounds to modulate NADPH metabolism from a comprehensive view. Specifically, NADPHnet identified key proteins involved in regulation of NADPH metabolism using network-based methods, and characterized the impact of natural products on NADPH metabolism using a combined score, NADPH-Score. NADPHnet demonstrated a broader applicability domain and improved accuracy in the external validation set. This approach was further employed along with molecular docking to identify 27 compounds from a natural product library, 6 of which exhibited concentration-dependent changes of cellular NADPH level within 100 µM, with Oxyberberine showing promising effects even at 10 µM. Mechanistic and pathological analyses of Oxyberberine suggest potential novel mechanisms to affect diabetes and cancer. Overall, NADPHnet offers a promising method for prediction of NADPH metabolism modulation and advances drug discovery for complex diseases.

Serum analysis based on SERS combined with 2D convolutional neural network and Gramian angular field for breast cancer screening.

Breast cancer is a significant cause of death among women worldwide. It is crucial to quickly and accurately diagnose breast cancer in order to reduce mortality rates. While traditional diagnostic techniques for medical imaging and pathology samples have been commonly used in breast cancer screening, they still have certain limitations. Surface-enhanced Raman spectroscopy (SERS) is a fast, highly sensitive and user-friendly method that is often combined with deep learning techniques like convolutional neural networks. This combination helps identify unique molecular spectral features, also known as "fingerprint", in biological samples such as serum. Ultimately, this approach is able to accurately screen for cancer. The Gramian angular field (GAF) algorithm can convert one-dimensional (1D) time series into two-dimensional (2D) images. These images can be used for data visualization, pattern recognition and machine learning tasks. In this study, 640 serum SERS from breast cancer patients and healthy volunteers were converted into 2D spectral images by Gramian angular field (GAF) technique. These images were then used to train and test a two-dimensional convolutional neural network-GAF (2D-CNN-GAF) model for breast cancer classification. We compared the performance of the 2D-CNN-GAF model with other methods, including one-dimensional convolutional neural network (1D-CNN), support vector machine (SVM), K-nearest neighbor (KNN) and principal component analysis-linear discriminant analysis (PCA-LDA), using various evaluation metrics such as accuracy, precision, sensitivity, F1-score, receiver operating characteristic (ROC) curve and area under curve (AUC) value. The results showed that the 2D-CNN model outperformed the traditional models, achieving an AUC value of 0.9884, an accuracy of 98.13%, sensitivity of 98.65% and specificity of 97.67% for breast cancer classification. In this study, we used conventional nano-silver sol as the SERS-enhanced substrate and a portable laser Raman spectrometer to obtain the serum SERS data. The 2D-CNN-GAF model demonstrated accurate and automatic classification of breast cancer patients and healthy volunteers. The method does not require augmentation and preprocessing of spectral data, simplifying the processing steps of spectral data. This method has great potential for accurate breast cancer screening and also provides a useful reference in more types of cancer classification and automatic screening.

CsCuAO1 Associated with CsAMADH1 Confers Drought Tolerance by Modulating GABA Levels in Tea Plants.

Our previous study showed that COPPER-CONTAINING AMINE OXIDASE (CuAO) and AMINOALDEHYDE DEHYDROGENASE (AMADH) could regulate the accumulation of γ-aminobutyric acid (GABA) in tea through the polyamine degradation pathway. However, their biological function in drought tolerance has not been determined. In this study, Camellia sinensis (Cs) CsCuAO1 associated with CsAMADH1 conferred drought tolerance, which modulated GABA levels in tea plants. The results showed that exogenous GABA spraying effectively alleviated the drought-induced physical damage. Arabidopsis lines overexpressing CsCuAO1 and CsAMADH1 exhibited enhanced resistance to drought, which promoted the synthesis of GABA and putrescine by stimulating reactive oxygen species' scavenging capacity and stomatal movement. However, the suppression of CsCuAO1 or CsAMADH1 in tea plants resulted in increased sensitivity to drought treatment. Moreover, co-overexpressing plants increased GABA accumulation both in an Agrobacterium-mediated Nicotiana benthamiana transient assay and transgenic Arabidopsis plants. In addition, a GABA transporter gene, CsGAT1, was identified, whose expression was strongly correlated with GABA accumulation levels in different tissues under drought stress. Taken together, CsCuAO1 and CsAMADH1 were involved in the response to drought stress through a dynamic GABA-putrescine balance. Our data will contribute to the characterization of GABA's biological functions in response to environmental stresses in plants.

