Association of triglyceride glucose-related parameters with all-cause mortality and cardiovascular disease in NAFLD patients: NHANES 1999-2018.

BACKGROUND: The relationship between the triglyceride-glucose (TyG) index and its derived index, the triglyceride glucose-waist height ratio (TyG-WHtR), with mortality and cardiovascular diseases (CVDs) in patients with non-alcoholic fatty liver disease (NAFLD) remains unclear. METHODS: This study enrolled 6627 adults aged 18 and above diagnosed NAFLD from the National Health and Nutrition Examination Survey (NHANES, 1999-2018). Binary weighted logistic regression analyses, cox proportional hazards model and restricted cubic spline (RCS) were used to analyze the relationship between TyG and TyG-WHtR with all-cause mortality, CVD mortality and CVDs. Mediation analysis explored the mediating role of glycohemoglobin, insulin and hypertension in the above relationships. Meanwhile, the incremental predictive value of the TyG index and TyG-WHtR was further assessed. RESULTS: Except for no significant association between the TyG index and both all-cause mortality and chronic heart failure (CHF), both TyG and TyG-WHtR exhibited significant positive correlations or trends of positive correlation with all-cause mortality, CVD mortality, total-CVD, CHF, coronary heart disease (CHD) and angina pectoris. For all-cause mortality, CVD mortality and CHF, TyG-WHtR was a better predictor than TyG (TyG-WHtR: HR 1.31, 95%CI 1.03-1.66; HR 2.22, 95%CI 1.42-3.47; OR 3.99, 95%CI 1.79-8.93). In contrast, TyG index demonstrated a stronger association with total-CVD, CHD and angina pectoris (TyG index: OR 2.00, 95%CI 1.26-3.18; OR 1.85, 95%CI 1.19-2.91; OR 2.93, 95%CI 1.23-7.00). RCS analysis showed that after adjusting for covariates, most of the aforementioned relationships were linear(P overall < 0.0001, P-nonlinear > 0.05), while the associations of the TyG index and TyG-WHtR with all-cause mortality and CHF were non-linear(P overall < 0.0001, P nonlinear < 0.05). The addition of the TyG index and TyG-WHtR to the basic model for outcomes improved the C-statistics, net reclassification improvement value, and integrated discrimination improvement value. CONCLUSIONS: The predictive value of TyG or TyG-WHtR for all-cause mortality and cardiovascular risk in NAFLD patients was significant. The TyG index and TyG-WHtR might be valid predictors of cardiovascular outcomes of patients with NAFLD.

Dissecting the Superior Drivers for the Simultaneous Improvement of Fiber Quality and Yield Under Drought Stress Via Genome-Wide Artificial Introgressions of Gossypium barbadense into Gossypium hirsutum.

Global water scarcity and extreme weather intensify drought stress, significantly reducing cotton yield and quality worldwide. Drought treatments are conducted using a population of chromosome segment substitution lines generated from E22 (G. hirsutum) and 3-79 (G. barbadense) as parental lines either show superior yields or fiber quality under both control and drought conditions. Fourteen datasets, covering 4 yields and 4 quality traits, are compiled and assessed for drought resistance using the drought resistance coefficient (DRC) and membership function value of drought resistance (MFVD). Genome-wide association studies, linkage analysis, and bulked segregant analysis are combined to analyze the DR-related QTL. A total of 121 significant QTL are identified by DRC and MFVD of the 8 traits. CRISPR/Cas9 and virus-induced gene silencing techniques verified DRR1 and DRT1 as pivotal genes in regulating drought resistant of cotton, with hap3-79 exhibiting greater drought resistance than hapE22 concerning DRR1 and DRT1. Moreover, 14 markers with superior yield and fiber quality are selected for drought treatment. This study offers valuable insights into yield and fiber quality variations between G. hirsutum and G. barbadense amid drought, providing crucial theoretical and technological backing for developing cotton varieties resilient to drought, with high yield and superior fiber quality.

