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Abstract Astragalus membranaceus (Fisch.) Bge (AM) is a medicinal herb plant belonging to the Leguminosae family. In this study, we present a chromosome-scale genome assembly of AM, aiming to enhance the molecular biology and functional studies of Astragali Radix. The genome size of AM is about 1.43 Gb, with a contig N50 value of 1.67 Mb. A total of 98.16% of the assembly anchored to 9 pseudochromosomes using Hi-C technology. The assembly completeness was estimated to be 97.27% using BUSCO with the long terminal repeat assembly index (LAI) of 16.22 and quality value (QV) of 48.58. Additionally, the genome contained 67.98% repetitive sequences. Genome annotation predicted 29,914 protein-coding genes, including 73 genes involved in the flavonoid biosynthetic pathway and 2,048 transcription factors. The high-quality genome assembly and gene annotation resources will greatly facilitate future functional genomic studies in Leguminosae species.

Abstract In nature, diploids and tetraploids are two common types of polyploid evolution. Misgurnus anguillicaudatus (mud loach) is a remarkable fish species that exhibits both diploid and tetraploid forms. However, reconstructing the four haplotypes of its autotetraploid genome remains unresolved. Here, we generated the first haplotype-resolved, chromosome-level genome of autotetraploid M. anguillicaudatus with a size of 4.76 Gb, contig N50 of 6.78 Mb, and scaffold N50 of 44.11 Mb. We identified approximately 2.9 Gb (61.03% of genome) of repetitive sequences and predicted 91,485 protein-coding genes. Moreover, allelic gene expression levels indicated the absence of significant dominant haplotypes within the autotetraploid loach genome. This genome will provide a valuable biological model for unraveling the mechanisms of polyploid formation and evolution, adaptation to environmental changes, and benefit for aquaculture applications and biodiversity conservation.

ObjectivesIn order to fully leverage electricity and seawater resources, this paper carries out the thermodynamic analysis and optimization design of an alkaline water electrolysis（AWE） hydrogen production system for offshore wind power. The focus comprises the impacts of operating pressure, temperature and lye flow rate on the operational characteristics of the system. MethodsThermodynamic, kinetic and flux balance analyses are carried out to develop a thermodynamic equilibrium model for hydrogen production by alkaline water electrolysis using Aspen Plus software, which is then validated in comparison with the experimental results.ResultsThe optimum working pressure and temperature of the alkaline water electrolysis hydrogen production system are 9 bar and 70 °C respectively, and the optimum lye flow rate is 1600 t/h. The system energy loss and exergy loss increase with the increase of input current density. When the alkaline water electrolysis input current density reaches 3000 A/m2, the system energy efficiency and exergetic efficiency are 63.58% and 57.27% respectively, and the system energy loss accounts for 26% of the total energy input, of which the exergy loss of the electrolyzer is the highest, accounting for 93.39% of the total exergy loss of the system.ConclusionsThrough this parametric optimization method, a suitable range of operating parameters can be obtained, providing useful references for the selection of offshore wind power hydrogen production parameters.

Abstract This study aims to explore the risk factors associated with frozen shoulder (FS) and develop a predictive model for diagnosing FS, in order to facilitate early detection of the condition. A total of 103 patients diagnosed with FS and admitted to the Department of Joint Surgery at Suining Central Hospital between October 2021 and October 2023 were consecutively included in the study. Additionally, 309 individuals without shoulder joint diseases, matched for age and gender, who visited the department during the same time, were included as the control group.The complete recording of clinical data for all patients was followed by the utilization of statistical tests such as the Mann–Whitney U test, sample t test, and chi-square test to compare different groups. Additionally, multivariate binary logistic regression analysis was employed to identify risk factors associated with the occurrence of FS in patients, leading to the establishment of a prediction model and derivation of a simplified equation. The diagnostic effectiveness of individual indicators and prediction models was assessed through the use of receiver operating characteristic (ROC) curve analysis. In the sample of 103 individuals, 35 were identified as male and 68 as female, with an average age range of 40–70 years (mean age: 54.20 ± 6.82 years). The analysis conducted between different groups revealed that individuals with a low body mass index (BMI), in conjunction with other factors such as diabetes, cervical spondylosis, atherosclerosis, and hyperlipidemia, were more susceptible to developing FS. Logistic regression analysis further indicated that low BMI, diabetes, cervical spondylosis, and hyperlipidemia were significant risk factors for the occurrence of FS. These variables were subsequently incorporated into a predictive model, resulting in the creation of a simplified equation.The ROC curve demonstrated that the combined indicators in the predictive model exhibited superior diagnostic efficacy compared to single indicators, as evidenced by an area under the curve of 0.787, sensitivity of 62.1%, and specificity of 82.2%. Low BMI, diabetes, cervical spondylosis, and hyperlipidemia are significant risk factors associated with the occurrence of FS. Moreover, the utilization of a prediction model has demonstrated superior capability in forecasting the likelihood of FS compared to relying solely on individual indicators. This finding holds potential in offering valuable insights for the early diagnosis of FS.

Abstract Background Astragaloside IV (AST-IV), as an effective active ingredient of Astragalus membranaceus (Fisch.) Bunge. It has been found that AST-IV inhibits the replication of dengue virus, hepatitis B virus, adenovirus, and coxsackievirus B3. Enterovirus 71 (EV71) serves as the main pathogen in severe hand-foot-mouth disease (HFMD), but there are no specific drugs available. In this study, we focus on investigating whether AST-IV can inhibit EV71 replication and explore the potential underlying mechanisms. Methods The GES-1 or RD cells were infected with EV71, treated with AST-IV, or co-treated with both EV71 and AST-IV. The EV71 structural protein VP1 levels, the viral titers in the supernatant were measured using western blot and 50% tissue culture infective dose (TCID50), respectively. Network pharmacology was used to predict possible pathways and targets for AST-IV to inhibit EV71 replication. Additionally, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was used to investigate the potential targeted metabolites of AST-IV. Associations between metabolites and apparent indicators were performed via Spearman’s algorithm. Results This study illustrated that AST-IV effectively inhibited EV71 replication. Network pharmacology suggested that AST-IV inhibits EV71 replication by targeting PI3K-AKT. Metabolomics results showed that AST-IV achieved these effects by elevating the levels of hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-hydroxy-1 H-indole-3- acetamide, oxypurinol, while reducing the levels of PC (14:0/15:0). Furthermore, AST-IV also mitigated EV71-induced oxidative stress by reducing the levels of MDA, ROS, while increasing the activity of T-AOC, CAT, GSH-Px. The inhibition of EV71 replication was also observed when using the ROS inhibitor N-Acetylcysteine (NAC). Additionally, AST-IV exhibited the ability to activate the PI3K-AKT signaling pathway and suppress EV71-induced apoptosis. Conclusion This study suggests that AST-IV may activate the cAMP and the antioxidant stress response by targeting eight key metabolites, including hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-Hydroxy-1 H-indole-3-acetamide, oxypurinol and PC (14:0/15:0). This activation can further stimulate the PI3K-AKT signaling to inhibit EV71-induced apoptosis and EV71 replication. Graphical Abstract

ABSTRACT Entamoeba histolytica is an enteric protozoan parasite that causes human amebic colitis and extraintestinal abscesses. As a prerequisite for parasite colonization and invasion, adherence of E. histolytica is predominantly mediated by galactose (Gal)- and N-acetyl-d-galactosamine (GalNAc)-inhibitable lectins. The intermediate subunit (Igl) of Gal-/GalNAc-inhibitable lectin is a cysteine-rich protein containing multiple CXXC motifs and is considered a key factor affecting trophozoite’s pathogenicity. However, details of the function of Igl during parasite adherence remain unclear. Here, using segmentally expressed Igl proteins and a CHO cell model transfected with Igl fragments, we identified a carbohydrate-recognition domain (CRD)-like region between amino acids 989 and 1,088. Through single- and double-point mutations in the Igl segments, two core CXXC motifs responsible for carbohydrate recognition in the CRD-like region, which are highly conserved among several lectins, were confirmed. In addition to adhesion, the roles of CRD-like region and its core CXXC motifs in various pathogenic effects were further explored. To our knowledge, this is the first report showing an adhesion-related region in E. histolytica Igl. The identification and characterization of this CRD-like region provides further insights into molecular mechanisms underlying E. histolytica pathogenicity and also aids in the determination of a potential drug target in this parasite.IMPORTANCEEntamoeba histolytica adhesion mainly depends on galactose (Gal)-/N-acetyl-d-galactosamine (GalNAc)-inhibitable lectins, subsequently triggering a series of amebic reactions. Among the three subunits of Gal-/GalNAc-inhibitable lectin, heavy subunit and intermediate subunit (Igl) have exhibited lectin activity, but that of Igl remains poorly understood. In this study, we confirmed a carbohydrate-recognition domain (CRD)-like limiting region in E. histolytica Igl and further identified its two core CXXC motifs responsible for carbohydrate recognition. Moreover, the role of Igl's CRD-like region and its CXXC motifs in hemolysis and pathogenic effects was explored. This is the first study to determine an adhesion-related region in E. histolytica Igl protein, providing a new reference direction for subsequent research studies. Since the potential homogeneity of galectin-2 in several mammals and Igl CRD-like region, it could be meaningful to relate the corresponding pathogeneses and phenotypes of these two proteins. Except for adhesion, studies on the involvement of Igl CRD-like region in different parasite–host interactions are also promising.

