Mitochondrial GCN5L1 acts as a novel regulator for iron homeostasis to promote sorafenib sensitivity in hepatocellular carcinoma.

BACKGROUND: Sorafenib resistance is becoming increasingly common and disadvantageous for hepatocellular carcinoma (HCC) treatment. Ferroptosis is an iron dependent programmed cell death underlying the mechanism of sorafenib. Iron is crucial for synthesis of cofactors essential to mitochondrial enzymes and necessary for HCC proliferation, while mitochondrial iron overload and oxidative stress are associated with sorafenib induced ferroptosis. However, the crosstalk among iron homeostasis and sorafenib resistance is unclear. METHODS: We conducted bioinformatics analysis of sorafenib treated HCC datasets to analyze GCN5L1 and iron related gene expression with sorafenib resistance. GCN5L1 deleted HCC cell lines were generated by CRISPR technology. Sorafenib resistant HCC cell line was established to validate dataset analysis and evaluate the effect of potential target. RESULTS: We identified GCN5L1, a regulator of mitochondrial acetylation, as a modulator in sorafenib-induced ferroptosis via affecting mitochondrial iron homeostasis. GCN5L1 deficiency significantly increased sorafenib sensitivity in HCC cells by down-regulating mitochondrial iron transporters CISD1 expression to induce iron accumulation. Mitochondrial iron accumulation leads to an acceleration in cellular and lipid ROS. Sorafenib resistance is related to CISD1 overexpression to release mitochondrial iron and maintaining mitochondrial homeostasis. We combined CISD1 inhibitor NL-1 with sorafenib, which significantly enhanced sorafenib-induced ferroptosis by promoting mitochondrial iron accumulation and lipid peroxidation. The combination of NL-1 with sorafenib enhanced sorafenib efficacy in vitro and in vivo. CONCLUSIONS: Our findings demonstrate that GCN5L1/CISD1 axis is crucial for sorafenib resistance and would be a potential therapeutic strategy for sorafenib resistant HCC.

[Tofacitinib inhibits the transformation of lung fibroblasts into myofibroblasts through JAK/STAT3 pathway].

