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Abstract Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMBR630H) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMBR630H knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMBR630H knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.

Abstract This study aimed to evaluate the association between low-density lipoprotein cholesterol (LDL-C) and serum uric acid to serum creatinine (SUA/SCr) ratio in male gout patients at different BMIs. This real-world study included 956 male gout patients aged 18–83 years. We retrospectively analyzed the medical records of Chinese male gout patients from 2017 to 2019. The correlation between LDL-C and SUA/SCr was tested after adjusting for confounding factors. We found a nonlinear relationship between LDL-C and SUA/SCr in the whole study population. Stratification analysis showed that there was actually a nonlinear relationship between LDL-C and SUA/SCr in men with a BMI of 24–28, the inflection point of LDL-C was 1.8 mmol/L, when LDL-C was greater than 1.8 mmol/L, there was a positive correlation between LDL-C levels and SUA/SCr (β = 0.67, 95% CI 0.35–0.98, P

Background and Aims. The aim of this study was to investigate the association between serum phosphate levels and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods and Results. The study sample consisted of 1657 T2DM patients hospitalized between 2017 and 2019. Patients were categorized into quartiles based on their serum phosphate levels (Q1–Q4). An increasing trend in the prevalence of DR was observed across these quartiles. Subsequently, logistic regression analysis was employed to adjust for potential confounders, such as gender, age, BMI, and duration of diabetes, and to evaluate the odds ratios (ORs) associated with these quartiles. The prevalence of DR showed an increasing trend with elevated serum phosphate levels. Logistic regression further confirmed that serum phosphate levels remain an independent risk factor for DR. Conclusion. Elevated serum phosphate levels are closely associated with the prevalence of DR in hospitalized T2DM patients. Further studies are needed to establish causality. This trial is registered with chiCTR2000032374.

Abstract Background Exenatide is a stable analogue of glucagon-like peptide 1 that can reduce postprandial hyperglycemia and has been utilized as adjunctive therapy for type 1 diabetes mellitus (T1DM). The human umbilical cord is a rich source of MSCs, and human umbilical cord mesenchymal stem cells (hUCMSCs) also show potential to enhance insulin secretion. Here, we aimed to explore the effects of hUCMSCs carrying exenatide in T1DM and further identify the possible mechanisms involved. Methods hUCMSCs were isolated from human umbilical cord tissues, identified, and transduced with recombinant lentivirus carrying exenatide to obtain exenatide-carrying hUCMSCs (hUCMSCs@Ex-4). Results The results showed that hUCMSCs@Ex-4 restored the blood glucose levels and body weight of NOD mice, and repressed immune cell infiltration and islet tissue changes. Additionally, in T1DM mice, treatment with hUCMSCs@Ex-4 reduced the blood glucose levels and promoted repair of islet tissue damage. Moreover, hUCMSCs@Ex-4 attenuated renal tissue lesions in T1DM mice. Applying bioinformatic analysis, the effects of hUCMSCs@Ex-4 were suggested to correlate with decreased abundance of pro-inflammatory intestinal bacteria and increased abundance of anti-inflammatory intestinal bacteria. Conclusion Overall, the study indicated that hUCMSCs carrying exenatide might improve beneficial intestinal microflora abundance and promote islet tissue damage repair, thereby alleviating T1DM.

Abstract Tacrolimus is an independent risk factor for new‐onset diabetes after transplantation (NODAT). This study aimed to identify the mechanisms underlying tacrolimus‐induced NODAT. About 80 kidney‐transplant patients receiving tacrolimus were divided into NODAT and non‐NODAT groups after 1 year. Binary logistic regression was used to identify risk factors for NODAT. Insulin resistance indices were estimated using the homeostasis model assessment. The blood levels of 13 adipocytokines were measured 1 week after transplantation. A tacrolimus‐induced diabetes mouse model was used to reveal the underlying mechanisms. The cumulative NODAT incidence was 12.7% at 1 year (median, 6 months; range, 3–12 months). Tacrolimus trough levels ≥10 ng/mL during the first 3 months (odds ratio: 2.54, p = .012) were related to NODAT. Insulin resistance indices were higher in NODAT patients than in non‐NODAT patients at 3, 6, and 12 months. Monocyte chemoattractant protein (MCP)‐1 was overexpressed in blood in NODAT patients. In the animal experiments, postprandial blood glucose and insulin levels, insulin pathway protein levels in adipose tissue, MCP‐1 expression in blood and adipose tissue, and number of macrophages in adipose tissue were markedly higher in tacrolimus‐treated mice than in control mice, and these increases were dose‐dependent. The expression of endoplasmic reticulum (ER) stress proteins in adipose tissue was increased in a tacrolimus dose‐dependent manner. In conclusion, tacrolimus‐induced insulin resistance. Tacrolimus trough levels ≥10 ng/mL during the first 3 postoperative months were an independent risk factor for NODAT. ER stress and MCP‐1 underlie tacrolimus‐induced diabetes.