Dendrobium officinale polysaccharide promotes angiogenesis as well as follicle regeneration and hair growth through activation of the WNT signaling pathway.

Introduction: Hair loss is one of the common clinical conditions in modern society. Although it is not a serious disease that threatens human life, it brings great mental stress and psychological burden to patients. This study investigated the role of dendrobium officinale polysaccharide (DOP) in hair follicle regeneration and hair growth and its related mechanisms. Methods: After in vitro culture of mouse antennal hair follicles and mouse dermal papilla cells (DPCs), and mouse vascular endothelial cells (MVECs), the effects of DOP upon hair follicles and cells were evaluated using multiple methods. DOP effects were evaluated by measuring tentacle growth, HE staining, immunofluorescence, Western blot, CCK-8, ALP staining, tube formation, scratch test, and Transwell. LDH levels, WNT signaling proteins, and therapeutic mechanisms were also analyzed. Results: DOP promoted tentacle hair follicle and DPCs growth in mice and the angiogenic, migratory and invasive capacities of MVECs. Meanwhile, DOP was also capable of enhancing angiogenesis and proliferation-related protein expression. Mechanistically, DOP activated the WNT signaling and promoted the expression level of ß-catenin, a pivotal protein of the pathway, and the pathway target proteins Cyclin D1, C-Myc, and LDH activity. The promotional effects of DOP on the biological functions of DPCs and MVECs could be effectively reversed by the WNT signaling pathway inhibitor IWR-1. Conclusion: DOP advances hair follicle and hair growth via the activation of the WNT signaling. This finding provides a mechanistic reference and theoretical basis for the clinical use of DOP in treating hair loss.

Apolipoprotein O modulates cholesterol metabolism via NRF2/CYB5R3 independent of LDL receptor.

Apolipoprotein O (APOO) plays a critical intracellular role in regulating lipid metabolism. Here, we investigated the roles of APOO in metabolism and atherogenesis in mice. Hepatic APOO expression was increased in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout (Apoo-/-) model, it was found that APOO depletion aggravated diet-induced obesity and elevated plasma cholesterol levels. Upon crossing with low-density lipoprotein receptor (LDLR) and apolipoprotein E (APOE) knockout hyperlipidemic mouse models, Apoo-/- Apoe-/- and Apoo-/- Ldlr-/- mice exhibited elevated plasma cholesterol levels, with more severe atherosclerotic lesions than littermate controls. This indicated the effects of APOO on cholesterol metabolism independent of LDLR and APOE. Moreover, APOO deficiency reduced cholesterol excretion through bile and feces while decreasing phospholipid unsaturation by inhibiting NRF2 and CYB5R3. Restoration of CYB5R3 expression in vivo by adeno-associated virus (AAV) injection reversed the reduced degree of phospholipid unsaturation while decreasing blood cholesterol levels. This represents the first in vivo experimental validation of the role of APOO in plasma cholesterol metabolism independent of LDLR and elucidates a previously unrecognized cholesterol metabolism pathway involving NRF2/CYB5R3. APOO may be a metabolic regulator of total-body cholesterol homeostasis and a target for atherosclerosis management. Apolipoprotein O (APOO) regulates plasma cholesterol levels and atherosclerosis through a pathway involving CYB5R3 that regulates biliary and fecal cholesterol excretion, independently of the LDL receptor. In addition, down-regulation of APOO may lead to impaired mitochondrial function, which in turn aggravates diet-induced obesity and fat accumulation.