OBJECTIVE: To investigate the effect of tofacitinib, a pan-Janus kinase (JAK) inhibitor, on transforming growth factor-beta 1 (TGF-ß1)-induced fibroblast to myofibroblast transition (FMT) and to explore its mechanism. To provide a theoretical basis for the clinical treatment of connective tissue disease-related interstitial lung disease (CTD-ILD). METHODS: (1) Human fetal lung fibroblast 1 (HFL-1) were cultured in vitro, and 6 groups were established: DMSO blank control group, TGF-ß1 induction group, and TGF-ß1 with different concentrations of tofacitinib (0.5, 1.0, 2.0, 5.0 µmol/L) drug intervention experimental groups. CCK-8 was used to measure the cell viability, and wound-healing assay was performed to measure cell migration ability. After 48 h of combined treatment, quantitative real-time PCR (RT-PCR) and Western blotting were used to detect the gene and protein expression levels of α-smooth muscle actin (α-SMA), fibronectin (FN), and collagen type Ⅰ (COL1). (2) RT-PCR and enzyme-linked immunosorbnent assay (ELISA) were used to detect the interleukin-6 (IL-6) gene and protein expression changes, respectively. (3) DMSO carrier controls, 1.0 µmol/L and 5.0 µmol/L tofacitinib were added to the cell culture media of different groups for pre-incubation for 30 min, and then TGF-ß1 was added to treat for 1 h, 6 h and 24 h. The phosphorylation levels of Smad2/3 and signal transducer and activator of transcription 3 (STAT3) protein were detected by Western blotting. RESULTS: (1) Tofacitinib inhibited the viability and migration ability of HFL-1 cells after TGF-ß1 induction. (2) The expression of α-SMA, COL1A1 and FN1 genes of HFL-1 in the TGF-ß1-induced groups was significantly up-regulated compared with the blank control group (P < 0.05). Compared with the TGF-ß1 induction group, α-SMA expression in the 5.0 µmol/L tofacitinib intervention group was significantly inhi-bited (P < 0.05). Compared with the TGF-ß1-induced group, FN1 gene was significantly inhibited in each intervention group at a concentration of 0.5-5.0 µmol/L (P < 0.05). Compared with the TGF-ß1-induced group, the COL1A1 gene expression in each intervention group did not change significantly. (3) Western blotting results showed that the protein levels of α-SMA and FN1 in the TGF-ß1-induced group were significantly higher than those in the control group (P < 0.05), and there was no significant difference in the expression of COL1A1. Compared with the TGF-ß1-induced group, the α-SMA protein level in the intervention groups with different concentrations decreased. And the differences between the TGF-ß1-induced group and 2.0 µmol/L or 5.0 µmol/L intervention groups were statistically significant (P < 0.05). Compared with the TGF-ß1-induced group, the FN1 protein levels in the intervention groups with different concentrations showed a downward trend, but the difference was not statistically significant. There was no difference in COL1A1 protein expression between the intervention groups compared with the TGF-ß1-induced group. (4) After TGF-ß1 acted on HFL-1 cells for 48 h, the gene expression of the IL-6 was up-regulated and IL-6 in culture supernatant was increased, the intervention with tofacitinib partly inhibited the TGF-ß1-induced IL-6 gene expression and IL-6 in culture supernatant. TGF-ß1 induced the increase of Smad2/3 protein phosphorylation in HFL-1 cells for 1 h and 6 h, STAT3 protein phosphorylation increased at 1 h, 6 h and 24 h, the pre-intervention with tofacitinib inhibited the TGF-ß1-induced Smad2/3 phosphorylation at 6 h and inhibited TGF-ß1-induced STAT3 phosphorylation at 1 h, 6 h and 24 h. CONCLUSION: Tofacitinib can inhibit the transformation of HFL-1 cells into myofibroblasts induced by TGF-ß1, and the mechanism may be through inhibiting the classic Smad2/3 pathway as well as the phosphorylation of STAT3 induced by TGF-ß1, thereby protecting the disease progression of pulmonary fibrosis.

Peptide macrocyclisation via intramolecular interception of visible-light-mediated desulfurisation.

Synthetic methods that enable the macrocyclisation of peptides facilitate the development of effective therapeutic and diagnostic tools. Herein we report a peptide cyclisation strategy based on intramolecular interception of visible-light-mediated cysteine desulfurisation. This method allows cyclisation of unprotected peptides in an aqueous solution via the installation of a hydrocarbon linkage. We explore the limits of this chemistry using a range of model peptides of increasing length and complexity, including peptides of biological/therapeutic relevance. The method is applied to replace the native disulfide of the peptide hormone, oxytocin, with a proteolytically/redox-stable hydrocarbon, and internal macrocyclisation of an MCL-1-binding peptide.

Iron alloys of volatile elements in the deep Earth's interior.

Investigations into the compositional model of the Earth, particularly the atypical concentrations of volatile elements within the silicate portion of the early Earth, have attracted significant interest due to their pivotal role in elucidating the planet's evolution and dynamics. To understand the behavior of such volatile elements, an established 'volatility trend' has been used to explain the observed depletion of certain volatile elements. However, elements such as Se and Br remain notably over-depleted in the silicate Earth. Here we show the results from first-principles simulations that explore the potential for these elements to integrate into hcp-Fe through the formation of substitutional alloys, long presumed to be predominant constituents of the Earth's core. Based on our findings, the thermodynamic stability of these alloys suggests that these volatile elements might indeed be partially sequestered within the Earth's core. We suggest potential reservoirs for volatile elements within the deep Earth, augmenting our understanding of the deep Earth's composition.

Endovascular Interventional Procedure is a Significant Risk Factor of Postsurgical Gout: A Retrospective Cohort Study.