ObjectiveThis study aims to compare the levels of serum pancreatic polypeptide (PP), insulin (INS), C-peptide (C-P), and glucagon (GCG) before and after glucose stimulation in type 2 diabetes mellitus (T2DM) patients with different body mass indexes (BMI), analyze the relevant factors associated with PP secretion, and further investigate the role of PP in the development of obesity and diabetes.MethodsData were collected from 83 patients from the hospital. The subjects were divided into normal-weight group, overweight group, and obese group according to their BMI. All subjects were tested with the standard bread meal test (SBMT). PP and relevant parameters were measured, and the area under the curve (AUC) was calculated after 120 min of SBMT. AUCpp (AUC of PP) was used as the dependent variable, and the potential influencing factors were used as independent variables for multiple linear regression analysis.ResultsThe obese and overweight groups had significantly lower PP secretion than the normal-weight group (485.95 pg·h/ml, 95% CI 76.16–895.74, p = 0.021; 664.61 pg·h/ml, 95% CI 285.46–1043.77, p = 0.001) at 60 min postprandial. PP secretion in the obese and overweight groups was also significantly lower than that in the normal-weight group (520.07 pg·h/ml, 95% CI 186.58–853.56, p = 0.003; 467.62 pg·h/ml, 95% CI 159.06–776.18, p = 0.003) at 120 min postprandial. AUCpp was negatively associated with BMI (r = -0.260, p = 0.017) and positively associated with AUCGCG (r = 0.501, p< 0.001). Multiple linear regression analysis showed that there was a linear correlation between AUCGCG, BMI, and AUCpp (p< 0.001, p = 0.008). The regression equation was calculated as follows: AUCpp = 1772.255–39.65 × BMI + 0.957 × AUCGCG (R2 = 54.1%, p< 0.001).ConclusionCompared with normal-weight subjects, overweight and obese subjects had impaired PP secretion after glucose stimulation. In T2DM patients, PP secretion was mainly affected by BMI and GCG.Clinical trial registryThe Ethics Committee of the Affiliated Hospital of Qingdao University.Clinical trial registrationhttp://www.chictr.org.cn, identifier ChiCTR2100047486.

Abstract Background The purpose of this study is to compare serum pancreatic polypeptide (PP), insulin, C‐peptide, and glucagon in different glucose tolerance stages; analyze the influencing factors of PP secretion; and further explore the role of PP in the pathogenesis of diabetes mellitus. Methods Data were collected from 100 subjects from hospital. According to the results of oral glucose tolerance test (OGTT), the subjects were divided into a normal glucose tolerance (NGT) group, an impaired glucose regulation (IGR) group, and a newly diagnosed type 2 diabetes mellitus (T2DM) group. PP and the related parameters were measured, and the area under the curve (AUC) 120 min after OGTT was calculated. AUCpp (AUC of PP) was used as the dependent variable and the potentially influencing factors were used as the independent variable for multiple linear regression analysis. Results Postprandial 60 min PP in the IGR group was higher than those in the NGT group (2973.80 [±547.49] pg·h/mL vs 2663.55 [±594.89] pg·h/mL, p

BackgroundDiabetic ketosis (DK) is one of the leading causes of hospitalization among patients with diabetes. Failure to recognize DK symptoms may lead to complications, such as diabetic ketoacidosis, severe neurological morbidity, and death.PurposeThis study aimed to develop and validate a model to predict DK in patients with type 2 diabetes mellitus (T2DM) based on both clinical and biochemical characteristics.MethodsA cross-sectional study was conducted by evaluating the records of 3,126 patients with T2DM, with or without DK, at The Affiliated Hospital of Qingdao University from January 2015 to May 2022. The patients were divided randomly into the model development (70%) or validation (30%) cohorts. A risk prediction model was constructed using a stepwise logistic regression analysis to assess the risk of DK in the model development cohort. This model was then validated using a second cohort of patients.ResultsThe stepwise logistic regression analysis showed that the independent risk factors for DK in patients with T2DM were the 2-h postprandial C-peptide (2hCP) level, age, free fatty acids (FFA), and HbA1c. Based on these factors, we constructed a risk prediction model. The final risk prediction model was L= (0.472a - 0.202b - 0.078c + 0.005d – 4.299), where a = HbA1c level, b = 2hCP, c = age, and d = FFA. The area under the curve (AUC) was 0.917 (95% confidence interval [CI], 0.899–0.934; p

BackgroundSlit guidance ligand 2 (Slit-2), as a member of the Slit family, can regulate the inflammatory response and glucose metabolism. The purpose of this study was to explore the expression of Slit-2 in maternal peripheral blood and neonatal cord blood of gestational diabetes mellitus (GDM) patients and its potential importance in disease progression.MethodsThis study included 57 healthy pregnant women and 61 GDM patients. The levels of Slit-2, C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), C-peptide (C-P), galectin-3(Gal-3), HbA1c, fasting blood glucose (FBG) and fasting insulin (FINS) in maternal peripheral blood and neonatal cord blood were detected by ELISA. Spearman’s rank correlation test was used to assess the association between peripheral Slit-2 and inflammatory indicators, insulin resistance, and pregnancy outcomes. Logistic regression analysis was used to analyze the risk factors of GDM.ResultsSlit-2 levels in maternal peripheral blood and neonatal cord blood of the GDM patients were higher than those of the HC. Slit-2 levels in maternal peripheral blood and neonatal cord blood of the GDM patients were positively correlated with inflammatory factors CRP and MCP-1 levels. The level of Slit-2 in the maternal peripheral blood of the GDM patients was positively correlated with the level of homeostasis model assessment insulin resistance (HOMA-IR) and HbA1c in maternal peripheral blood, but was negatively correlated with the level of homeostasis model assessment –β (HOMA-β). We also found that the Slit-2 level in the maternal peripheral blood of the GDM patients was negatively correlated with neonatal blood glucose, positively correlated with neonatal weight and independent of neonatal total bilirubin.ConclusionOur study suggests that the abnormal increase in Slit-2 in GDM may be related to its pathogenesis, and it was correlated with neonatal blood glucose and weight in patients with GDM, suggesting that Slit-2 may be a potential biomarker of GDM.