Depression is a common psychological complication in osteoarthritis (OA) patients, and its incidence gets more and more attention year by year worldwide. This study investigates the association between OA and depression through a bibliometric analysis of published studies. It aims to identify leading authors, institutions, and countries to highlight research hotspots and suggest potential future directions. We collected publications on OA and depression from 1994 to 2024 using the Web of Science Core Collection (WOSCC) database. Bibliographic information, including authorship, country of origin, citation frequency, and visualizations, was generated using VOSviewer, R software, and CiteSpace. A total of 2,342 articles were identified. The United States led in publications with 906 articles, Boston University was the most prolific institution with 56 publications, BMC Musculoskeletal Disorders was the top journal with 71 publications, and Stefania Maggi was the most productive author with 19 publications. The primary research hotspots identified were: “The relationship between depression and OA,” “Disability and prevalence,” and “Characteristics of older people suffering depression after OA.” Predicted future research frontiers include: “Treating depression in OA patients with multimorbidity,” “Psychometric properties of instruments for assessing depression and anxiety in OA patients,” “Depression or anxiety in patients with surgical intervention,” and “Other mental diseases in OA patients.” This bibliometric analysis underscores the importance of understanding the link between OA and depressive disorders, potentially guiding new research directions.

Abstract Background Tumor morphology, immune function, inflammatory levels, and nutritional status play critical roles in the progression of intrahepatic cholangiocarcinoma (ICC). This multicenter study aimed to investigate the association between markers related to tumor morphology, immune function, inflammatory levels, and nutritional status with the prognosis of ICC patients. Additionally, a novel tumor morphology immune inflammatory nutritional score (TIIN score), integrating these factors was constructed. Methods A retrospective analysis was performed on 418 patients who underwent radical surgical resection and had postoperative pathological confirmation of ICC between January 2016 and January 2020 at three medical centers. The cohort was divided into a training set (n = 272) and a validation set (n = 146). The prognostic significance of 16 relevant markers was assessed, and the TIIN score was derived using LASSO regression. Subsequently, the TIIN-nomogram models for OS and RFS were developed based on the TIIN score and the results of multivariate analysis. The predictive performance of the TIIN-nomogram models was evaluated using ROC survival curves, calibration curves, and clinical decision curve analysis (DCA). Results The TIIN score, derived from albumin-to-alkaline phosphatase ratio (AAPR), albumin–globulin ratio (AGR), monocyte-to-lymphocyte ratio (MLR), and tumor burden score (TBS), effectively categorized patients into high-risk and low-risk groups using the optimal cutoff value. Compared to individual metrics, the TIIN score demonstrated superior predictive value for both OS and RFS. Furthermore, the TIIN score exhibited strong associations with clinical indicators including obstructive jaundice, CEA, CA19-9, Child–pugh grade, perineural invasion, and 8th edition AJCC N stage. Univariate and multivariate analysis confirmed the TIIN score as an independent risk factor for postoperative OS and RFS in ICC patients (p

Identification of the S genotype of Malus plants will greatly promote the discovery of new genes, the cultivation and production of apple, the breeding of new varieties, and the origin and evolution of self-incompatibility in Malus plants. In this experiment, 88 Malus germplasm resources, such as Aihuahong, Xishuhaitang, and Reguanzi, were used as materials. Seven gene-specific primer combinations were used in the genotype identification. PCR amplification using leaf DNA produced a single S-RNase gene fragment in all materials. The results revealed that 70 of the identified materials obtained a complete S-RNase genotype, while only one S-RNase gene was found in 18 of them. Through homology comparison and analysis, 13 S-RNase genotypes were obtained: S1S2 (Aihuahong, etc.), S1S28 (Xixian Haitang, etc.), S1S51 (Hebei Pingdinghaitang), S1S3 (Xiangyangcun Daguo, etc.), S2S3 (Zhaiyehaitang, etc.), S3S51 (Xishan 1), S3S28 (Huangselihaerde, etc.), S2S28 (Honghaitang, etc.), S4S28 (Bo 11), S7S28 (Jiuquan Shaguo), S10Se (Dongchengguan 13), S10S21 (Dongxiangjiao) and SeS51 (Xiongyue Haitang). Simultaneously, the frequency of the S gene in the tested materials was analyzed. The findings revealed that different S genes had varying frequencies in Malus resources, as well as varying frequencies between intraspecific and interspecific. S3 had the highest frequency of 68.18%, followed by S1 (42.04%). In addition, the phylogenetic tree and origin evolution analysis revealed that the S gene differentiation was completed prior to the formation of various apple species, that cultivated species also evolved new S genes, and that the S50 gene is the oldest S allele in Malus plants. The S1, S29, and S33 genes in apple-cultivated species, on the other hand, may have originated in M. sieversii, M. hupehensis, and M. kansuensis, respectively. In addition to M. sieversii, M. kansuensis and M. sikkimensis may have also played a role in the origin and evolution of some Chinese apples.

Background and objective Lung cancer is a common malignant tumor of the lung. To explore the molecular mechanism of the occurrence and development of lung cancer is a hot topic in current research. Cyclic RNA D1 (CircCCND1) is highly expressed in lung cancer and may be a potential target for the treatment of lung cancer. The aim of this study was to investigate the effect of CircCCND1 on the malignant biological behaviors of lung cancer cells by regulating the miR-340-5p/transforming growth factor β-induced factor homeobox 1 (TGIF1) axis. Methods The expression of CircCCND1, miR-340-5p, and TGIF1 mRNA in human normal lung epithelial cells BEAS-2B and human lung cancer H446 cells were detected. H446 cells cultured in vitro were randomly divided into control group, CircCCND1 siRNA group, miR-340-5p mimics group, negative control group, and CircCCND1 siRNA+miR-340-5p inhibitor group. Cell proliferation, mitochondrial membrane potential, apoptosis, migration, and invasion were detected, and the expressions of CircCCND1, miR-340-5p, TGIF1 mRNA, BCL2-associated X protein (Bax), cleaved Caspase-3, N-cadherin, E-cadherin, and TGIF1 proteins in each group were detected. The targeting relationship of miR-340-5p with CircCCND1 and TGIF1 was verified. Results Compared with BEAS-2B cells, CircCCND1 and TGIF1 mRNA were increased in H446 cells, and miR-340-5p expression was decreased (P

Summary: The immune evasion of emerging SARS-CoV-2 variants significantly undermines current vaccination efforts, calling for an updated vaccine composition. To identify optimal booster candidates against circulating JN.1, a panel of variant spikes were characterized. The omicron spikes exhibited reduced plasma membrane expression, accompanied by lower cell-cell fusion but increased viral entry. Regimens with DNA prime-DNA boost or DNA prime-adenoviral vectored vaccine boost by intramuscular immunization elicited neutralizing antibody (NAbs) and T cell responses against all variants except BA.2.86 and JN.1. Intranasal immunization induced high IgA and NAb titers in bronchoalveolar lavage against all variants except BA.2.86 and JN.1. T cell responses were generally comparable for all immunogens tested. JN.1 completely escaped NAbs in one immunized cohort, and breakthrough infections marginally boosted antibody titers. Overall, this study indicates intrinsic difficulty in eliciting NAbs against the JN.1 strain, whereas vaccines based on XBB and EG.5.1 are relatively superior in generating cross-reactive NAbs.