INTRODUCTION: Surgery is a risk factor for flares in people with gout. However, gout flares after endovascular interventional procedures are not well understood. The aim of this study was to evaluate the clinical features and risk factors for gout flare that develop during the postsurgical period including endovascular procedures. METHODS: We enrolled 222 patients with gout who developed postsurgical gout and 196 controls who had histories of gout but did not develop gout flares after surgery within 20 days. Clinical characteristics of patients who developed a postsurgical gout flare were compared with the controls. RESULTS: The rate of endovascular interventional procedures was higher (38.74% vs. 13.48%, P < 0.001) in the flare group than in the no-flare group and lower in orthopedic surgery (13.96% vs. 41.84%, P < 0.001). The Cox model showed that endovascular interventional procedures (HR, hazard ratio 1.752; 95% CI, confidence interval 1.126-2.724, P = 0.013) and presurgical uric acid levels of ≥ 7 mg/dl (HR 1.489; 95% CI 1.081-2.051, P = 0.015) were significantly associated with increased risks of postsurgical gout flare, and taking colchicine before surgery were significantly associated with decreased risk of postsurgical gout flare (HR 0.264; 95% CI 0.090-0.774, P = 0.015). There was no significant difference in the types of endovascular interventional procedures between the flare group and the no-flare group. CONCLUSIONS: Patients with a history of gout should be more alert to recurrence gout flares after endovascular interventional procedures. Adequate presurgical control of serum uric acid levels and/or prophylactic treatment with colchicine will help prevent gout flares during the postsurgical period.

Dicer-like2b suppresses the wiry leaf phenotype in tomato induced by tobacco mosaic virus.

Dicer-like (DCL) proteins are principal components of RNA silencing, a major defense mechanism against plant virus infections. However, their functions in suppressing virus-induced disease phenotypes remain largely unknown. Here, we identified a role for tomato (Solanum lycopersicum) DCL2b in regulating the wiry leaf phenotype during defense against tobacco mosaic virus (TMV). Knocking out SlyDCL2b promoted TMV accumulation in the leaf primordium, resulting in a wiry phenotype in distal leaves. Biochemical and bioinformatics analyses showed that 22-nt virus-derived small interfering RNAs (vsiRNAs) accumulated less abundantly in slydcl2b mutants than in wild-type plants, suggesting that SlyDCL2b-dependent 22-nt vsiRNAs are required to exclude virus from leaf primordia. Moreover, the wiry leaf phenotype was accompanied by upregulation of Auxin Response Factors (ARFs), resulting from a reduction in trans-acting siRNAs targeting ARFs (tasiARFs) in TMV-infected slydcl2b mutants. Loss of tasiARF production in the slydcl2b mutant was in turn caused by inhibition of miRNA390b function. Importantly, silencing SlyARF3 and SlyARF4 largely restored the wiry phenotype in TMV-infected slydcl2b mutants. Our work exemplifies the complex relationship between RNA viruses and the endogenous RNA silencing machinery, whereby SlyDCL2b protects the normal development of newly emerging organs by excluding virus from these regions and thus maintaining developmental silencing.

Molecular targets and mechanisms of Guanxinning tablet in treating atherosclerosis: Network pharmacology and molecular docking analysis.