Helicobacter pylori vacA affects the expression of COX-2 in the duodenal mucosa of patients with duodenitis.

Duodenitis refers to inflammation that occurs in the duodenum. Helicobacter pylori (Hp) is a known risk factor for duodenitis. This paper attempted to analyze the correlation between Hp virulence genotypes and the initiation and development of duodenal bulbar inflammation (DBI) to lay the foundation for the management of duodenitis induced by Hp infection. Total RNA was extracted from duodenal samples of 156 Hp-positive patients [70 with DBI and 86 with duodenal bulbar ulcer (DBU)] and 80 Hp-free DBI patients, followed by RT-qPCR detection of COX-2 mRNA expression and the presence of virulence factors. The cagA positive (62.2%), vacAs1 (21.79%), vacAm2 (23.72%), vacAs1m2 (19.87%) and iceA1 (55.80%) genotypes were dominant in 156 Hp-positive samples. Statistical difference was observed in vacAs and vacA mixtures between DBI and DBU patients. Gastric metaplasia had an association with vacA allelotypes, and its occurrence had strong correlations with vacAs1 and vacAs1m2 genotypes. The vacAs1 and vacAs1m2 genotypes were correlated with gastric metaplasia occurrence (all p<0.05). There were significant correlations between vacAs and vacA mixtures with cagA genotypes, and between iceA genotypes with vacA mixtures (all p<0.05). COX-2 was strongly expressed in Hp-infected duodenal mucosa and showed correlations with vacA genotype. COX-2 was differentially expressed in vacAs1- and vacAs2-positive patients. COX-2 was more highly upregulated in vacAs1m1- and vacAs1m2-positive patients than vacAs2m2-positive patients. Overall, Hp virulence genotype vacA was correlated with DBI and DBU initiation and development.

Salvianolic acid B-loaded polydopamine-modified hollow mesoporous organic silica nanoparticles for treatment of breast cancer metastasis via suppressing cancer-associated fibroblasts.

OBJECTIVE: Drug Delivery System was constructed using dopamine-coated organic-inorganic hybrid hollow mesoporous organic silica nanoparticles (HMON-PDA) as drug carriers and salvianolic acid B (SAB) as a model drug. Then, we further investigated whether it can inhibit lung metastasis of breast cancer by inhibiting cancer-associated fibroblasts (CAFs). METHODS: The organic-inorganic hybrid hollow mesoporous organic silica nanoparticles (HMON) were prepared. The particle size, zeta potential, and polydispersion coefficient were characterized. High-performance liquid chromatography was used to determine the effect of different feed ratios of HMON and SAB on drug loading rate. Then, SAB-loaded HMON were modified by polydopamine, which is called SAB@HMON-PDA. Cell viability was detected by MTT assay. The migration of 4T1 cells was investigated by wound healing experiment, and the invasion of 4T1 cells was detected by the transwell method. Finally, the mouse breast cancer lung metastasis models were used to explore whether SAB@HMON-PDA can inhibit lung metastasis of breast cancer by inhibiting CAFs. RESULTS: The obtained nanoparticles have hollow spherical structure. The average particle sizes of HMON, SAB@HMON, and SAB@HMON-PDA were 143.5 ± 0.03, 138.3 ± 0.02, and 172.3 ± 0.18 nm, respectively. The zeta potentials were -44.33±0.15, -41.4 ± 1.30, and -24.13±0.47 mV, respectively. When the ratio of HMON to SAB was 2:1, the drug loading rate reached (18.37±0.04)%. In addition, the prepared SAB@HMON-PDA responded to release SAB under acidic and GSH conditions. The prepared SAB@HMON-PDA could inhibit the migration and invasion of 4T1 cells. The results showed that SAB@HMON-PDA and SAB could inhibit lung metastasis of breast cancer in mice, and SAB@HMON-PDA had a more significant inhibitory effect than SAB. CONCLUSION: We successfully prepared SAB@HMON-PDA with the dual response of pH and GSH. SAB@HMON-PDA can inhibit the migration and invasion of 4T1 cells, and the effect is more significant than free SAB. This inhibitory effect may be related to the inhibition of CAFs. In vivo experiments demonstrated that SAB@HMON-PDA can inhibit lung metastasis of breast cancer by inhibiting CAFs, and its effect was more significant than that of free SAB.

Value of Pretreatment Inflammation-nutrition Score to Predict Non-response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer.