This study aimed to investigate the inhibitory effect of astragaloside IV (AS-IV) on enterovirus 71 (EV71)-induced pyroptosis. The results indicated that AST-IV inhibited EV71-induced pyroptosis in normal human gastric epithelial (GES-1) cells. Therefore, we investigated the mechanisms underlying pyroptosis inhibition by AST-IV. We found that EV71 inhibited the Nrf2-Keap1 pathway, whereas AST-IV treatment activated it. Overexpression of Nrf2 led to the inhibition of EV71-induced pyroptosis. EV71 infection and AST-IV treatment upregulated and downregulated thioredoxin interacting protein (TXNIP), respectively. Downregulation of TXNIP activated the Keap1/Nrf2 signaling pathway and inhibited EV71-induced pyroptosis. Furthermore, transcription factor 12 (TCF12) reduced the protein and mRNA levels of TXNIP, and AST-IV treatment upregulated TCF12. These results demonstrate that the TCF12-TXNIP-Keap1/Nrf2 axis participates in the inhibition of pyroptosis by AST-IV in EV71-infected GES-1 cells, suggesting that AST-IV could be used as a dietary supplement to alleviate EV71-induced pyroptosis.

Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a highly malignant tumor with a poor prognosis. This study aimed to investigate whether Hemoglobin, Albumin, Lymphocytes, and Platelets (HALP) score and Tumor Burden Score (TBS) serves as independent influencing factors following radical resection in patients with ICC. Furthermore, we sought to evaluate the predictive capacity of the combined HALP and TBS grade, referred to as HTS grade, and to develop a prognostic prediction model. Methods Clinical data for ICC patients who underwent radical resection were retrospectively analyzed. Univariate and multivariate Cox regression analyses were first used to find influencing factors of prognosis for ICC. Receiver operating characteristic (ROC) curves were then used to find the optimal cut-off values for HALP score and TBS and to compare the predictive ability of HALP, TBS, and HTS grade using the area under these curves (AUC). Nomogram prediction models were constructed and validated based on the results of the multivariate analysis. Results Among 423 patients, 234 (55.3%) were male and 202 (47.8) were aged ≥ 60 years. The cut-off value of HALP was found to be 37.1 and for TBS to be 6.3. Our univariate results showed that HALP, TBS, and HTS grade were prognostic factors of ICC patients (all P

The H shale gas block in the Yangtze plate of China has undergone multistage tectonic evolution, which has resulted in the development of faults and natural fractures that are multistage, multi-scale, multi-type, and multi-strike in nature. To precisely characterize the natural fractures, this study used the seismic attribute analysis method to conduct a multi-scale prediction and natural fracture modelling. Initially, manual fault interpretation and the conventional seismic attributes including variance attribute, curvature and edge detection are used to interpret large-to medium-scale faults. Subsequently, the ant-tracking attribute based on the divided-frequency seismic cubes is used to predict and quantitatively interpret the mid- and small-scale fractures; The third step is to quantitatively divide the ant-tracking attribute value into multiple scales and convert them linearly into fracture intensity. The fourth step is to establish a multi-scale fracture model. This approach has established a comprehensive prediction workflow, progressing from large-scale to small-scale analysis, and shifting from qualitative to quantitative assessment. Compared with traditional fracture prediction and modeling methods, this method not only enhances the accuracy, but also satisfies the engineering requirements of multi-scale modeling. By applying the method in the H shale gas block, we gained a microscopic understanding of the fractures, which are predominantly NW, NE, and nearly NS trending, with a minimal occurrence of nearly EW trending faults/fractures. This method can be effectively applied to characterize multi-scale fractures in areas similar to the geological background of the H shale gas block.

Summary: Pancreatic cancer (PC) is a lethal disease and associated with metabolism dysregulation. Nogo-B is related to multiple metabolic related diseases and types of cancers. However, the role of Nogo-B in PC remains unknown. In vitro, we showed that cell viability and migration was largely reduced in Nogo-B knockout or knockdown cells, while enhanced by Nogo-B overexpression. Consistently, orthotopic tumor and metastasis was reduced in global Nogo knockout mice. Furthermore, we indicated that glucose enhanced cell proliferation was associated to the elevation expression of Nogo-B and nuclear factor κB (NF-κB). While, NF-κB, glucose transporter type 1 (GLUT1) and sterol regulatory element-binding protein 1 (SREBP1) expression was reduced in Nogo-B deficiency cells. In addition, we showed that GLUT1 and SREBP1 was downstream target of NF-κB. Therefore, we demonstrated that Nogo deficiency inhibited PC progression is regulated by the NF-κB/GLUT1 and SREBP1 pathways, and suggested that Nogo-B may be a target for PC therapy.

PurposeGiven the rising prevalence of high fasting plasma glucose (HFPG) over the past three decades, it is crucial to assess its global, national, and regional impact on chronic kidney disease (CKD). This study aims to investigate the burden of CKD attributed to HFPG and its distribution across various levels.Methods and materialsThe data for this research was sourced from the Global Burden of Diseases Study 2019. To estimate the burden of CKD attributed to HFPG, we utilized DisMod-MR 2.1, a Bayesian meta-regression tool. The burden was measured using age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life years (DALYs) rate. Correlation analysis was performed using the Spearman rank order correlation method. Temporal trends were analyzed by estimating the estimated annual percentage change (EAPC).ResultsGlobally in 2019, there were a total of 487.97 thousand deaths and 13,093.42 thousand DALYs attributed to CKD attributed to HFPG, which represent a substantial increase of 153.8% and 120%, respectively, compared to 1990. Over the period from 1990 to 2019, the burden of CKD attributable to HFPG increased across all regions, with the highest increases observed in regions with high socio-demographic index (SDI) and middle SDI. Regions with lower SDI exhibited higher ASMR and age-standardized DALYs (ASDR) compared to developed nations at the regional level. Additionally, the EAPC values, which indicate the rate of increase, were significantly higher in these regions compared to developed nations. Notably, high-income North America, belonging to the high SDI regions, experienced the greatest increase in both ASMR and ASDR over the past three decades. Furthermore, throughout the years from 1990 to 2019, males bore a greater burden of CKD attributable to HFPG.ConclusionWith an increasing population and changing dietary patterns, the burden of CKD attributed to HFPG is expected to worsen. From 1990 to 2019, males and developing regions have experienced a more significant burden. Notably, the EAPC values for both ASMR and ASDR were higher in males and regions with lower SDI (excluding high-income North America). This emphasizes the pressing requirement for effective interventions to reduce the burden of CKD attributable to HFPG.

Abstract Purpose This study aimed to evaluate the efficacy of arthroscopic sciatic neurolysis for treating deep gluteal syndrome (DGS) and to analyse the application value of high-frequency ultrasound during perioperative period. Methods Between June 2020 and February 2022, 30 patients with DGS who underwent failed conservative treatment were retrospectively analysed. Lateral arthroscopic exploration of the deep gluteal space and sciatic neurolysis were performed. In addition to pelvic X-ray, lumbar disc and hip magnetic resonance imaging (MRI), ultrasonography of the sciatic nerve was also performed in all patients. The visual analogue scale pain score (VAS), modified Harris hip score (mHHS) and Benson symptom-rating scale were used to evaluate the clinical efficacy. The correlation between preoperative sciatic nerve ultrasound and arthroscopic findings was analysed. Results The median follow-up for these patients was 13 months (range,12–21 months). Preoperative ultrasonography showed precise morphological changes in 26 sciatic nerves of patients. The VAS score decreased from 5.0 (4.0, 6.0) preoperatively to 0.5 (0, 1.0) postoperatively (p

Lycopene (LYC) is a natural phytonutrient with various bioactivities, such as anti-oxidative stress and anti-inflammation. In this study, human endothelial cells (HUVECs), macrophages and human platelets, and carrageenan-induced thrombosis mouse model were used to evaluate the antithrombosis effects of LYC. In vitro, LYC reduced reactive oxygen species (ROS) production by activating antioxidant enzymes and inhibiting cellular inflammatory factors. LYC inhibited platelets activation by enhancing antioxidant enzymes expression through reducing AKT/FoxO3a signaling pathway. In vivo, LYC effectively improved carrageenan-induced thrombosis in mouse tail, liver and lung tissues. Additionally, in mouse liver and lung tissues, LYC reduced inflammation by inhibiting toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway, and inhibited oxidative stress by increasing antioxidant enzymes expression. In conclusion, LYC can inhibit thrombosis in mouse model, which suggesting that LYC could act as a potential functional food for prevention or treatment of thrombus.