BACKGROUND: Guanxinning tablet (GXNT), a Chinese patent medicine, is composed of salvia miltiorrhiza bunge and ligusticum striatum DC, which may play the role of endothelial protection through many pathways. We aimed to explore the molecular mechanisms of GXNT against atherosclerosis (AS) through network pharmacology and molecular docking verification. METHODS: The active ingredients and their potential targets of GXNT were obtained in traditional Chinese medicine systems pharmacology database and analysis platform and bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine databases. DrugBank, TTD, DisGeNET, OMIM, and GeneCards databases were used to screen the targets of AS. The intersection targets gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis were performed in DAVID database. GXNT-AS protein-protein interaction network, ingredient-target network and herb-target-pathway network were constructed by Cytoscape. Finally, we used AutoDock for molecular docking. RESULTS: We screened 65 active ingredients of GXNT and 70 GXNT-AS intersection targets. The key targets of protein-protein interaction network were AKT1, JUN, STAT3, TNF, TP53, IL6, EGFR, MAPK14, RELA, and CASP3. The Kyoto encyclopedia of genes and genomes pathway enrichment analysis showed that pathways in cancer, lipid and atherosclerosis, and PI3K-Akt signaling pathway were the main pathways. The ingredient-target network showed that the key ingredients were luteolin, tanshinone IIA, myricanone, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone. The results of molecular docking showed that tanshinone IIA, dihydrotanshinlactone, dan-shexinkum d, 2-isopropyl-8-methylphenanthrene-3,4-dione, miltionone I, deoxyneocryptotanshinone, Isotanshinone II and 4-methylenemiltirone all had good binding interactions with AKT1, EGFR and MAPK14. CONCLUSION: The results of network pharmacology and molecular docking showed that the multiple ingredients within GXNT may confer protective effects on the vascular endothelium against AS through multitarget and multichannel mechanisms. AKT1, EGFR and MAPK14 were the core potential targets of GXNT against AS.

Hit Identification Driven by Combining Artificial Intelligence and Computational Chemistry Methods: A PI5P4K-ß Case Study.

Computer-aided drug design (CADD), especially artificial intelligence-driven drug design (AIDD), is increasingly used in drug discovery. In this paper, a novel and efficient workflow for hit identification was developed within the ID4Inno drug discovery platform, featuring innovative artificial intelligence, high-accuracy computational chemistry, and high-performance cloud computing. The workflow was validated by discovering a few potent hit compounds (best IC50 is ∼0.80 µM) against PI5P4K-ß, a novel anti-cancer target. Furthermore, by applying the tools implemented in ID4Inno, we managed to optimize these hit compounds and finally obtained five hit series with different scaffolds, all of which showed high activity against PI5P4K-ß. These results demonstrate the effectiveness of ID4inno in driving hit identification based on artificial intelligence, computational chemistry, and cloud computing.

Human UC-MSC-derived exosomes facilitate ovarian renovation in rats with chemotherapy-induced premature ovarian insufficiency.

Premature ovarian insufficiency (POI) induced by chemotherapy is an intractable disorder with a considerable incidence that commonly results in insufficient fertility and concomitant complications in female patients. Due to limitations in the current progress in POI diagnosis and treatment, there is an urgent need to develop novel remedies to improve ovarian function and protect fertility. The ameliorative effect of human umbilical cord mesenchymal stem cells (hUCMSCs) and exosomes derived from them in POI treatment could be a new hope for patients. Herein, we identified exosomes from hUCMSCs (hUCMSC-Exos). Then, systematic infusion of hUCMSC-Exos was accomplished via tail intravenous injection to investigate the feasibility of the treatment of rats with chemotherapy-induced POI by intraperitoneal injection of cyclophosphamide (CTX) and busulfan (BUS). Ovarian functions in the indicated group were evaluated, including oestrous cycle, serum sex hormone levels, follicle counts, ovarian pathological changes, proliferation and apoptosis of granulosa cells (GCs), and reproductive ability testing. Furthermore, the potential influence of hUCMSC-Exos on ovarian tissues was illuminated by conducting RNA-seq and multifaceted bioinformatics analyses. POI rats with hUCMSC-Exos transplantation exhibited a decrease in follicle-stimulating hormone (FSH) and apoptosis of GCs but an increase in oestradiol (E2), anti-Müllerian hormone (AMH), and the number of ovarian follicles and foetuses in the uterus. And the immunomodulation- and cellular vitality-associated gene sets in rats had also undergone moderate changes. Our data indicated the feasibility of hUCMSC-Exos in improving ovarian function and protecting fertility in chemotherapy-induced POI rats. HUCMSC-Exos can improve the local microenvironment of ovarian tissue in POI rats by participating in immune regulation, cellular viability, inflammation regulation, fibrosis and metabolism, and other related signal pathways.