Objective Acute gout is a painful, inflammatory arthritis that features a rapidly escalating inflammatory response resulting from the formation of monosodium urate crystals in the affected joint space. Previously, we found that Chuanhu anti-gout mixture (CAGM) had similar effects as colchicine against gout in the clinic. Subsequently, to improve its effectiveness and efficacy, we modified the original formulation of CAGM. The current study evaluated the effectiveness of the modified formulation in mice. Methods Potassium oxonate (PO) was used to establish a mouse model of hyperuricemia. Plasma levels of uric acid and creatine were determined using the respective test kits. Hepatic xanthine oxidase (XOD) expression was examined by enzyme-linked immunosorbent assay. To explore the underlying mechanism, renal urate transporter 1 (URAT1) mRNA levels were evaluated by quantitative real-time PCR. Allopurinol and benzbromarone were used as reference drugs. Results The original CAGM and its modified high-dose formulation significantly reduced serum uric acid and creatine levels in hyperuricemic mice. In addition, the CAGM-treated groups displayed lower mRNA levels of hepatic XOD and renal URAT1. Conclusions CAGM and its modified formulation significantly ameliorated PO-induced hyperuricemia in mice, which might be partially attributable to reductions of hepatic XOD and renal URAT1 levels.

ABSTRACT Objective Type 2 diabetes (T2DM) is characterized by the progressive deterioration of pancreatic islet β-cell function over time and insulin resistance. Knowing more about the differences in pancreatic islet function in T2DM patients who have had diabetes for different lengths of time can help improve therapy for T2DM. Subjects and methods We conducted a cross-sectional study to compare islet β-cell function and insulin resistance in T2DM patients (n = 3,254) who had had diabetes for different lengths of time and those in normal controls (n = 794) using ANOVA and LSD analysis. Results We found that compared with that in normal controls, HOMA-β in T2DM patients with a history of diabetes of less than 1 year was lower (approximately 52% of that of normal controls, p = 0.003), while HOMA-IR in these patients was higher (approximately 50% of that of normal controls, p = 0.007). Compared with that in other diabetic patients, HOMA-β in patients with a history of diabetes of more than 30 years was the lowest. HOMA-IR in patients with a history of diabetes of between 20 and 30 years was lower than that in other diabetic patients (p < 0.05). Conclusions There were obvious decreases in HOMA-β and increases in HOMA-IR in T2DM patients with a history of diabetes of less than 1 year compared with those in normal controls. Therefore, early screening and intervention for T2DM might help improve islet function and delay the progression of diabetes.

Although several epidemiological studies assessed the relationship between fasting plasma glucose (FPG) and serum uric acid (SUA) levels, the results were inconsistent. A cross-sectional study was conducted to investigate this relationship in Chinese individuals with normal glucose tolerance.A total of 5,726 women and 5,457 men with normal glucose tolerance were enrolled in the study. All subjects underwent a 75-g oral glucose tolerance test. Generalized additive models and two-piecewise linear regression models were applied to assess the relationship.A U-shaped relationship between FPG and SUA was observed. After adjusting for potential confounders, the inflection points of FPG levels in the curves were 4.6 mmol/L in women and 4.7 mmol/L in men respectively. SUA levels decreased with increasing fasting plasma glucose concentrations before the inflection points (regression coefficient [β] = -36.4, P < 0.001 for women; β = -33.5, P < 0.001 for men), then SUA levels increased (β = 17.8, P < 0.001 for women; β = 13.9, P < 0.001 for men). Additionally, serum insulin levels were positively associated with FPG and SUA (P < 0.05).A U-shaped relationship between FPG and SUA levels existed in Chinese individuals with normal glucose tolerance. The association is partly mediated through serum insulin levels.

Epstein-Barr virus (EBV) is an important DNA virus which establishes latent infection in human malignancies. Expression of EBV-encoded genes in the associated tumors is strongly modulated by promoter CpG methylation of EBV genome. This study aimed to explore the methylation status of the promoters of EBV BamHI-A rightward frame 1 (BARF1) and BamHI-H rightward open reading frame 1 (BHRF1) and their influence on transcriptional expression, to further understand the roles of BARF1 and BHRF1 in the occurrence of EBV-associated cancer. We evaluated the methylation status of BARF1 and BHRF1 promoters in 43 EBV-associated gastric carcinoma (EBVaGC) tissues and EBV-positive cell lines. Their expressions were evaluated by real-time quantitative PCR. We found that the promoters of BARF1 and BHRF1 were methylated by varying degrees in different EBV-positive cell lines and were almost hypermethylated in all EBVaGC tissues. The methylation status of BARF1 and BHRF1 promoters were significantly reduced by 5-Aza-CdR along with the increasing gene expressions. Hypermethylation of Ap and Hp mediates the frequent silencing of BARF1 and BHRF1 in EBV-associated tumors, which could be reactivated by a demethylation agent, suggesting that promoter demethylation and activation is important for BARF1 and BHRF1 transcription and their further action.

In order to elucidate the effect of cooling rate on the carbide formation during the solidification process of high manganese steel Mn13, the solidification process is artificially divided into two stages, namely the liquid-solid phase transition stage and solid-state cooling stage. The final Mn13 samples with different cooling rates are used to the analysis of solidification structure and carbides by high-temperature confocal microscopy (HTCLSM), optical microscopy (OM), electron backscatter diffraction (EBSD), and scanning electron microscopy (SEM). The result shows that the change of cooling rate at the liquid-solid phase transition stage has a great influence on the solidification structure and carbide precipitation. At this stage, with the increase of cooling rate from 0.2 °C/s to 5.0 °C/s, the dendrite structure is obviously refined, and the secondary dendrite arm spacing and cooling rate are satisfied with the relationship: λΠ=54.14×v−0.33. Also, the average grain size in the Mn13 sample decreases from 549 μm to 346 μm, and the aspect ratio of gains in the Mn13 sample increases from 1.7 to 2.0. Moreover, the distribution of carbide in the interdendritic regions and grain boundaries increases, and the morphology of carbide at the grain boundary change from block to dendrite. But it seems that the change of cooling rate from 1 °C/s to 5.0 °C/s at the solid-state cooling stage has a slight effect on the secondary dendrite arm spacing, the average size and aspect ratio of the grain structure and the amount and morphology of carbide precipitation at the grain boundary.