Objective: To investigate the value of pretreatment inflammatory-nutritional biomarkers in predicting the pathological response of locally advanced rectal cancer (LARC) after neoadjuvant chemotherapy (nCT). Methods: This retrospective study included eligible participants who underwent nCT followed by radical surgery. Pretreatment inflammatory nutritional biomarkers were calculated within one week prior to nCT. Correlations between biomarkers and pathological responses were analyzed. The cut-off values of the pretreatment biomarkers for predicting non-response were determined using receiver operating characteristic (ROC) curve analysis. The inflammation-nutrition score was calculated using the lymphocyte level, neutrophil-to-lymphocyte ratio (NLR), and prognostic nutritional index (PNI). Results: A total of 235 patients were retrospectively recruited between January 2017 and September 2022. Lower lymphocyte levels, lymphocyte monocyte ratio (LMR), and PNI, and higher NLR and platelet-to-lymphocyte ratio (PLR) were observed in patients without response. Multivariate logistic regression analysis revealed that NLR could independently predict non-response to nCT in patients with LARC. The sensitivity and specificity of the inflammation-nutrition score for predicting nonresponse were 71.2% and 61.7%, respectively. Conclusion: The pretreatment inflammation-nutrition score is a practical parameter for predicting non-response to nCT in patients with LARC. Patients with high scores were more likely to respond poorly to nCT.

Air-ventilated normothermic machine perfusion alleviates hepatic injury from DCD rat through CYP1A2.

BACKGROUND: Normothermic machine perfusion (NMP) could provide protection to organs from donation after circulatory death (DCD) before transplantation, and its molecular mechanism remains unclear. Our previous study discovered that the air-ventilated NMP confers a better DCD liver recovery than oxygen-ventilated NMP. The purpose in the current study was to investigate the protective mechanism of air-ventilated NMP in a rat model of DCD liver by metabolomics, and to select biomarker to predict liver function recovery. MATERIALS AND METHODS: Peroxisome proliferator activator receptor-α (PPARα) agonist or antagonist was administered via the perfusion circuit in the air-ventilated NMP. Perfusate samples were taken for measurements of aminotransferases using standard biochemical methods, tumor necrosis factor-alpha and interleukin-6. Liver biopsies were allocated for detection of metabolomics, PPARα and cytochrome P450 1A2 (CYP1A2). RESULTS: Metabolomics analysis revealed the significant increased γ-linolenic acid and decreased adrenic acid during the air-ventilated NMP, indicating linoleic acid metabolism pathway was associated with a better DCD liver recovery; as a major enzyme involved in linolenic acid metabolism, CYP1A2 was found correlated with a less inflammation and better liver function with the air-ventilated NMP; PPARα agonist could increase CYP1A2 expression and activity, decrease inflammation response, and improve liver function with the air-ventilated NMP, while PPARα antagonist played the opposite. CONCLUSION: Air-ventilated NMP confers a better liver recovery from DCD rats through the activated linoleic acid metabolism and CYP1A2 upregulation; CYP1A2 expression and activity might function as biomarker to predict DCD liver function recovery with NMP.

miR-552 promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma by targeting FOXO1.

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly malignant cancer. Few effective systemic targeted therapies are available for patients with unresectable ICC, but there exists an urgent need to explore mechanisms underlying the initiation and progression of ICC. MicroRNA (miRNA) plays vital roles in the initiation, progression, and drug resistance of different cancers. Recently, the biological function of a novel miRNA, miR-552, has been widely analyzed in hepatocellular carcinoma and colorectal, cervical, gastric, and other cancers. However, its role in ICC has not yet been elucidated. In this study, we found that miR-552 expression was upregulated in ICC and that miR-552 predicted poor prognosis. Using functional studies, we found that miR-552 enhanced the proliferation and invasion ability of ICC cells. Mechanistic research identified that forkhead box O1 (FOXO1) is the target of miR-552 in ICC. Moreover, the combined panels of miR-552 and FOXO1 exhibited a better prognostic value for ICC patients than did miR-552 alone. In conclusion, these findings demonstrated that the miR-552/FOXO1 axis drove ICC progression, further suggesting that targeting this axis could be a novel therapeutic strategy for ICC.

The application of nanomedicine in clinical settings.