Exogenous spraying of IAA improved the efficiency of microspore embryogenesis in Wucai (Brassica campestris L.) by affecting the balance of endogenous hormones, energy metabolism, and cell wall degradation.

BACKGROUND: Microspore embryogenesis is an extraordinarily complicated process, comprehensively regulated by a composite network of physiological and molecular factors, among which hormone is one of the most crucial factors. Auxin is required for stress-induced microspore reprogramming, however, the mechanism of its regulation of microspore embryogenesis is still unclear. RESULTS: In this study, we found exogenously spraying 100 mg·L- 1 IAA on the buds of Wucai significantly increased the rate of microspore embryogenesis, and moreover accelerated the process of embryogenesis. Physiological and biochemical tests showed that the contents of amino acids, soluble total sugar, soluble protein, and starch were significantly increased after IAA treatment. Furthermore, exogenously spraying 100 mg·L- 1 IAA significantly enhanced IAA, GA4, and GA9 content, increased catalase (CAT) and malondialdehyde (MDA) activity, and reduced abscisic acid (ABA), MDA and soluble protopectin content, H2O2 and O2·- production rate in the bud with the largest population of late-uninucleate-stage microspores. Transcriptome sequencing was performed on buds respectively treated with 100 mg·L- 1 IAA and fresh water. A total of 2004 DEGs were identified, of which 79 were involved in micropores development, embryonic development and cell wall formation and modification, most of which were upregulated. KEGG and GO analysis revealed that 9.52% of DEGs were enriched in plant hormone synthesis and signal transduction pathways, pentose and glucuronic acid exchange pathways, and oxidative phosphorylation pathways. CONCLUSIONS: These findings indicated that exogenous IAA altered the contents of endogenous hormone content, total soluble sugar, amino acid, starch, soluble protein, MDA and protopectin, the activities of CAT and peroxidase (POD), and the production rate of H2O2 and O2·-. Combined with transcriptome analysis, it was found that most genes related to gibberellin (GA) and Auxin (IAA) synthesis and signal transduction, pectin methylase (PME) and polygalacturonase (PGs) genes and genes related to ATP synthesis and electron transport chain were upregulated, and genes related to ABA synthesis and signal transduction were downregulated. These results indicated that exogenous IAA treatment could change the balance of endogenous hormones, accelerate cell wall degradation, promote ATP synthesis and nutrient accumulation, inhibit ROS accumulation, which ultimately promote microspore embryogenesis.

Vaccination of TLR7/8 Agonist-Conjugated Antigen Nanoparticles for Cancer Immunotherapy.

Nanovaccine-based immunotherapy can initiate strong immune responses and establish a long-term immune memory to prevent tumor invasion and recurrence. Herein, the assembly of redox-responsive antigen nanoparticles (NPs) conjugated with imidazoquinoline-based TLR7/8 agonists for lymph node-targeted immune activation is reported, which can potentiate tumor therapy and prevention. Antigen NPs are assembled via the templating of zeolitic imidazolate framework-8 NPs to cross-link ovalbumin with disulfide bonds, which enables the NPs with redox-responsiveness for improved antigen cross-presentation and dendritic cell activation. The formulated nanovaccines promote the lymphatic co-delivery of antigens and agonists, which can trigger immune responses of cytotoxic T lymphocytes and strong immunological memory. Notably, nanovaccines demonstrate their superiority for tumor prevention owing to the elicited robust antitumor immunity. The reported strategy provides a rational design of nanovaccines for enhanced cancer immunotherapy.

Role of ionizing radiation activated NRF2 in lung cancer radioresistance.