Abstract Background Conflicting results comparing bivalirudin versus heparin anticoagulation in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), in part due to the confounding effect of glycoprotein IIb/IIIa inhibitors (GPI). The aim of the study was to compare the safety and effectiveness of bivalirudin plus a post-PCI high-dose infusion vs heparin with or without bail-out GPI use. Methods We conducted a pre-specified subgroup analysis from the BRIGHT-4 trial that randomized 6016 STEMI patients who underwent primary PCI to receive either bivalirudin plus a post-PCI high-dose infusion for 2–4 h or heparin monotherapy. GPI use was only reserved as bail-out therapy for procedural thrombotic complications. The primary outcome was a composite of all-cause death or Bleeding Academic Research Consortium (BARC) types 3–5 bleeding at 30 days. Results A total of 5250 (87.4%) patients received treatment without GPI while 758 (12.6%) received bail-out GPI. Bail-out GPI use was associated with an increased risk of the primary outcome compared to non-GPI use (5.28% vs. 3.41%; adjusted hazard ratio (aHR), 1.62; 95% confidence interval (CI), 1.13–2.33; P = 0.009) and all-cause death (5.01% vs. 3.12%; aHR, 1.74; 95% CI, 1.20–2.52; P = 0.004) but not in the risk of BARC types 3–5 bleeding (0.53% vs. 0.48%; aHR, 0.90; 95% CI, 0.31–2.66; P = 0.85). Among patients without GPI use, bivalirudin was associated with lower rates of the primary outcome (2.63% vs. 4.21%; aHR, 0.55; 95% CI, 0.39–0.77; P = 0.0005), all-cause death (2.52% vs. 3.74%; aHR, 0.58; 95% CI, 0.41–0.83; P = 0.003), and BARC types 3–5 bleeding (0.15% vs. 0.81%; aHR, 0.19; 95% CI, 0.06–0.57; P = 0.003) compared with heparin. However, among patients requiring bail-out GPI, there were no significant differences observed in the rates of the primary outcome (5.76% vs. 4.87%; aHR, 0.77; 95% CI, 0.36–1.66; P = 0.50; P interaction = 0.07) or its individual components between bivalirudin and heparin groups. Conclusions Bivalirudin plus a post-PCI high-dose infusion was associated with significantly reduced 30-day composite rate of all-cause death or BARC types 3–5 bleeding compared with heparin monotherapy in STEMI patients undergoing primary PCI without GPI use. However, these benefits might be less pronounced in patients requiring bail-out GPI due to thrombotic complications during primary PCI. Trial registration ClinicalTrials.gov NCT03822975.

Abstract A lightweight fruit detection algorithm is important to ensure real‐time detection on low‐power computing devices while maintaining detection accuracy. In addition, the fruit detection algorithm is also faced with some environmental factors. To solve these challenges, lightweight detection algorithms termed YOLO‐Lite, YOLO‐Liter and YOLO‐Litest were developed based on the YOLOv5 framework. The compared mean average precision (mAP) detection revealed that YOLO‐Lite at 0.86 is 2%, 4%, 5%, 7%, and 16% more than YOLO‐Liter and YOLOv5n at 0.84 each, YOLOv4‐tiny at 0.82, YOLO‐Liter at 0.81, YOLO‐MobileNet at 0.79, and YOLO‐ShuffleNet at 0.70, respectively, but not for YOLOv8n at 0.87. On the Computer platform, except for YOLOv4‐tiny at 178.6 frames per second (FPS), the speed of YOLO‐Litest at 158.7 FPS is faster than YOLO‐Liter at 129.9 FPS, YOLO‐Lite at 120.5 FPS, YOLO‐ShuffleNet at 119.0 FPS, YOLOv8n at 116 FPS, YOLOv5n at 111.1 FPS, and YOLO‐MobileNet at 89.3 FPS. Using Jetson Nano, the 32.3 FPS of YOLO‐Litest is faster than other algorithms, but not YOLOv4‐tiny's 34.1 FPS. On the Raspberry Pi 4B, YOLO‐Litest with 4.69 FPS, outperformed other algorithms. The choices for an accurate and faster detection algorithm are YOLO‐Lite and YOLO‐Litest respectively, while YOLO‐Liter maintains a balance between them.

Tight sandstone water-bearing gas reservoirs typically exhibit low porosity and low permeability, with reservoir rocks characterized by complex pore structures, often featuring micron-scale or smaller pore throats. This intricate reservoir structure significantly restricts fluid flow within the reservoir, necessitating a certain threshold pressure gradient (TPG) to be overcome before flow can commence. This study focuses on the Ordos Basin and explores the influence of high water content tight sandstone gas reservoirs on TPG under different water saturation and formation pressure conditions through experiments. A mathematical model of TPG is established using multiple linear regression method. The results show that TPG is primarily affected by water saturation, followed by formation pressure. As the water saturation increases, the TPG of the core decreases, and the change becomes more pronounced when the water saturation exceeds 50%. As formation pressure increases, the weakening of the slippage effect in gas molecules leads to TPG stabilization, especially when local pressure exceeds 25.0 MPa. The research also shows that low-permeability cores exhibit greater TPG variation with pressure changes, while high-permeability cores remain more stable. A mathematical model was developed and validated to predict TPG based on permeability, water saturation, and formation pressure. These findings highlight the need to monitor formation water content during tight sandstone gas reservoir development to optimize production strategies, providing valuable insights for improving reservoir management and guiding future research.