Deep-water turbidite systems on passive continental margins are of interest for oil and gas exploration. However, their complexity poses challenges for reservoir characterization. In this study, we proposed a reservoir characterization workflow for the Macedon member turbidite, employing a combination of 90° phase adjustment, geobody extraction, and genetic inversion, based on the abundant well logging and seismic data from the Enfield field, Northern Carnarvon Basin. Our workflow involved seismic sedimentology to determine the morphology of sand bodies and inversion to determine the net reservoir range, resulting in 3D geological attribute modeling. We applied a 90° phase adjustment correlated seismic events and well logging responses. By stratal slice interpretation and geological body extraction, it was revealed the turbidite reservoir distribution. Finally, we achieved net reservoir characterization of the Macedon member through genetic inversion porosity and geostatistical methods. The results showed that the Macedon turbidite reservoir can be divided into the top and base reservoirs. The top reservoir is sheet-like, and the base reservoir is channelized. The average porosity of the former was 24%, while the average porosity of the later is 20%. The top reservoir has better reservoir quality. Furthermore, we discussed sea level changes affect turbidite distribution and reservoir quality. During the Falling Stage Systems Tract (FSST), the long transportation distance led to relatively less sediment supply and a low sand/mud ratio, resulting in confined, channelized, poor quality turbidite reservoir. In contrast, during the Lowstand Systems Tract (LST), unconfined, amalgamated, good quality turbidite sheet reservoirs were formed. The improved workflow based on seismic sedimentology presented in this article proves effective in characterizing complex reservoirs and contributes to the simplified and efficient management of reservoirs.

Abstract Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Abstract Tribology behaviors of energetic crystals play critical roles in the friction-induced hotspot in high-energy explosive, however, the binder and energetic crystals are not distinguished properly in previous investigations. In this study, for the first time, the nanoscale friction of β-octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (β-HMX) crystal is studied with nanoscratch tests under the ramping load mode. The results show that the nanoscale friction and wear of β-HMX crystal, as a typical energetic material, is highly depended on the applied load. The friction coefficient of β-HMX crystal is initially high when no discernible wear is observed, and then it decreases to a stable value which varies from ∼0.2 to ∼0.7, depending on the applied load, scratch direction, and crystal planes. The β-HMX (011) surfaces show weakly friction and wear anisotropy behavior; in contrast, the β-HMX (110) surfaces show strongly friction and wear anisotropy behavior where the friction coefficient, critical load for the elastic—plastic deformation transition and plastic—cracking deformation transition, and deformation index at higher normal load are highly depended on the scratch directions. Further analyses indicate the slip system and direction of β-HMX surfaces play key roles in determining the nanoscale friction and wear of β-HMX surfaces. The obtained results can provide deeper insight into the friction and wear of energetic crystal materials.

BackgroundThe degree of inflammation and immune status is widely recognized to be associated with intrahepatic cholangiocarcinoma (ICC) and is closely linked to poor postoperative survival. The purpose of this study was to evaluate whether the systemic immune-inflammatory index (SII) and the albumin bilirubin (ALBI) grade together exhibit better predictive strength compared to SII and ALBI separately in patients with ICC undergoing curative surgical resection.MethodsA retrospective analysis was performed on a cohort of 374 patients with histologically confirmed ICC who underwent curative surgical resection from January 2016 to January 2020 at three medical centers. The cohort was divided into a training set comprising 258 patients and a validation set consisting of 116 patients. Subsequently, the prognostic predictive abilities of three indicators, namely SII, ALBI, and SII+ALBI grade, were evaluated. Independent risk factors were identified through univariate and multivariate analyses. The identified independent risk factors were then utilized to construct a nomogram prediction model, and the predictive strength of the nomogram prediction model was assessed through Receiver Operating Characteristic (ROC) survival curves and calibration curves.ResultsUnivariate analysis of the training set, consisting of 258 eligible patients with ICC, revealed that SII, ALBI, and SII+ALBI grade were significant prognostic factors for overall survival (OS) and recurrence-free survival (RFS) (p < 0.05). Multivariate analysis revealed the independent significance of SII+ALBI grade as a risk factor for postoperative OS and RFS (p < 0.05). Furthermore, we conducted an analysis of the correlation between SII, ALBI, SII+ALBI grade, and clinical features, indicating that SII+ALBI grade exhibited stronger associations with clinical and pathological characteristics compared to SII and ALBI. We constructed a predictive model for postoperative survival in ICC based on SII+ALBI grade, as determined by the results of multivariate analysis. Evaluation of the model’s predictive strength was performed through ROC survival curves and calibration curves in the training set and validation set, revealing favorable predictive performance.ConclusionThe SII+ALBI grade, a novel classification based on inflammatory and immune status, serves as a reliable prognostic indicator for postoperative OS and RFS in patients with ICC.

Apple (Malus domestica) is an important multi-functional horticultural crop. However, thus far, there have been few reports concerning the molecular mechanism by which interstock regulates rootstock and scion growth. MicroRNAs (miRNAs) are a type of post-transcriptional regulator that regulates apple growth and development, fruit quality, hormone signal transduction, and stress response. Interstock grafting resulted in differences in miRNA distribution between apple tissues. The regulatory roles of miRNAs in the grafting of apples are not yet clear. In this study, 15 libraries were constructed using the phloem of an apple grafted on two types of interstock and rootstock by high-throughput sequencing. A total of 281 miRNAs were catalogued into 80 families, and 159 novel ones were identified. Compared with the control, the grafting combination with the interstock resulted in 79 differentially expressed miRNAs (DEMs) in the scion, with 36 up-regulated and 43 down-regulated miRNAs, and 57 DEMs in the rootstock, including 22 up-regulated and 35 down-regulated miRNAs. Grafting with the dwarfing interstock led to DEMs in the whole plant, including a decrease in the expression of mdm-miR156 in the scion and mdm-miR172 in the rootstock. Predictive analysis of the DEMs and their target genes suggested that miRNAs mediate scion growth through several aspects, such as plant hormone synthesis and signal transduction, and nutrient absorption and balance. Through combined miRNA and mRNA analysis, the dwarfing effect of the interstock may affect the expression of genes related to the starch and sucrose metabolism pathways in the rootstock and the plant hormone signal transduction pathway in the scion. The available evidence facilitates a better understanding of the role of miRNAs in the response of apples after grafting interstock. One possible reason for the stunting of apple trees and the promotion of early flowering caused by the dwarfing interstock is the decrease in expression levels of mdm-miR156 and mdm-miR172.

Introduction This study aims to investigate the feasibility of a noninvasive handheld electroporation pulses delivery device (EPDD) for electroporation-based treatment (EBT) of skin superficial lesions through numerical analysis and animal study.Methods Finite element analysis was performed to investigate the performance of the EPDD. The electric field, temperature, EI and TI were calculated under pulse voltages of 600, 800, and 1000 V. A mouse subcutaneous tumor model was established to evaluate the performance of the EPDD through histopathology and survival analyses.Results The electrical field strength increased from 151 (600 V) to 252 V/cm (1000 V) in the skin and from 1302 (600 V) to 2171 V/cm (1000 V) in the tumor. The volume of EI grew and reached a plateau at the 165th pulse, whereas the maximum volume of EI increased with higher voltage. The growth tendency of TI differed between groups, and it was higher in the high-voltage group (HVG) than in the low-voltage group. Histopathological analysis showed that the depth and range of the ablation area could be controlled by adjusting pulse voltage. Survival analysis showed that the survival of the HVG was better than that of the low-voltage and the control group (p

''Gannan navel orange'' was used as the test fruit, the effects of the solution of Heracleum hemsleyanum Diels extracts，carboxymethyl cellulose sodium/polyvinyl pyrrolidone and γ-aminobutyric acid with different concentrations on citrus fruit fresh-keeping were studied by response surface methodology with decay rate, weight loss rate and the content of ascorbic acid as evaluation parameters. And then the best formula was determined and its fresh-keeping effects on citrus were explored. The optimal formulation was determined as follow: The concentration of Heracleum hemsleyanum Diels extracts, carboxymethyl cellulose sodium/polyvinyl pyrrolidone and γ-aminobutyric acid were 2.0%, 0.6%/0.4% and 1.0%, respectively. The experimental results of the fresh-keeping effect test can be obtained：Compared with the control group, adding the Heracleum hemsleyanum Diels extracts could significantly reduce the decay rate, delay the decrease of fruit hardness, and keep the activities of superoxide dismutase and β-1,3-glucanase, reduce the content of malondialdehyde. The composite coating could prevent the loss of water in citrus fruits, and keep soluble solids, titratable acid, ascorbic acid and total sugar content, and maintain fruit flavor. The combination of the two components to prepare composite coating preservative could play a role of effect superposition, the comprehensive fresh-keeping effect is better than the two alone.