As nanotechnology develops in the fields of mechanical engineering, electrical engineering, information and communication, and medical care, it has shown great promises. In recent years, medical nanorobots have made significant progress in terms of the selection of materials, fabrication methods, driving force sources, and clinical applications, such as nanomedicine. It involves bypassing biological tissues and delivering drugs directly to lesions and target cells using nanorobots, thus increasing concentration. It has also proved useful for monitoring disease progression, complementary diagnosis, and minimally invasive surgery. Also, we examine the development of nanomedicine and its applications in medicine, focusing on the use of nanomedicine in the treatment of various major diseases, including how they are generalized and how they are modified. The purpose of this review is to provide a summary and discussion of current research for the future development in nanomedicine.

Translation and validation study of the Chinese version of the service user technology acceptability questionnaire.

Objective: This study aimed to assess the reliability and validity of the translated Chinese version of the Service User Technology Acceptability Questionnaire (C-SUTAQ). Methods: Patients with cancer (n â€‹= â€‹554) from a tertiary hospital in China completed the C-SUTAQ. Item analysis, content and construct validity test, internal consistency test, and test-retest reliability analysis were conducted on the instrument to test its applicability. Results: The critical ratio of each item of the C-SUTAQ ranged from 11.869 to 29.656; the correlation of each item and subscale ranged from 0.736 to 0.929. The Cronbach's α value for each subscale ranged from 0.659 to 0.941, and the test-retest reliability ranged from 0.859 to 0.966. The content validity index of the scale level and the item level content validity index of the instrument were both 1. Exploratory factor analysis indicated it was reasonable that the C-SUTAQ consists of six subscales after rotation. Confirmatory factor analysis demonstrated good construct validity (χ2/df â€‹= â€‹2.459, comparative fit index â€‹= â€‹0.922, incremental fit index â€‹= â€‹0.907, standardized root mean square residual â€‹= â€‹0.060, root-mean-square error of approximation â€‹= â€‹0.073, goodness of fit index â€‹= â€‹0.875, normed fit index â€‹= â€‹0.876. Conclusions: The C-SUTAQ had good reliability and validity and may be useful to assess Chinese patients' acceptability of telecare. However, the small sample size limited generalization and there is a need to expand the sample to include persons with other diseases. Further studies are required using the translated questionnaire.

Pectolinarigenin ameliorates acetaminophen-induced acute liver injury via attenuating oxidative stress and inflammatory response in Nrf2 and PPARa dependent manners.

BACKGROUND: Cirsii Japonici Herba Carbonisata (Dajitan in Chinese) has been used to treat liver disorders in Asian countries. Pectolinarigenin (PEC), an abundant constituent in Dajitan, has been found to possess a wide range of biological benefits, including hepatoprotective effects. However, the effects of PEC on acetaminophen (APAP)-induced liver injury (AILI) and the underlying mechanisms have not been studied. PURPOSES: To explore the role and mechanisms of PEC in protecting against AILI. STUDY DESIGN AND METHODS: The hepatoprotective benefits of PEC were studied using a mouse model and HepG2 cells. PEC was tested for its effects by injecting it intraperitoneally before APAP administration. To assess liver damage, histological and biochemical tests were performed. The levels of inflammatory factors in the liver were measured using RT-PCR and ELISA. Western blotting was used to measure the expression of a panel of key proteins involved in APAP metabolism, as well as Nrf2 and PPARα. PEC mechanisms on AILI were investigated using HepG2 cells, while the Nrf2 inhibitor (ML385) and PPARα inhibitor (GW6471) were used to validate the importance of either Nrf2 and PPARα in the hepatoprotective effects of PEC. RESULTS: PEC treatment decreased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) levels in the liver. PEC pretreatment increased the activity of superoxide dismutase (SOD) and glutathione (GSH) while decreasing malondialdehyde production (MDA). PEC could also up-regulate two important APAP detoxification enzymes (UGT1A1 and SULT1A1). Further research revealed that PEC reduced hepatic oxidative damage and inflammation, and up-regulated APAP detoxification enzymes in hepatocytes by activating the Nrf2 and PPARα signaling pathways. CONCLUSIONS: PEC ameliorates AILI by decreasing hepatic oxidative stress and inflammation while increasing phase Ⅱ detoxification enzymes related to APAP harmless metabolism through activation of Nrf2 and PPARα signaling. Hence, PEC may serve as a promising therapeutic drug against AILI.

One-Step Electrical Insulating Oil Regeneration on Electret PVDF/BaTiO3 Composite Nanofibers.