Abstract Radiated tumor cell‐derived extracellular vesicles (RT‐EVs) encapsulate abundant DNA fragments from irradiated tumor cells, in addition to acting as integrators of multiple tumor antigens. Accumulating evidence indicates these DNA fragments from damaged cells are involved in downstream immune responses, but most of them are degraded in cells before incorporation into derived RT‐EVs, thus the low abundance of DNA fragments limits immune responses of RT‐EVs. Here, this study found that different radiations affected fates of DNA fragments in RT‐EVs. Boron neutron capture therapy (BNCT) induced DNA accumulation in RT‐EVs (BEVs) by causing more DNA breaks and DNA oxidation resisting nuclease degradation. This is attributed to the high‐linear energy transfer (LET) properties of alpha particles from the neutron capture reaction of 10B. When being internalized by dendritic cells (DCs), BEVs activated the DNA sensing pathway, resulting in functional enhancements including antigen presentation, migration capacity, and cytokine secretion. After vaccination of the BEVs‐educated DCs (BEV@BMDCs), the effector T cells significantly expanded and infiltrated into tumors, suggesting robust anti‐tumor immune activation. BEV@BMDCs not only effectively inhibited the primary tumor growth and metastasis formation but also elicited long‐term immune memory. In conclusion, a successful DC vaccine is provided as a promising candidate for tumor vaccine.

Abstract Background Casuarina equisetifolia (C. equisetifolia) is a woody species with many excellent features. It has natural resistance against drought, salt and saline-alkali stresses. WRKY transcription factors (TFs) play significant roles in plant response to abiotic stresses, therefore, molecular characterization of WRKY gene family under abiotic stresses holds great significance for improvement of forest trees through molecular biological tools. At present, WRKY TFs from C. equisetifolia have not been thoroughly studied with respect to their role in salt and saline-alkali stresses response. The current study was conducted to bridge the same knowledge gap. Results A total of 64 WRKYs were identified in C. equisetifolia and divided into three major groups i.e. group I, II and III, consisting of 10, 42 and 12 WRKY members, respectively. The WRKY members in group II were further divided into 5 subgroups according to their homology with Arabidopsis counterparts. WRKYs belonging to the same group exhibited higher similarities in gene structure and the presence of conserved motifs. Promoter analysis data showed the presence of various response elements, especially those related to hormone signaling and abiotic stresses, such as ABRE (ABA), TGACG (MeJA), W-box ((C/T) TGAC (T/C)) and TC-rich motif. Tissue specific expression data showed that CeqWRKYs were mainly expressed in root under normal growth conditions. Furthermore, most of the CeqWRKYs were up-regulated by NaCl and NaHCO3 stresses with few of WRKYs showing early responsiveness to both stresses while few others exhibiting late response. Although the expressions of CeqWRKYs were also induced by cold stress, the response was delayed compared with other stresses. Transgenic C. equisetifolia plants overexpressing CeqWRKY11 displayed lower electrolyte leakage, higher chlorophyll content, and enhanced tolerance to both stresses. The higher expression of abiotic stress related genes, especially CeqHKT1 and CeqPOD7, in overexpression lines points to the maintenance of optimum Na+/K+ ratio, and ROS scavenging as possible key molecular mechanisms underlying salt stress tolerance. Conclusions Our results show that CeqWRKYs might be key regulators of NaCl and NaHCO3 stresses response in C. equisetifolia. In addition, positive correlation of CeqWRKY11 expression with increased stress tolerance in C. equisetifolia encourages further research on other WRKY family members through functional genomic tools. The best candidates could be incorporated in other woody plant species for improving stress tolerance.

Abstract Background Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. Materials and methods The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and β-glycerophosphate (β-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. Results In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/β-GP-induced VSMCs. In HG/β-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/β-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. Conclusion EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

Abstract Herein, the feasibility of artificial black soil (ABS) derived from hydrothermal humification-hydrothermal carbonization (HTH-HTC) for restructuration of weak soil was verified. This study breaks through the long history of soil formation and evolution, and obtains reconstructed anthropogenic soil (AS) system which only takes one month, for the further application of rice seedlings. HTH-HTC derived by-products are slightly acidic, which facilitates the effective nutrient uptake and prevention of wilt diseases for acid-loving rice seedlings. AS mainly consists of the inherent components retained from weak soil such as SiO2 and minerals, and exogenous components such as artificial humic substances and hydrochar, as introduced by hydrothermal humification processes. Results exhibit that AS has high contents of ammonium nitrogen, organic matter, organic carbon, and abundant porous structure for nutrient transport and water holding, especially, the community diversity and richness of microbial system gets the expected recovery and new beneficial bacteria (such as Caballeronia calidae) or fungi (such as Humicola) appear. Positive effects of AS on agronomic traits in rice seedlings are quantified. As a general result, this study supports the application of AS in sustainable agriculture, and provides a novel strategy to tackle the already-omnipresent land degradation by anthropogenic misuse and larger scale accidents.