Various studies have shown that the heavy use of pharmaceuticals poses serious ecological risks, especially in metropolitan areas with intensive human activities. In this study, the spatial distribution, sources, and ecological risks of 29 pharmaceuticals in 82 surface waters collected from the North Canal Basin in Beijing were studied. The results showed that the pharmaceutical concentrations ranged from not detected to 193 ng/L, with ampicillin being undetected while ofloxacin had a 100% detection frequency, which indicates the widespread occurrence of pharmaceutical pollution in the North Canal Basin. In comparison with other freshwater study areas, concentrations of pharmaceuticals in the North Canal Basin were generally at moderate levels. It was found that pharmaceutical concentrations were always higher in rivers that directly received wastewater effluents. Source analysis was conducted using the positive matrix factorization model. Combining the spatial pollution patterns of pharmaceuticals, it has been found that wastewater effluents contributed the most to the loads of pharmaceuticals in the studied basin, while in suburban areas, a possible contribution of untreated wastewater was demonstrated. Risk assessment indicated that approximately 55% of the pharmaceuticals posed low-to-high ecological risks, and combining the results of risk analyses, it is advised that controlling WWTP effluent is probably the most cost-effective measure in treating pharmaceutical pollution.

The nanoindentation behavior of P92 steel with thermomechanical treatment under 3.5 MeV Fe13+ ion irradiation at room temperature, 400 and 700 °C was investigated. Pop-in behavior is observed for all the samples with and without irradiation at room temperature, while the temperature dependence of pop-in behavior is only observed in irradiated samples. The average load and penetration depth at the onset of pop-in increase as the irradiation temperature increases, in line with the results of the maximum shear stress. Irradiation induced hardening is exhibited for all irradiated samples, but there is a significant reduction in the hardness of sample irradiated at 700 °C in comparison to the samples irradiated at room temperature and 400 °C. The ratio of hardness to elastic modulus for all samples decreases with increasing penetration depth except for samples at 700 °C. With the increasing of irradiation temperature, the ratio of the irreversible work to the total work gradually decreases. In contrast, it increases for samples without irradiation.

BackgroundThe stemness characteristic of breast cancer (BC) is a crucial factor underlying cancer recurrence and metastasis after operative therapy and chemoradiotherapy. Understanding the potential mechanism of breast cancer stem cells (BCSCs) may ameliorate the prognosis of patients.MethodsWe collected clinical specimens of BC patients for staining and statistical analysis to verify the expression status and clinical significance of complement C1q-like 4 (C1ql4). Western blot and qRT-PCR were employed to detect the expression of molecules. Flow cytometry was used to examine cell cycle, cell apoptosis and the portion of BCSCs. Wound healing and Transwell assays were used to detect cell metastasis. The effect of C1ql4 on breast cancer progression in vivo was examined in a nude mouse tumor bearing model.ResultsOur clinical analysis showed that C1ql4 was highly expressed in BC tissues and cell lines, and the high expression of C1ql4 was significantly corelated with the malignancy of BC patients. Moreover, we also found that C1ql4 was overexpressed in BCSCs. C1ql4 knockdown suppressed the BCSC and EMT properties, promoted cell cycle progression, enhanced BC cell apoptosis, and inhibited cell migration and invasion, whereas the C1ql4 overexpression exhibited the opposite effects. Mechanistically, C1ql4 promoted the activation and nuclear location of NF-κB and the expression of downstream factors TNF-α and IL-1β. Moreover, inhibition of PI3K/AKT signaling suppressed the C1ql4-induced stemness and EMT.ConclusionsOur findings suggest that C1ql4 promotes the BC cell stemness and EMT via modulating the PI3K/AKT/NF-κB signaling, and provides a promising target for BC treatment.

BackgroundSurgery is an important means for patients with colorectal liver metastases (CRLM) to improve their long-term survival, and accurate screening of high-risk factors is crucial to guiding postoperative monitoring and treatment. With this in mind, the aim of this study was to investigate the expression levels and prognostic roles of Mismatch Repair (MMR), Ki67, and Lymphovascular invasion(LVI) in the tumor tissues of colorectal of CRLM.Methods85 Patients with CRLM who received surgical treatment for liver metastases after colorectal cancer resection from June, 2017 and Jan, 2020 were included in this study. Independent risk factors affecting the survival of patients with CRLM were investigated using a Cox regression model and the Kaplan-Meier method, and a nomogram for predicting the OS of patients with CRLM was established according to a Cox multivariate regression model. Calibration plots and Kaplan-Meier curves were used to assess the performance of the nomogram.ResultsThe median survival time was 39 months (95% CI: 32.05-45.950), and MMR, Ki67 and LVI were significantly correlated with prognosis. Univariate analysis indicated that larger metastasis size (p=0.028), more than one liver metastases (p=0.001),higher serum CA199 (p

Radiomics was proposed by Lambin et al. in 2012 and since then there has been an explosion of related research. There has been significant interest in developing high-throughput methods that can automatically extract a large number of quantitative image features from medical images for better diagnostic or predictive performance. There have also been numerous radiomics investigations on intrahepatic cholangiocarcinoma in recent years, but no pertinent review materials are readily available. This work discusses the modeling analysis of radiomics for the prediction of lymph node metastasis, microvascular invasion, and early recurrence of intrahepatic cholangiocarcinoma, as well as the use of deep learning. This paper briefly reviews the current status of radiomics research to provide a reference for future studies.

Context Farrerol, a typical natural flavanone isolated from the traditional Chinese herb ‘Man-shan-hong’ [Rhododendron dauricum L. (Ericaceae)] with phlegm-reducing and cough-relieving properties, is widely used in China for treating bronchitis and asthma. Objective To present the anti-inflammatory, antioxidant, vasoactive, antitumor, and antimicrobial effects of farrerol and its underlying molecular mechanisms. Methods The literature was reviewed by searching PubMed, Medline, Web of Knowledge, Scopus, and Google Scholar databases between 2011 and May 2021. The following key words were used: ‘farrerol,’ ‘flavanone,’ ‘anti-inflammatory,’ ‘antioxidant,’ ‘vasoactive,’ ‘antitumor,’ ‘antimicrobial,’ and ‘molecular mechanisms’. Results Farrerol showed anti-inflammatory effects mainly mediated via the inhibition of interleukin (IL)-6/8, IL-1β, tumour necrosis factor(TNF)-α, NF-κB, NO, COX-2, JNK1/2, AKT, PI3K, ERK1/2, p38, Keap-1, and TGF-1β. Farrerol exhibited antioxidant effects by decreasing JNK, MDA, ROS, NOX4, Bax/Bcl-2, caspase-3, p-p38 MAPK, and GSK-3β levels and enhancing Nrf2, GSH, SOD, GSH-Px, HO-1, NQO1, and p-ERK levels. The vasoactive effects of farrerol were also shown by the reduced α-SMA, NAD(P)H, p-ERK, p-Akt, mTOR, Jak2, Stat3, Bcl-2, and p38 levels, but increased OPN, occludin, ZO-1, eNOS, CaM, IP3R, and PLC levels. The antitumor effects of farrerol were evident from the reduced Bcl-2, Slug, Zeb-1, and vimentin levels but increased p27, ERK1/2, p38, caspase-9, Bax, and E-cadherin levels. Farrerol reduced α-toxin levels and increased NO production and NF-κB activity to impart antibacterial activity. Conclusions This review article provides a theoretical basis for further studies on farrerol, with a view to develop and utilise farrerol for treating of vascular-related diseases in the future.

Effective systemic treatment for hepatocellular carcinoma (HCC) remains urgently needed. Sorafenib is the first FDA-approved systemic treatment for HCC. However, individual HCC patents’ response to sorafenib varies greatly. How to enhance the anti-HCC effect of sorafenib is still a significant challenge. T cell immunoglobulin mucin-3 (Tim-3) is a newly identified immune checkpoint molecule and a promising target for HCC treatment. Herein, we developed a novel pH-triggered drug-eluting nanoparticle (CC@SR&SF@PP) for simultaneously delivery of Tim-3 siRNA and sorafenib to HCC in situ. By a single emulsification method, a representative HCC targeted-therapeutic drug sorafenib (SF) was encapsulated into the pH-triggered positive-charged mPEG5K-PAE10K (PP) nanoparticles, followed by condensing of negative-charged Tim-3 siRNA. Then, carboxymethyl chitosan (CMCS), an amphoteric polysaccharide with negative charge in the physiological pH and positive charge in the acidic environment of the tumor, was eventually adsorbed onto the surface of nanoparticles. This co-delivery nanoparticle rapidly and specifically accumulated in the tumor site of the liver and enhanced the targeted, specific and multiple release of siRNA and sorafenib. Enhanced Tim-3 siRNA transfected into tumor cells can not only directly inhibit the growth of tumor cells by knock down the expression Tim-3, but also induce the immune response and enhance the recruitment of cytotoxic T cells to kill tumor cells. The following pH-triggered sorafenib release from SF@PP NPs greatly inhibited the tumor proliferation and angiogenesis, resulting in remarkable tumor growth inhibition in a mouse hepatoma 22 (H22) orthotopic tumor model. Thus, co-delivery of Tim-3 siRNA and sorafenib via this novel pH triggered drug-eluting nanoparticle enhances their anti-tumor efficacy. We expect that such combination treatment strategy will have great potential in future clinical applications.