Insulating oil is a pivotal component of power transformers, but it suffers from aging byproducts during service operation. The aging byproducts from the degradation of oil insulation tend to induce insulation failure, which poses a significant threat to the security of the power grid. Therefore, the regeneration of insulating oil is required to prolong the useful life of insulating oil and hence be of economic and ecological interests. Typical in-use oil regeneration routes employ multi-step procedures. In this work, a one-step regeneration method using a PVDF/BaTiO3 composite membrane is proposed. BaTiO3 endows the composite membrane with improved hydrophobicity and an electret state. The regeneration performance of the PVDF/BaTiO3 nanofiber membrane was assessed by considering the acid value, moisture content, dielectric loss factor tan δ, and the AC breakdown voltage of the refreshed oil. The test results showed that the filtration efficiencies toward formic acid and moisture were up to 77.5% and 60.6%, respectively. Moreover, the dielectric loss factor tan δ of the refreshed oil decreased evidently at a power frequency, and the AC breakdown voltage rose from 23.7 kV to 38.9 kV. This suggests that the PVDF/BaTiO3 composite membrane may be employed efficiently, and it minimizes aging byproducts via the one-step filtration.

Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion.

Recurrent MEF2D fusions with poor prognosis have been identified in B-cell precursor ALL (BCP-ALL). The molecular mechanisms underlying the pathogenic function of MEF2D fusions are poorly understood. Here, we show that MEF2D-HNRNPUL1 (MH) knock-in mice developed a progressive disease from impaired B-cell development at the pre-pro-B stage to pre-leukemia over 10 to 12 months. When cooperating with NRASG12D, MH drove an outbreak of BCP-ALL, with a more aggressive phenotype than the NRASG12D-induced leukemia. RNA-sequencing identified key networks involved in disease mechanisms. In chromatin immunoprecipitation-sequencing experiments, MH acquired increased chromatin-binding ability, mostly through MEF2D-responsive element (MRE) motifs in target genes, compared with wild-type MEF2D. Using X-ray crystallography, the MEF2D-MRE complex was characterized in atomic resolution, whereas disrupting the MH-DNA interaction alleviated the aberrant target gene expression and the B-cell differentiation arrest. The C-terminal moiety (HNRNPUL1 part) of MH was proven to contribute to the fusion protein's trans-regulatory activity, cofactor recruitment, and homodimerization. Furthermore, targeting MH-driven transactivation of the HDAC family by using the histone deacetylase inhibitor panobinostat in combination with chemotherapy improved the overall survival of MH/NRASG12D BCP-ALL mice. Altogether, these results not only highlight MH as an important driver in leukemogenesis but also provoke targeted intervention against BCP-ALL with MEF2D fusions.

A Novel Nomogram for Predicting Postoperative Liver Failure After Major Hepatectomy for Hepatocellular Carcinoma.

Background: Post-hepatectomy liver failure (PHLF) is the most common cause of mortality after major hepatectomy in hepatocellular carcinoma (HCC) patients. We aim to develop a nomogram to preoperatively predict grade B/C PHLF defined by the International Study Group on Liver Surgery Grading (ISGLS) in HCC patients undergoing major hepatectomy. Study Design: The consecutive HCC patients who underwent major hepatectomy at the Eastern Hepatobiliary Surgery Hospital between 2008 and 2013 served as a training cohort to develop a preoperative nomogram, and patients from 2 other hospitals comprised an external validation cohort. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied to identify preoperative predictors of grade B/C PHLF. Multivariable logistic regression was utilized to establish a nomogram model. Internal and external validations were used to verify the performance of the nomogram. The accuracy of the nomogram was also compared with the conventional scoring models, including MELD and ALBI score. Results: A total of 880 patients who underwent major hepatectomy (668 in the training cohort and 192 in the validation cohort) were enrolled in this study. The independent risk factors of grade B/C PHLF were age, gender, prothrombin time, total bilirubin, and CSPH, which were incorporated into the nomogram. Good prediction discrimination was achieved in the training (AUROC: 0.73) and validation (AUROC: 0.72) cohorts. The calibration curve also showed good agreement in both training and validation cohorts. The nomogram has a better performance than MELD and ALBI score models. Conclusion: The proposed nomogram showed more accurate ability to individually predict grade B/C PHLF after major hepatectomy in HCC patients than MELD and ALBI scores.

DNA crosslinking and recombination-activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia.