In order to address the challenges related to exploration target search and sustainable development of oilfields in the Weixinan Sag of Beibuwan Basin, this study focused on fault-lithologic composite traps within the structural trap development section of the third member of Oligocene Weizhou Formation in the No.2 fracture zone of Weixinan Sag. By examining the relationship between the evolution of depression-controlling faults and the sedimentary characteristics of the third member of Weizhou Formation, it was observed that the No.2 fault zone exhibited weak activity during the sedimentary period of the third member, facilitating the continuous transportation of underwater distributary channels of the braided river delta along the long axis direction of the sag towards the depression. Conversely, the regional tectonic activities were intense during the sedimentary periods of the second and first members of Weizhou Formation, leading to the formation of a series of en-echelon faults. The interaction between relatively isolated underwater distributary channels of the braided river delta front and en-echelon faults resulted in angled staggered formations and intersecting channels, ultimately creating a distinctive channel-type structural-lithologic trap group characterized by NE-SW trending fault sealing and NW-SE trending sand body pinching. The research findings indicate the development of a three-factor coupling fault-lithologic trap model in the third member of the Weizhou Formation. This model includes the depression faulted uplift background of the No.2 fracture zone, low-frequency oscillating channel, and en-echelon tension-torsion fault. The intersection area of the main stream line of underwater distributary channel in a braided river delta and the No.2 fracture zone is identified as a favorable zone for structural-lithologic traps. Additionally, composite structural-lithologic traps are predominantly found in the near-source intersection area, while isolated structural-lithologic traps are more common in the far-source intersection area, leading to the formation of an accumulation model involving axial channel sand control, fault, and sand body composite control. The fault-lithologic trap model and accumulation model have demonstrated effective application in practice. Several favorable fault-lithologic composite trap groups with distinct fault sealing and sand body pinching orientations have been identified, particularly in the Wei B-E structure. Notably, well WB-E 1 has successfully drilled nearly 100 meters of oil layer, with subsequent wells yielding positive results. The exploration efforts in the third member of the Weizhou Formation within the No.2 fault zone of the Weixinan Sag have led to the discovery of geological reserves exceeding 10 million cubic meters, underscoring the significance of fault-lithologic composite traps in this region.

Background Cell death modulates the biological behaviors of tumors. However, the comprehensive role of the multiple forms of cell death in lower-grade glioma (LGG) is unknown.Methods We collected the transcriptional data of LGG patients from public repositories to comprehensively examine six cell death patterns (autophagy, apoptosis, cuproptosis, necroptosis, ferroptosis, and pyroptosis) in LGG samples and systematically correlated these patterns with patient survival, underlying biological processes, and drug sensitivity using serial bioinformatics analysis, clinical sample validation and in vitro assays.Results We identified and independently validated three reproducible cell death-based clusters associated with distinct clinical outcomes and tumor microenvironment characteristics. The Tumor Immune Dysfunction and Exclusion algorithm was applied for predicting how these three clusters would respond to immune checkpoint blockade (ICB) therapy; we found potential resistance of cluster B to ICB therapy. We also performed drug screening to identify cluster-specific drugs. Furthermore, a scoring system, designated as the CDPM score, was developed to estimate the cell death patterns of patients with LGG; this system could predict both LGG patients’ prognosis and immunotherapy efficacy. By performing multiplex immunofluorescence staining, we validated the correlations of GNAL expression with the molecular and clinical features of LGG in an independent LGG cohort. Finally, in vitro assays showed that GNAL promoted apoptosis and inhibited the proliferation of LGG cells.Conclusion The new cell death-based subtype system indicates several features of LGG biology and reveals novel insights into the use of precision medicine for treating LGG. The CDPM score could be used to predict the immunotherapy response and prognosis of LGG patients; moreover, it could indicate a novel direction for improving LGG management.

Mild thermal stimulation plays an active role in bone tissue repair and regeneration. In this work, a bioactive polydopamine/Ti3C2/poly(vinylidene fluoride trifluoroethylene) (PDA/Ti3C2/P(VDF-TrFE)) nanocomposite coating with excellent near-infrared light (NIR)-triggered photothermal effect was designed to improve the osteogenic ability of implants. By incorporating dopamine (DA)-modified Ti3C2 nanosheets into the P(VDF-TrFE) matrix and combining them with alkali initiated in situ polymerization, the resulting PDA/Ti3C2/P(VDF-TrFE) nanocomposite coating gained high adhesion strength on Ti substrate, excellent tribological and corrosion resistance properties, which was quite important for clinical application of implant coatings. Cell biology experiments showed that NIR-triggered mild thermal stimulation on the coating surface promoted cell spreading and growth of BMSCs, and also greatly upregulated the osteogenic markers, including Runt-Related Transcription Factor 2 (RUNX2), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OCN). Simultaneously, the synthesis of heat shock protein 47 (HSP47) was significantly promoted by the mild thermal stimulation, which strengthened the specific interaction between HSP47 and collagen Ⅰ (COL-Ⅰ), thereby activating the integrin-mediated MEK/ERK osteogenic differentiation signaling pathway. In addition, the results also showed that the mild thermal stimulation induced the polarization of macrophages towards M2 phenotype, which can attenuate the inflammatory response of injured bone tissue. Antibacterial results indicated that the coating exhibited an outstanding antibacterial ability against S. aureus and E. coli. Conceivably, the versatile implant bioactive coatings developed in this work will show great application potential for implant osseointegration.