Abstract Background Irreversible electroporation (IRE) is an emerging tissue ablation technique with widespread potential, especially for cancer treatment. Although the safety and efficacy of IRE for gastric tissue ablation have been demonstrated, there is a gap of knowledge regarding the effect of electroporation pulse (EP) on the physiology and histopathology of the stomach. This study applied EP to the stomach of healthy rats and investigated the digestive function, serum marker levels, and gastric tissue structure of EP-treated rats. Methods Ninety male rats were divided into nine groups and examined up to 28 days post-treatment. A single burst of electroporation pulse (500 V, 99 pluses, 1 Hz, 100 µs) was delivered to the stomachs of rats using a tweezer-style round electrode. Gastric emptying, small intestinal transit, and gastric secretion were measured to evaluate the digestive function. Serum marker levels were determined using ELISA. Haematoxylin–eosin, Masson trichrome, and immunofluorescence were performed for histopathological analysis. Results No significant effect on gastric emptying or secretion was found post-EP, whereas the small intestinal transit decreased at 4 h and rapidly recovered to normal on 1-day post-EP. Further, serum TNF-α and IL-1β levels temporarily changed during the acute phase but returned to baseline within 28 days. Moreover, histopathological analysis revealed that cell death occurred immediately post-EP in the ablation area, whereas the gastric wall scaffold in the ablation region remained intact post-EP. Conclusions This study demonstrates the safety and efficacy of EP on the physiology and histopathology of the stomach and lays a foundation for more comprehensive applications of this technique.

Renal fibrosis is an incurable disorder characterised by an imbalance of the extracellular matrix (ECM) favouring excess production over degradation. The identification of actionable pathways and agents that promote ECM degradation to restore ECM homeostasis may help mitigate renal fibrosis. In this study, we identified 5,2′-dibromo-2,4′,5′-trihydroxydiphenylmethanone (LM49), a compound we previously synthesised, as a small-molecule inducer of ECM degradation. LM49 administration efficiently reduced ECM deposition in renal tissue of diabetic nephropathy rats and in transforming growth factor β-treated renal fibroblast cells. LM49 promoted the cytosol-to-nucleus translocation of transcription factor EB (TFEB) to increase lysosome biogenesis, leading to lysosome-based degradation of the ECM. TFEB-mediated lysosome biogenesis was induced by LM49 directly inhibiting the activity of glycogen synthase kinase 3β (GSK3β) rather than mammalian target of rapamycin complex 1. LM49 inhibited GSK3β kinase activity concentration-dependently via competing with ATP. Direct binding between LM49 and GSK3β was confirmed by the bio-layer interferometry assay, cellular thermal shift assay, and drug affinity responsive target stability. A molecular docking and molecular dynamic simulation revealed that LM49 occupied the ATP pocket of GSK3β, which was consistent with the kinase activity assay. In summary, LM49 enhances TFEB-mediated lysosome biogenesis by directly inhibiting GSK3β, leading to the degradation of the ECM by lysosomes. The enhancement of GSK3β-dependent lysosome biogenesis to rebalance the ECM may be a novel strategy to counteract renal fibrosis, and LM49 may be a viable clinical candidate for treating this disorder.

Background and objectivesThis study aimed to establish a mathematical survival model database containing cell-specific coefficients from human digestive system cells exposed to electroporation pulses (EPs).Materials and methodsA total of 20 types of human digestive system cell lines were selected to investigate the effect of EPs on cell viability. Cell viability was measured after exposure to various pulse settings, and a cell survival model was established using the Peleg–Fermi model. Next, the cell-specific coefficients of each cell line were determined.ResultsCell viability tended to decrease when exposed to stronger electric field strength (EFS), longer pulse duration, and more pulse number, but the decreasing tendency varied among different cell lines. When exposed to a lower EFS (

Abstract Background Non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB-DLBCL) has worse clinical outcome than GCB-DLBCL, and some relapsed/refractory non-GCB-DLBCL (R/R non-GCB-DLBCL) are even resistant to CD20 monoclonal antibody (rituximab). Bruton’s tyrosine kinase inhibitors (BTKis) are new drugs for B-cell lymphoma. BTKis can promote apoptosis of DLBCL by inactivating nuclear transcription factor κB (NFκB) signaling pathway. Cylindromatosis (CYLD) is a tumor suppressor and ubiquitinase. CYLD can inactivate NFκB signaling pathway through ubiquitination and regulate the apoptosis of hematological tumors. The ubiquitination of CYLD can be regulated by phosphorylation, suggesting that the regulation of CYLD phosphorylation can be a potential mechanism to promote the apoptosis of hematological tumors. Therefore, we hypothesized that BTKis could promote the apoptosis of non-GCB-DLBCL by regulating the phosphorylation of CYLD, especially in rituximab resistant cases, and we proved this hypothesis through both in vivo and in vitro experiments. Methods The baseline expression levels of CYLD phosphorylation in non-GCB-DLBCL patients and cell lines were detected by Western Blotting. The non-GCB-DLBCL cell lines were treated with BTKis, and apoptosis induced by BTKis treatment was detected by Western blotting, cell viability assay and Annexin V assay. To verify whether the effect of BTKis on apoptosis in non-GCN-DLBCL cells is CYLD dependent, the expression of CYLD was knocked down by lentiviral shRNAs. To verify the effect of BTKis on the phosphorylation of CYLD and the apoptosis in vivo and in rituximab resistant non-GCB-DLBCL, the xeograft model and rituximab resistant non-GCB-DLBCL cells were generated by tumor cell inoculation and escalation of drug concentrations, respectively. Results BTKis induced apoptosis by down-regulating CYLD phosphorylationin in non GCB-DLBCL, xenograft mouse model, and rituximab-resistant cells, and this effect could be enhanced by rituximab. Knocking-down CYLD reversed apoptosis which was induced by BTKis. BTKis induced CYLD-dependent apoptosis in non-GCB-DLBCL including in rituximab-resistant cells. Conclusions The present results indicated that CYLD phosphorylation is a potential clinical therapeutic target for non-GCB-DLBCL, especially for rituximab-resistant relapsed/refractory cases.

In this study, we used genotyping to determine the genetic structure and molecular identities of apple landraces from six species of Malus Mill. in China, based on the fingerprints revealed by microsatellite markers with tailed primer M13. A total of 46 apple landraces of Malus Mill. selected from the National Apple and Pear Germplasm Repository in Xingcheng, China were genotyped with 14 SSR markers. The primers differentiated all the accessions. At least three SSR primers, CH04h02, CH01f07a and CH04g07, with a higher heterozygosity and Shannon’s information index than other combinations can distinguish all the accessions. All the alleles for these three primers were arranged in descending order, and they were assigned values beginning with 01. Character strings were constituted by combining all the codes of the three primers for every accession. By such means, separate and special molecular identities were obtained for every apple landrace, which could be expressed in the form of a bar code. Using such bar codes, trees can be labeled and scanned, which aids in the identification and tracking of genebank collections. The eight-step method for establishing the molecular identities of apple landraces reported here may serve as a reference when determining the molecular identities establishment of other apple germplasms of Malus Mill. This method might also be used for the establishment of a molecular database to aid the preservation of Malus Mill., which is in imminent danger in China. It may also be used to improve the gene bank management of Malus Mill.

Abstract Background The role of platelets on the prognosis of patients with liver transplantation remains unclear. Thus, we aimed to evaluate the influence of preoperative platelet count on postoperative morbidity after liver transplantation. Methods Clinical data of the patients who received liver transplantation from January 2015 to September 2018 were evaluated. Results Of the 329 patients included, the average age was 46.71 ± 0.55 years, and 243 were men (75.2%). The incidence of posttransplant portal vein complication was significantly higher in the high platelet count group (> 49.5 × 109/L; n = 167) than in the low platelet count group (≤ 49.5 × 109/L, n = 162, 12.6% vs. 1.9%). After multivariable regression analysis, high platelet count was independently associated with postoperative portal vein complication (odds ratio [OR]: 8.821, 95% confidence interval [CI]: 2.260 to 34.437). After the inverse probability of treatment weighting analysis, patients in the high platelet count group had significantly higher risk of portal vein complication (OR: 9.210, 95%CI: 1.907 to 44.498, p = 0.006) and early allograft dysfunction (OR: 2.087, 95%CI: 1.131 to 3.853, p = 0.019). Conclusions Preoperative platelet count > 49.5 × 109/L was an independent risk factor for posttransplant portal vein complication and early allograft dysfunction. High preoperative platelet count could be an adverse prognostic predictor for liver transplantation recipients.