BACKGROUND: Abnormal alternative splicing is frequently associated with carcinogenesis. In B-cell acute lymphoblastic leukemia (B-ALL), double homeobox 4 fused with immunoglobulin heavy chain (DUX4/IGH) can lead to the aberrant production of E-26 transformation-specific family related gene abnormal transcript (ERGalt ) and other splicing variants. However, the molecular mechanism underpinning this process remains elusive. Here, we aimed to know how DUX4/IGH triggers abnormal splicing in leukemia. METHODS: The differential intron retention analysis was conducted to identify novel DUX4/IGH-driven splicing in B-ALL patients. X-ray crystallography, small angle X-ray scattering (SAXS), and analytical ultracentrifugation were used to investigate how DUX4/IGH recognize double DUX4 responsive element (DRE)-DRE sites. The ERGalt biogenesis and B-cell differentiation assays were performed to characterize the DUX4/IGH crosslinking activity. To check whether recombination-activating gene 1/2 (RAG1/2) was required for DUX4/IGH-driven splicing, the proximity ligation assay, co-immunoprecipitation, mammalian two hybrid characterizations, in vitro RAG1/2 cleavage, and shRNA knock-down assays were performed. RESULTS: We reported previously unrecognized intron retention events in C-type lectin domain family 12, member A abnormal transcript (CLEC12Aalt ) and chromosome 6 open reading frame 89 abnormal transcript (C6orf89alt ), where also harbored repetitive DRE-DRE sites. Supportively, X-ray crystallography and SAXS characterization revealed that DUX4 homeobox domain (HD)1-HD2 might dimerize into a dumbbell-shape trans configuration to crosslink two adjacent DRE sites. Impaired DUX4/IGH-mediated crosslinking abolishes ERGalt , CLEC12Aalt , and C6orf89alt biogenesis, resulting in marked alleviation of its inhibitory effect on B-cell differentiation. Furthermore, we also observed a rare RAG1/2-mediated recombination signal sequence-like DNA edition in DUX4/IGH target genes. Supportively, shRNA knock-down of RAG1/2 in leukemic Reh cells consistently impaired the biogenesis of ERGalt , CLEC12Aalt , and C6orf89alt . CONCLUSIONS: All these results suggest that DUX4/IGH-driven DNA crosslinking is required for RAG1/2 recruitment onto the double tandem DRE-DRE sites, catalyzing V(D)J-like recombination and oncogenic splicing in acute lymphoblastic leukemia.

The Biogenesis, Biological Functions, and Applications of Macrophage-Derived Exosomes.

Macrophage-derived exosomes have been implicated on the modulation of inflammatory processes. Recent studies have shown that macrophage-derived exosomes contribute to the progression of many diseases such as cancer, atherosclerosis, diabetes and heart failure. This review describes the biogenesis of macrophage-derived exosomes and their biological functions in different diseases. In addition, the challenges facing the use of macrophage-derived exosomes as delivery tools for drugs, genes, and proteins in clinical applications are described. The application of macrophage-derived exosomes in the diagnosis and treatment of diseases is also discussed.

Pharmacological Activating Transcription Factor 6 Activation Is Beneficial for Liver Retrieval With ex vivo Normothermic Mechanical Perfusion From Cardiac Dead Donor Rats.

Background: Normothermic machine perfusion (NMP) could be beneficial for organ retrieval from donors after cardiac death (DCD). Activating transcription factor 6 (ATF6) was recently shown to mitigate liver ischemia/reperfusion injury and confer protection. The aims of this study were to assess the implication of ATF6 in liver retrieval from DCD rat livers with NMP and explore the effect of pharmacologic ATF-6 activation on liver retrieval. Methods: The livers from DCD rats were exposed to 30 min of warm ischemia and 8 h cold preservation followed by 2 h NMP with or without an ATF6 activator in the perfusate. Perfusates and livers were harvested to detect ATF6 expression, liver function, and inflammation. Results: DCD livers with NMP were associated with ATF6 overexpression and activation based on IHC and WB (P < 0.05). The ATF6 activator downregulated perfusate aminotransferases, decreased the Suzuki score, downregulated CD68 and MPO based on IHC, induced the expression of cytochrome c in mitochondria and inhibited the expression of cytochrome c in cytoplasm based on WB, reduced TNFα and IL-6 levels based on ELISA, decreased levels of MDA, GSSG and ATP, and increased SOD activity and GSH levels in the perfused livers (P < 0.05). Conclusion: ATF6 is important for liver retrieval, and an exogenous ATF6 activator accelerates liver retrieval from DCD rats in an ex vivo NMP model.