Osseointegration commences with foreign body inflammation upon implant placement, where macrophages play a crucial role in the immune response. Subsequently, during the intermediate and late stages of osseointegration, mesenchymal stem cells (MSCs) migrate and initiate their osteogenic functions, while macrophages support MSCs in osteogenesis. The utilization of ferroelectric P(VDF-TrFE) covered ITO planar microelectrodes facilitated the simulation of various surface charge to investigate their effects on MSCs’ osteogenic differentiation and macrophage polarization and the results indicated a parabolic increase in the promotional effect of both with the rise in piezoelectric coefficient. Furthermore, the surface charge with a piezoelectric coefficient of −18 exhibited the strongest influence on the promotion of M1 polarization of macrophages and the promotion of MSCs’ osteogenic differentiation. The impact of macrophage polarization and MSC osteogenesis following the interaction of macrophages affected by surface charge and MSC was ultimately investigated. It was observed that macrophages affected by the surface charge of −18 piezoelectric coefficient still exerted the most profound induced osteogenic effect, validating the essential role of M1-type macrophages in the osteogenic differentiation of MSCs.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017–2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

A complete technical system of gas field rolling exploration such as target search, evaluation and drilling was introduced to promote the development of the deep-water marginal gas field A in the central canyon of the Qiongdongnan Basin. In addition to the traditional target search technology of oil and gas potential in the zone, a target search technology of evaluation process was proposed for the marginal gas field A. A total of five potential oil and gas blocks were searched, and the structure A4 was selected for oil and gas target evaluation. The main controlling factors of hydrocarbon accumulation in the structure A4 were studied from two aspects: trap interpretation and implementation, and trap hydrocarbon detection. The predicted dominant gas-bearing areas in the central part of structure A4 have favorable gas-bearing information characteristics such as strong amplitude attributes, low density, low velocity, low P-wave impedance, and low P-wave and S-wave velocity ratios. They were generally classified as class Ⅲ AVO anomaly, which can upgrade the HL_0 gas group to control natural gas geological reserves. The rolling exploration well A4-1 was drilled, encountering a gas layer of over 20 m in the Huangliu Formation, and a suspicious gas layer of nearly 10 m in the second member of Yinggehai Formation. The proven geological reserves of natural gas were nearly 3 billion cubic meters, and the drilling effect was good. The application of rolling exploration research in the deep-water marginal gas field A not only effectively promotes the subsequent rolling exploration activities of the marginal gas field A, but also confirms that rolling exploration is also applicable to deep-water oil and gas exploration.

The advancement of graph neural networks (GNNs) has made it possible to accurately predict metabolic sites. Despite the combination of GNNs with XGBOOST showing impressive performance, this technology has not yet been applied in the realm of metabolic site prediction. Previous metabolic site prediction tools focused on bonds and atoms, regardless of the overall molecular skeleton. This study introduces a novel tool, named D-CyPre, that amalgamates atom, bond, and molecular skeleton information via two directed message-passing neural networks (D-MPNN) to predict the metabolic sites of the nine cytochrome P450 enzymes using XGBOOST. In D-CyPre Precision Mode, the model produces fewer, but more accurate results (Jaccard score: 0.497, F1: 0.660, and precision: 0.737 in the test set). In D-CyPre Recall Mode, the model produces less accurate, but more comprehensive results (Jaccard score: 0.506, F1: 0.669, and recall: 0.720 in the test set). In the test set of 68 reactants, D-CyPre outperformed BioTransformer on all isoenzymes and CyProduct on most isoenzymes (5/9). For the subtypes where D-CyPre outperformed CyProducts, the Jaccard score and F1 scores increased by 24% and 16% in Precision Mode (4/9) and 19% and 12% in Recall Mode (5/9), respectively, relative to the second-best CyProduct. Overall, D-CyPre provides more accurate prediction results for human CYP450 enzyme metabolic sites.

A statistical analysis is conducted on the hourly precipitation at 105 national meteorological stations in the Xinjiang region of China from 2011 to 2020. The purpose of this analysis is to determine the total quantity of precipitation during the warm and cold seasons, as well as the precipitation frequency at each station. The results of the analysis indicate that there is a more pronounced inter-annual variation in precipitation during the warm and cold seasons in Xinjiang, where the total amount of precipitation during the warm season is significantly higher than that during the cold season, with the warm season experiencing at least twice as much precipitation. In terms of the inter-annual incremental amount of precipitation, both the warm and cold seasons exhibit a trend of increasing and then decreasing over the years. However, the curvature change is more prominent in the cold season compared to the warm season, suggesting that the inter-annual variation in precipitation during the warm season remains relatively stable. The spatial distribution characteristics of the total precipitation in Xinjiang indicate that warm-season precipitation is more scattered, while cold-season precipitation is mainly concentrated in the northern region of the territory. This pattern holds true at low, medium, medium–high, and high altitudes. The cumulative precipitation during the warm season is always higher than that in the cold season, and this difference becomes more prominent with increasing altitude. This indicates that warm-season precipitation in Xinjiang is closely related to its complex topographic structure, particularly the convective weather generated by topographic clouds. On the other hand, precipitation in the cold season is mainly concentrated in the low- and medium-altitude stations, and there is not much correlation between precipitation and altitude. Precipitation is mainly affected by the mesoscale and the direct influence of large-scale weather systems. Analysis of precipitation in extreme moments reveals that during the warm season, extreme precipitation events occur mainly from the evening to early morning (19:00–03:00 the next day), accounting for 75.24% of the 105 stations. In contrast, during the cold season, extreme precipitation events occur between 03:00 and 18:00, corresponding to 74.29% of the stations. The relationship between precipitation and altitude differs in the warm and cold seasons. In the warm season, there is a linear relationship between precipitation and altitude, with a slope of 0.72 and a correlation coefficient of 0.52, indicating that precipitation increases with increasing altitude. However, in the cold season, the linear relationship between precipitation and altitude is very inconspicuous, with a slope of −0.05 and a correlation coefficient of −0.05, suggesting that there is no significant relationship between precipitation and altitude during this season. These findings provide valuable insights into the changing patterns of precipitation gradients at different altitudes and seasons in Xinjiang. This information can be used for the site selection of smokestack operations in high-altitude areas and for ground and air weather modification operations in low-altitude areas. Additionally, these data contribute to the understanding of precipitation patterns in Xinjiang, further improving the effectiveness of weather modification efforts and increasing the utilization of airborne water resources.