Abstract Objective To provide guidelines for surgery and reduce the incidence of fracture, this study analyzed the relationship between femoral fracture and related factors in direct anterior approach (DAA) total hip arthroplasty (THA) in the lateral decubitus position. Method A retrospective series of 273 consecutive patients who underwent THA with the DAA in the lateral decubitus position was analyzed. Each surgery was performed by the same surgeon with a conventional operation bed and femoral stem. The correlations between the incidence of fracture and sex, age, body mass index (BMI), height, osteoporosis, the anterior superior iliac spine-greater trochanter distance (ASIS-GTD), and hip joint disease were analyzed by univariate analysis and logistic regression analysis. Results Among all hip arthroplasty procedures, 35 hips had femoral fractures, including 30 greater trochanter fractures, 4 proximal femoral splits, and 1 femoral perforation. The incidence of fracture was 12.82%. Univariate analysis showed no significant difference in the incidence of fracture by sex, BMI, or age. However, osteoporosis caused an increase in the incidence of fracture, while the incidence of fracture decreased as height and the ASIS-GTD increased. The incidence of femoral neck fracture was lower in cases of osteonecrosis of the femoral head than in cases of other diseases. Logistic regression showed a significant correlation between osteoporosis, the ASIS-GTD, and fractures. Patients with osteoporosis had a high possibility of fracture (OR = 2.414); the possibility of fracture decreased with increasing ASIS-GTD (OR = 0.938). Conclusion Lateral decubitus DAA THA can be successfully performed using a conventional operation bed and stem, effectively saving medical resources. Osteoporosis and a shorter ASIS-GTD were independent risk factors for femoral fracture.

The Qaidam Basin is a large transpressional Mesozoic to Cenozoic basin in the Tibet Plateau, West China. Since the Indosinian Movement, it has been in the subsidence stage and more than 3 trillion cubic meters of natural gas accumulated at the same time. The palaeoclimate evolution during the Pliocene Shizigou stage not only controlled sequence stratigraphy development and evolution, but also worked as a key restraining factor for the largest biogas resource in the world. A case study was made in the well Qijia 1, which is the longest cored well in the Qaidam Basin. The palaeoclimate evolution during the Shizigou stage was reconstructed by using geochemistry methods, including the contents of chloride ion, trace elements and TOC, combined with core data, well logging, paleontology data and sequence stratigraphy. The contents of Sr/Ba and Sr/Ca have a positive correlation with chloride ion, which means that the values of Sr/Ba and Sr/Ca are high in an arid environment. But the contents of Rb/Sr and TOC have a negative correlation with chloride ion, which means that the values of Rb/Sr and TOC are low in an arid environment. The palaeoclimate during the Shizigou stage came through an arid-humid-arid evolution and the water body is brackish water. Based on sequence stratigraphy, five sub-palaeoclimate cycles were recognized for the first time. The palaeoclimate evolution and sequence evolution have the same cyclicity, which shows the controlling function of palaeoclimate.

High grade-gliomas are highly invasive and prone to metastasis, leading to poor survival and prognosis. Currently, we urgently need a new treatment strategy to effectively inhibit glioma. In this study, artemether and paclitaxel were used as two agents for tumour suppression. Two functional materials were synthesised and modified on the surface of the micelle as targeting molecules. The addition of two functional materials confers the ability of the micelles to effectively cross the blood-brain barrier (BBB) and then target the glioma cells. Thus, this dual-targeted delivery system allows the drug to play a better role in inhibiting tumour invasion and vasculogenic mimicry (VM) channels. In this paper, the anticancer effects of dual-targeted artemether plus paclitaxel micelles on glioma U87 cells were studied in three aspects: (I) In vitro and in vivo targeting assessment, including the role of penetrating BBB and targeting glioma; (II) In vitro regulation of invasion-associated proteins; (III) Inhibition of VM channels formation and invasion in vitro; (IV) The study of pharmacodynamics in tumour-bearing mice. These results suggest that dual-targeted artemether plus paclitaxel micelle may provide a new strategy to treat glioma via inhibiting invasive and VM channels.

A holonic multi-agent system combines the concept of a holon with a multi-agent system; this combination has been proven to be an effective way to build a complex system. Great progress has been made in this area, but previous studies are fragmented and lack of a task-based perspective to model different systems in the real world. Therefore, this article proposes a formalistic model for HMAS from a task-based perspective. Not only the static organizational structure is designed, but also the dynamic running mechanism, including the self-adaptive mechanism and the task assignment mechanism based on the proposed holonic structure, are also discussed. Finally, a case study is provided to verify the self-adaptive mechanism. The experimental results show that our proposed DHMAS has the ability to adapt to the changing environment, and performs better in terms of the success rate and the response time when the system is heavily loaded.

BackgroundCirculating tumor DNA (ctDNA) sequence analysis shows great potential in the management of non-small cell lung cancer (NSCLC) and the prediction of drug sensitivity or resistance in many cancers. Here, we drew and compared the somatic mutational profile using ctDNA and tumor tissue sequence analysis in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), and assess its potential clinical value.MethodsIn this study, 221 tumor tissues and 174 plasma samples from NSCLC patients were analyzed by hybridization capture-based next-generation sequencing (NGS) panel including 95 cancer-associated genes. Tumor response assessments were applied to 137 patients with advanced-stage (III and IV) NSCLC who first received targeted agents.ResultsTwenty significantly mutated genes were identified such as TP53, EGFR, RB1, KRAS, PIK3CA, CD3EAP, CTNNB1, ERBB2, APC, BRAF, TERT, FBXW7, and HRAS. Among them, TP53 was the most frequently mutated gene and had a higher mutation probability in male (p = 0.00124) and smoking (p < 0.0001) patients. A total of 48.35% (191/395) of NSCLC patients possessed at least one actionable alteration according to the OncoKB database. Although the sensitivity of genomic profiling from ctDNA was lower than that from tumor tissue DNA, the mutational landscape of target genes from ctDNA is similar to that from tumor tissue DNA, which led to 61.22% (30/49) of mutational concordance in NSCLC. Additionally, the mutational concordance between tissue DNA and ctDNA in LUAD differs from that in LUSC, which is 63.83% versus 46.67%, indicating that NSCLC subtypes influence the specificity of mutation detection in plasma-derived ctDNA. Lastly, patients with EGFR and TP53 co-alterations showed similar responses to Gefitinib and Icotinib, and the co-occurring TP53 mutation was most likely to be a poor prognostic factor for patients receiving Gefitinib, indicating that the distributions and types of TP53 mutations may contribute to the efficacy and prognosis of molecular targeted therapy.ConclusionsAs a promising alternative for tumor genomic profiling, ctDNA analysis is more credible in LUAD than in LUSC. Genomic subtyping has strong potential in prognostication and therapeutic decision-making for NSCLC patients, which indicated the necessity for the utility of target NGS in guiding clinical management.

Di-n-butyl-di-(4-chlorobenzohydroxamato) tin(IV) (DBDCT), a new patent agent, exhibited strong antitumor activity. In some cases, its activity was close to or even higher than cisplatin, a first-line clinical metallic agent. Similar to platinum compounds, it also showed toxicity. However, the effective targets and mechanisms for specific toxicity and biological activity are still unclear. In this study, proteomic analysis revealed that 146 proteins (98 upregulated and 48 downregulated) were differentially identified by label-free LC-MS/MS after DBDCT treatment. Meanwhile, network analysis of these differential proteins suggested that protein Galectin-1 (Gal-1) could regulate the apoptosis process (15 related proteins), which played an essential role in the potential targets of DBDCT-induced hepatotoxicity. Furthermore, it was demonstrated that DBDCT might promote ROS production, activate NF-κB p65, inhibit Ras and p-ERK1/2 expressions, increase the level of Gal-1, subsequently upregulate the expressions of Bax, p53, Fas, and FasL, and downregulate the expression of Bcl-2. As a result of these modulations, caspase cascades were finally activated, which executed apoptosis in HL7702 liver cells. Correspondingly, NAC (inhibitor of ROS), PDTC (inhibitor of NF-κB), EGF (ERK1/2 activator), and OTX008 (inhibitor of Gal-1) were found to reverse and abolish the DBDCT-associated cytotoxicity partially. In conclusion, Gal-1 might be the potential target for toxicity and biological activity. Moreover, the present study will lay the groundwork for future research about di-n-butyl-di-(4-chlorobenzohydroxamato) tin structure optimization and developing it into a new potential anticancer agent.