Radiotherapies are commonly used to target remaining tumor niches after surgery of solid tumors but are restricted due to therapeutic resistance. Several pathways of radioresistance have been reported in various cancers. This study investigates the pivotal role of Nuclear factor-erythroid 2-related factor 2 (NRF2) in the activation of DNA damage repair in lung cancer cells after x-rays exposure. To explore the NRF2 activation after ionizing irradiations, this study uses a knockdown of NRF2, which shows potential DNA damage after x-rays irradiation in lung cancers. This work further shows that NRF2 knockdown disrupts damaged DNA repair by inhibiting DNA-dependent protein kinase catalytic subunit. At the same time, NRF2 knockdown by shRNA considerably disparate homologous recombination by interfering with Rad51 expression. Further investigation of the associated pathway reveals that NRF2 activation mediates DNA damage response via the mitogen-activated protein kinase (MAPK) pathway as the knockout of NRF2 directly enhances intracellular MAPK phosphorylation. Similarly, both N-acetylcysteineand constitutive knockout of NRF2 disrupt DNA-dependent protein kinase catalytic subunit, while NRF2 knockout failed to upregulate Rad51 expression after irradiation in-vivo. Taken together, these findings advocate NRF2 plays a critical role in the development of radioresistance by upregulating DNA damage response via the MAPK pathway, which can be of great significance.

Maleimide constrained BAD BH3 domain peptides as BCL-xL Inhibitors: A versatile approach to rapidly identify sites compatible with peptide constraining.

Development of protein-protein interaction (PPI) inhibitors remains a major challenge. A significant number of PPIs are mediated by helical recognition epitopes; although peptides derived from such epitopes are attractive templates for inhibitor design, they may not readily adopt a bioactive conformation, are susceptible to proteolysis and rarely elicit optimal cell uptake properties. Constraining peptides has therefore emerged as a useful method to mitigate against these liabilities in the development of PPI inhibitors. Building on our recently reported method for constraining peptides by reaction of dibromomaleimide derivatives with two cysteines positioned in an i and i + 4 relationship, in this study, we showcase the power of the method for rapid identification of ideal constraining positions using a maleimide-staple scan based on a 19-mer sequence derived from the BAD BH3 domain. We found that the maleimide constraint had little or a detrimental impact on helicity and potency in most sequences, but successfully identified i, i + 4 positions where the maleimide constraint was tolerated. Analyses using modelling and molecular dynamics (MD) simulations revealed that the inactive constrained peptides likely lose interactions with the protein as a result of introducing the constraint.

Anthocyanins in Plant Food: Current Status, Genetic Modification, and Future Perspectives.

Anthocyanins are naturally occurring polyphenolic pigments that give food varied colors. Because of their high antioxidant activities, the consumption of anthocyanins has been associated with the benefit of preventing various chronic diseases. However, due to natural evolution or human selection, anthocyanins are found only in certain species. Additionally, the insufficient levels of anthocyanins in the most common foods also limit the optimal benefits. To solve this problem, considerable work has been done on germplasm improvement of common species using novel gene editing or transgenic techniques. This review summarized the recent advances in the molecular mechanism of anthocyanin biosynthesis and focused on the progress in using the CRISPR/Cas gene editing or multigene overexpression methods to improve plant food anthocyanins content. In response to the concerns of genome modified food, the future trends in developing anthocyanin-enriched plant food by using novel transgene or marker-free genome modified technologies are discussed. We hope to provide new insights and ideas for better using natural products like anthocyanins to promote human health.

Rational design of Harakiri (HRK)-derived constrained peptides as BCL-xL inhibitors.

Using the HRK BH3 domain, sequence hybridization and in silico methods we show dibromomaleimide staple scanning can be used to inform the design of BCL-xL selective peptidomimetic ligands. These HRK-inspired reagents may serve as starting points for the discovery of therapeutics to target BCL-xL-overexpressed cancers.

Promising Neutrophil-Associated Biomarkers in Lung Diseases of Patients with Antisynthetase Syndrome and Dermatomyositis.