Abstract Platelet-rich plasma (PRP) has gained significant attention in the field of regenerative medicine due to its potential therapeutic applications. However, few studies have reported the components, especially anti-ageing-related components, of PRP derived from umbilical cord blood (UCB). It is essential to understand the influence of age on the composition and efficacy of PRP to optimize its clinical use. The present study compared the concentrations of bioactive components in PRP from healthy female adults and UCB-derived PRP. PRP was obtained from blood samples from females in four age groups (12 per group): neonates (UCB donors) and adults aged 18–25, 26–45, and 46–65 years, respectively. The concentrations of epidermal growth factor, basic fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1, platelet-derived growth factor-AA (PDGF-AA), PDGF-AB/BB, vascular endothelial growth factor A, RANTES, TIMP-1, TIMP-2, GDF11, and clusterin and activity of superoxide dismutase, catalase, and glutathione peroxidase (GPx) in the PRP samples were determined and compared among groups. Pairwise comparisons between the groups showed statistically significant differences in the concentrations of some bioactive components of PRP, such as FGF-2, PDGF-AB/BB, and clusterin, and GPx activity. UCB-derived PRP contains various active ingredients such as VEGF-A, CAT activity, and TIMP-2. Contrary to expectations, UCB-derived PRP did not show higher concentrations of the anti-ageing protein GDF11. Because UCB is a rich source of bioactive components with low immunogenicity, its use in PRP preparation is an important research direction for future studies.

Full-thickness skin wounds are have continued to be reconstructive challenges in dermal and skin appendage regeneration, and skin substitutes are promising tools for addressing these reconstructive procedures. Herein, the one-step fabrication of a cell sheet integrated with a biomimetic hydrogel as a tissue engineered skin for skin wound healing generated in one step is introduced. Briefly, cell sheets with rich extracellular matrix, high cell density, and good cell connections were integrated with biomimetic hydrogel to fabricate gel + human skin fibroblasts (HSFs) sheets and gel + human umbilical vein endothelial cells (HUVECs) sheets in one step for assembly as a cell sheet-laden hydrogel (CSH). The designed biomimetic hydrogel formed with UV crosslinking and ionic crosslinking exhibited unique properties due to the photo-generated aldehyde groups, which were suitable for integrating into the cell sheet, and ionic crosslinking reduced the adhesive force toward the substrate. These properties allowed the gel + cell sheet film to be easily released from the substrate. The cells in the harvested cell sheet maintained excellent viability, proliferation, and definite migration abilities inside the hydrogel. Moreover, the CSH was implanted into a full-thickness skin defects to construct a required dermal matrix and cell microenvironment. The wound closure rate reached 60.00 ± 6.26% on the 2nd day, accelerating mature granulation and dermis formation with skin appendages after 14 days. This project can provide distinct guidance and strategies for the complete repair and regeneration of full-thickness skin defects, and provides a material with great potential for tissue regeneration in clinical applications.

In order to explore high-quality proven geological reserves for the "Deep Sea No.1" giant gas field in the central canyon of the Qiongdongnan Basin and promote the sustainable development of the giant gas field, the rolling exploration technology is innovatively introduced into the deep-water natural gas exploration in the central canyon. The main gas-bearing strata such as the Upper Miocene Huangliu Formation and the Pliocene Yinggehai Formation on the periphery of mature exploration area of the gas field are studied. Five potential blocks are searched for rolling exploration, and Block 4 with superior reservoir forming conditions and the ability to control geological reserves is selected. The reservoir forming conditions of T29B and T29E sand bodies in the Yinggehai Formation, upper HL-Ⅰ, HL-Ⅲ and HL-Ⅳ gas groups in the Huangliu Formation are studied. By analogy with drilling data and accumulation rules of the surrounding wells, the accumulation conditions such as trap, reservoir deposition and oil and gas migration and accumulation of Block 4 are studied. The T29E sand bodies of the Huangliu Formation and the Yinggehai Formation in Block 4 are all lithologic traps formed by the joint closure of the central canyon channel bank and the weak-amplitude muddy channel in the later stage of the canyon. The T29B sand body is an anticline trap formed by the local high point of the submarine fan under the canyon background. Through the amplitude attribute sand body characterization and forward modeling, the reservoir-seal combination of the target layer of the Huangliu and Yinggehai formations in Block 4 is well implemented. The vertical migration modes such as diapirs, high-angle fractures and micro-fractures are migrated to the target layer traps, and the effectiveness of the top and bottom plates of the traps is good, thus playing a good role in preserving oil and gas. According to the accumulation factors, the resource parameters and potential resources are implemented, and the deployment of deep-water rolling exploration wells is carried out. The deep-water directional drilling technology is innovatively introduced, and the well L17-10d is deployed to implement the gas-bearing strata and reserve scale as much as possible, and good drilling results are achieved. The well L17-10d encountered a pure gas layer in the T29B, T29E sand bodies and the HL-Ⅲ gas group. The vertical thickness of the gas layer was nearly 45 m, and the proven geological reserves were nearly 7 billion cubic meters. It further confirmed the accumulation law of the deep water area of the central canyon, pointed out the direction for the rolling exploration of the surrounding area, promoted the production of proven geological reserves and controlled geological reserves of some difficult-to-produce natural gas, and provided a strong guarantee for the subsequent sustainable development of the "Deep Sea No.1" giant gas field.