The breeding of salt-tolerant rootstock relies heavily on the availability of salt-tolerant Malus germplasm resources. The first step in developing salt-tolerant resources is to learn their molecular and metabolic underpinnings. Hydroponic seedlings of both ZM-4 (salt-tolerant resource) and M9T337 (salt-sensitive rootstock) were treated with a solution of 75 mM salinity. ZM-4’s fresh weight increased, then decreased, and then increased again after being treated with NaCl, whereas M9T337′s fresh weight continued to decrease. The results of transcriptome and metabolome after 0 h (CK) and 24 h of NaCl treatment showed that the leaves of ZM-4 had a higher content of flavonoids (phloretinm, naringenin-7-O-glucoside, kaempferol-3-O-galactoside, epiafzelechin, etc.) and the genes (CHI, CYP, FLS, LAR, and ANR) related to the flavonoid synthesis pathway showed up-regulation, suggesting a high antioxidant capacity. In addition to the high polyphenol content (L-phenylalanine, 5-O-p-coumaroyl quinic acid) and the high related gene expression (4CLL9 and SAT), the roots of ZM-4 exhibited a high osmotic adjustment ability. Under normal growing conditions, the roots of ZM-4 contained a higher content of some amino acids (L-proline, tran-4-hydroxy-L-prolin, L-glutamine, etc.) and sugars (D−fructose 6−phosphate, D−glucose 6−phosphate, etc.), and the genes (GLT1, BAM7, INV1, etc.) related to these two pathways were highly expressed. Furthermore, some amino acids (S-(methyl) glutathione, N-methyl-trans-4-hydroxy-L-proline, etc.) and sugars (D-sucrose, maltotriose, etc.) increased and genes (ALD1, BCAT1, AMY1.1, etc.) related to the pathways showed up-regulation under salt stress. This research provided theoretical support for the application of breeding salt-tolerant rootstocks by elucidating the molecular and metabolic mechanisms of salt tolerance during the early stages of salt treatment for ZM-4.

Apples are a major horticultural crop worldwide. Grafting techniques are widely utilized in apple production to keep the varieties pure. Interstocks are frequently used in Northern China to achieve intensive apple dwarfing cultivation. High-throughput sequencing was used to investigate differentially expressed genes in the phloem tissues of two different xenograft systems, M (‘Gala’/‘Mac 9’/Malus baccata (L.) Borkh.) and B (‘Gala’/Malus baccata (L.) Borkh.). The results showed that dwarfing interstocks could significantly reduce the height and diameters of apple trees while have few effects on the growth of annual branches. The interstocks were found to regulate the expression of genes related to hormone metabolism and tree body control (GH3.9, PIN1, CKI1, ARP1, GA2ox1 and GA20ox1), these effects may attribute the dwarf characters for apple trees with interstocks. Besides, the interstocks reduce photosynthesis-related genes (MADH-ME4 and GAPC), promote carbon (C) metabolism gene expression (AATP1, GDH and PFK3), promote the expression of nitrogen (N)-metabolism-related genes (NRT2.7, NADH and GDH) in rootstocks, and improve the expression of genes related to secondary metabolism in scions (DX5, FPS1, TPS21 and SRG1). We also concluded that the interstocks acquired early blooming traits due to promotion of the expression of flowering genes in the scion (MOF1, FTIP7, AGL12 and AGL24). This study is a valuable resource regarding the molecular mechanisms of dwarf interstocks’ influence on various biological processes and transplantation systems in both scions and rootstocks.

Understanding the different physiological responses of Malus species under salt stress in the seedling stages will be useful in breeding salt-tolerant dwarfing apple rootstocks. Seedlings of Malus Zumi (Mats.) Rehd. (M. zumi), Malus sieversii (Led.) Roem. (M. sieversii), and Malus baccata (L.) Borkh. (M. baccata) were treated with solution of 0, 0.20%, 0.40%, and 0.60% salinity. Physiological parameters of their leaves and roots were measured at 0 d, 4 d, 8 d and 12 d after salinity treatments. Superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), malondialdehyde (MDA), solution protein (SP), and proline (PRO) initially increased and then decreased. The activities and contents of these parameters were higher in the 0.40% and 0.60% NaCl treatments than in the 0.20% treatment and in the 0% control. M. zumi was the most resistant to salt stress, showing the lowest content of MDA in the leaves and roots, which increased slightly under salt stress. M. baccata had the highest increase in both the content and proportion of MDA. High enzyme activity was shown to play an important role in the salt resistance of M. zumi. Moreover, it can be speculated that there are other substances that also play a major role. We found that osmotic regulation played a key role in response to salt stress for M. baccata even though it was sensitive to salt stress. For M. sieversii, both the osmotic regulation and enzymatic antioxidants were observed to play a major role in mitigating salt stress.

‘Huahong’ is a popular apple cultivar because of its anti-browning properties and appealing aroma and flavor. It is mainly planted by grafting on dwarf interstocks in Northeast China. We investigated the different aroma profiles of apple fruits grown from six dwarf interstocks (‘CG24’, ‘SH38’, ‘SH3’, ‘MD001’, ‘Mac9’, and ‘CX5’) and from no interstocks (CK). A total of 55 VOCs were detected, including esters (25), aldehydes (14), alcohols (8), ketones (3), alkane hydroxyls (3), and acids (2). Among the VOCs, 48 were detected in the skin and 21 in the pulp. The skin of ‘Huahong’ apples had a strong sweet aroma, and the pulp was green with a subtle aroma. The dominant compounds (>5% of total content) in the skin were 2-methyl butyl acetate, hexyl 2-methyl butyrate, caproic acid butyl ester, hexanal, (Z)-2-heptene aldehyde, and 6-methyl-5-heptene-2-ketone, while in the pulp, they were 2-methyl butyl acetate, methanol, 2-methyl-1-butanol, hexanol, and hexane. Compared with CK, ‘SH38’, ‘MD001’, and ‘SH3’ interstocks had increased total aroma content, and ‘CX5’ and ‘CG24’ had suppressed aroma. The effects of interstocks on aroma were mainly reflected in skin. The VOC content ranged from 3297.52 to 9895.75 µg·kg−1 in skin, and from 748.62 to 1369.21 µg·kg−1 in pulp. PCA revealed that use of interstock ‘SH38’ mainly affected esters. ‘MD001’ affected hexane and 4-pentene-1-acetate; ‘Mac9’ and ‘SH3’ affected octanoic acid-2-methyl butyl ester, hexyl butyrate, and 2-methyl-1-butanol; and ‘CX5’ and ‘CG24’ had a greater impact on isoamyl propionate and 1-pentene-3-ol. Finally, ‘SH38’ had the highest principal comprehensive score. ‘SH38’ and ‘SH3’ interstocks resulted in significantly increased apple VOC content.

Abstract Background The drug-resistance and relapse of diffuse large B-cell lymphoma (DLBCL), which are related to mesenchymal stem cells (MSCs), have become increasingly common. However, the underlying mechanisms remain elusive. Methods CCK 8 assay, colony formation assay, and xenograft mouse model were used to investigate the effects of hBMSCs on DLBCL growth. Immunohistochemistry, qRT-PCR, and ELISA were used to study the expressions of IL-6 and IL-17A. Flow cytometry was used to analyze Th17 cells and Treg cells expressions. Western blot analysis, microarray analysis, and bioinformatics analysis were used to analyze the pathways of IL-6 or IL-17A mediated DLBCL growth. Results HBMSCs promoted DLBCL growth by secreting IL-6 in vitro and in vivo and simultaneously upregulating IL-17A in vitro. IL-6 and IL-17A synergistically promoted the growth and drug-resistance of DLBCL cells by protecting them from spontaneous or drug-induced apoptosis in vitro. IL-6 or IL-17A activated the JAK2/STAT3 pathway or upregulated cyclin D2 via activation of PI3K/Akt signaling in vitro, respectively. Conclusions The present results indicated that hBMSCs might have a “dual effect” on promoting DLBCL progression and drug-resistance by secreting IL-6 and upregulating IL-17A. IL-6, IL-17A, p-STAT3, p-Akt or cyclin D2 may be potential molecular targets for overcoming drug-resistance in patients with relapsed or refractory DLBCL.