Objectives: Antisynthetase syndrome (ASS) and dermatomyositis (DM) are serious autoimmune diseases, with lungs being the most frequently involved organ and sometimes fatal. This study is aimed at clarifying the role of neutrophil-associated biological markers in suggesting ASS and DM-associated respiratory infections and interstitial lung diseases. Methods: We carried out a retrospective review of the medical records of 46 cases of ASS and DM diagnosed at the Second Hospital of Zhejiang University College of Medicine, between January 2017 and December 2020. Serum myeloperoxidase (MPO), neutrophil elastase (NE), α1 anti-trypsin (AAT), and interleukin-6 (IL-6) were also detected. Results: Gottron's sign is characteristic of dermatomyositis, while polyarthritis is more characteristic of ASS. Pulmonary function is worse in ASS than in DM patients. Patients with ASS and DM had abnormal lymphocyte and neutrophil counts compared to healthy subjects, but not in relation to lung function and rapid progression of interstitial lung disease (RP-ILD). Elevated serum NE, MPO, and IL-6 levels are suggestive of respiratory infections, whereas decreased circulating IL-6 is predictive of RP-ILD. Conclusion: Our study identified the neutrophil-associated biomarkers MPO, NE, and IL-6 as promising indicators with different suggestive roles in respiratory infections and interstitial lung diseases in patients with ASS and DM.

Cadmium isotope fractionation during transport processes within agricultural soil profiles in a mining area: Implications for source tracing.

Cadmium (Cd) isotope fractionation patterns within soil profiles and the underlying mechanisms remain unclear and poorly documented. Here, Cd concentrations and isotope compositions of metal ore, surface soils and soil profile samples around a lead-zinc mine in southwest China were determined, and the relationships between soil properties and Cd isotope fractionation within the soil profiles were investigated. Cadmium concentrations of eleven surface soil samples were 0.49-66.1 mg kg-1 and the samples with high Cd concentrations had Cd isotope compositions similar to the metal ore (δ114/110Cd = 0.02‰), indicating that mining activity was the main Cd source at the study areas. Within three soil profiles with different Cd pollution levels the δ114/110Cd values gradually increased with increasing depth from 0 to 40 cm (Δ114/110Cd = 0.08-0.18‰), reaching a maximum at 30-40 cm depth, and then remained fairly constant or decreased with increasing soil depth below 40 cm. Soil δ114/110Cd values were negatively correlated with free iron and manganese oxides contents, which decreased at 0-40 cm depth then increased below 40 cm. This indicates that light Cd isotopes within 0-40 cm depth preferentially migrated downward with free iron and manganese oxides, leaving the soils at a depth of 0-40 cm enriched in heavy Cd isotopes. At 40-90 cm depth the preferential retention of heavy Cd isotopes by hydroxides may be responsible for the gradual decrease in δ114/110Cd values with increasing soil depth. These observations demonstrate that the vertical migration of Cd can induce detectable isotope fractionation within soil profiles and alter the δ114/110Cd values including those of the surface soils. Our study highlights the need to consider Cd mobilization and transport in soil profiles when tracing metal sources using isotope techniques.

Febuxostat Therapy for Patients with Gout and Stage 2-4 CKD: a Retrospective Study.

INTRODUCTION: The aim of this study is to explore the efficacy and renal safety of febuxostat in gout and stage 2-4 chronic kidney disease (CKD) and factors that correlated with target serum urate (SU). METHODS: A single-center retrospective study including male patients with gout and CKD was conducted. SU, the rate of SU < 360 µmol/L (RAT), and renal safety were analyzed in subjects who received febuxostat over 44 weeks. Factors that correlated with target SU were also explored. RESULTS: Between January 2017 and March 2021, 102 patients (stage 2 CKD: n = 27; stage 3 CKD: n = 70; stage 4 CKD: n = 5) were enrolled. The SU level reduced significantly over 44 weeks (600.76 ± 95.42 versus 405.52 ± 111.93 µmol/L; P < 0.05), and RAT increased to 39.20%. The overall estimated glomerular filtration rate (eGFR) level improved over 44 weeks (52.05 ± 11.68 versus 55.46 ± 14.49 mL/min/1.73 cm2, P < 0.05). An obvious improvement of eGFR was observed in stage 3 CKD, in patients with ≤ 1 risk factor (hypertension, diabetic mellitus, hyperlipidemia, or usage of non-steroidal anti-inflammatory drugs), and in patients with terminal SU < 360 µmol/L (P < 0.05). Logistic regression analysis indicated that baseline SU level and body weight were correlated with RAT. Further analysis revealed that patients with SU < 600 µmol/L and body weight ≤ 70 kg reached higher RAT (56.7%). CONCLUSIONS: Febuxostat demonstrated efficacy and renal safety in patients with gout and CKD in clinical practice. Achieving the target SU could obviously improve renal function. Baseline SU level and body weight could affect the achievement of target SU.

Incidence, trend and risk factors associated with suicide among patients with malignant intracranial tumors: a surveillance, epidemiology, and end results analysis.

BACKGROUND: Cancer patients are associated with an elevated risk of suicide. This study aims to investigate the suicide rates and identify risk factors for suicide among patients with malignant intracranial tumors (MITs). METHODS: Patients diagnosed with MITs during the years of 1975-2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) program. Suicide rates and standardized mortality ratios (SMR) were calculated. Cox regression analyses were used to identified risk factors for suicide among MIT patients. RESULTS: Among 115,668 patients with MITs collected from the SEER program, 99 committed suicide. The rate of suicide was 23.02 per 100,000 person-years, and SMR of suicide was 1.90. Diagnosis in recent era (years 2000-2015, SMR = 2.01), male gender (SMR = 1.78), older age (60-79 years, SMR = 3.54), white race (SMR = 1.86), married persons (SMR = 2.31), living in rural areas (SMR = 2.50), history of other malignancy (SMR = 3.81), diagnosis of glioblastoma (SMR = 4.05) and supratentorial location (SMR = 2.45) were associated with an increased incidence of suicide. In addition, the risk of suicide increased significantly within the first year after diagnosis (SMR = 13.04). Multivariate Cox regressions showed that older age, male sex, and supratentorial location were independent risk factors for suicide. CONCLUSIONS: The suicide mortality among patients with MITs steadily elevated in the past decades. Male sex, older age, and supratentorial location were significantly associated with risk of suicide, especially within the first year following diagnosis. Healthcare providers should early identify and effectively intervene with MIT patients at risk.

Hardness Prediction of Laser Powder Bed Fusion Product Based on Melt Pool Radiation Intensity.

The quality stability and batch consistency of laser powder bed fusion products are key issues that must be solved in additive manufacturing. The melt pool radiation intensity data of laser powder bed fusion contain a significant amount of forming process information, and studies have shown that the analysis of melt pool radiation intensity using data-driven methods can achieve online quality judgment; however, there are still speed and accuracy problems. In this study, we propose a data-driven model for hardness predictions of laser powder bed fusion products based on process parameters fused with power spectrum features of melt pool intensity data, which quickly and accurately predicts the microhardness of laser powder bed fusion specimens and can make constructive guidance for closed-loop feedback quality regulation in practical production. The effects of three integrated learning models, Random Forest, XGBoost and LightGBM, are also compared. The results indicate that random forest has the highest prediction accuracy in this dataset; however, it has the limitation of slow training and prediction speeds. The LightGBM algorithm has the fastest training and prediction speeds, about 1.4% and 4.4% of the random forest, respectively; however, the prediction accuracy is lower than that of random forest and XGBoost. XGBoost has the best overall comparative performance with adequate training and prediction speeds, about 23.7% and 37.9% of the random forest, respectively, while ensuring a specified prediction accuracy, which is suitable for application in engineering practices.