EIF2Ss, a Novel c-Myc-Correlated Gene Family, is Associated with Poor Prognosis and Immune Infiltration in Pancreatic Adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor in urgent need of novel diagnostics, prognostic markers, and treatments. Eukaryotic translation initiation factor 2 subunits (EIF2Ss), comprising Eukaryotic translation initiation factor 2 subunit alpha (EIF2S1), Eukaryotic translation initiation factor 2 subunit beta (EIF2S2), and Eukaryotic translation initiation factor 2 subunit gamma (EIF2S3), is a family of eukaryotic initiation factors that participate in early protein synthesis and are crucial for tumor initiation and progression. However, the role of EIF2Ss in PAAD has yet to be reported. The aim of this study was therefore to analyze EIF2Ss in relation to the diagnosis, prognosis, and treatment of PAAD. METHODS: The cancer genome atlas (TCGA) database was used to investigate gene expression and patient survival. Gene alterations, immune cell infiltration, and immune checkpoints in PAAD were also evaluated. Univariate and multivariate analysis, nomograms, calibration curves, and Decision Curve Analysis (DCA) diagrams were used to develop and evaluate a prediction model for patient outcome. Single-cell RNA-seq (scRNA) analysis, functional enrichment, co-IP assay, mass spectrometry, and western blot were used to study the relationship between EIF2Ss and c-myc in PAAD. RESULTS: EIF2Ss are over-expressed in PAAD tissue and are associated with poor prognosis. The frequency of EIF2S1, EIF2S2, and EIF2S3 gene alteration in PAAD was 0.2%, 0.4%, and 0.2%, respectively. High EIF2Ss expression was associated with Th2 cell infiltration, whereas low expression was associated with pDC infiltration. Moreover, EIF2Ss expression was positively correlated with the expression of the NT5E, ULBP1, PVR, CD44, IL10RB, and CD276 checkpoints. A prediction model developed using EIF2Ss and important clinicopathologic features showed good predictive value for the overall survival of PAAD patients. ScRNA-Seq data showed that EIF2Ss was associated with enrichment for endothelial cells, fibroblasts, malignant cells, and ductal cells. EIF2Ss expression was also correlated with adipogenesis, interferon-alpha response, epithelial-mesenchymal transition, myc targets, G2M checkpoint, oxidative phosphorylation, and hypoxia. Functional enrichment analysis of EIF2Ss showed a close correlation with the myc pathway, and interactions between EIF2Ss and c-myc were confirmed by co-IP assay and mass spectrometry. Importantly, knockdown of c-myc decreased the expression of EIF2S1, EIF2S2, and EIF2S3 in PAAD cells. CONCLUSIONS: EIF2Ss were found to have significant clinical implications for the prognosis and treatment of PAAD. Inhibition of c-myc caused the downregulation of EIF2S1, EIF2S2, and EIF2S3 expression.

Overexpression of CuZn superoxide dismutase improves high-density lipoprotein function in swine.

Cardiovascular disease (CVD) has been the leading cause of death worldwide. As a chronic inflammatory disease, atherosclerosis (AS) acts as the initiating factor for CVD and reactive oxygen species (ROS) play a vital role in its development. Superoxide dismutases (SOD) can alleviate the detrimental effects of ROS and serve as the first line of defense through detoxifying the products derived from oxidative stress in vivo. Considering the potential preventive effects of high-density lipoprotein (HDL) on AS and the close relationship between CuZn superoxide dismutase (CuZnSOD) and HDL, the present work investigated whether CuZnSOD overexpression in swine could improve the function of HDL. Seven CuZnSOD transgenic swine, constructed by sperm and magnetic nanoparticles, demonstrated overexpressed CuZnSOD in the liver (P < 0.01) but comparable level to control in plasma (P > 0.05). CuZnSOD overexpression significantly down-regulated the levels of triglyceride (TG), apolipoprotein A-I (apoA-I) (P < 0.05), and high-density lipoprotein cholesterol (HDL-C) (P < 0.01) in plasma. In the presence of CuZnSOD overexpression, HDL3 significantly inhibited levels of IL-6 and TNF-α induced by oxidized low-density lipoprotein (oxLDL) (P < 0.05), indicating enhanced anti-inflammatory activity of HDL. At the same time, HDL-mediated cholesterol efflux did not decrease (P > 0.05). CuZnSOD overexpression improves the anti-inflammatory function of HDL despite decreased levels of HDL-C. In Conclusion, CuZnSOD overexpression improves HDL function in swine.

The discrepancy distribution of macrophage subsets in preeclampsia placenta with or without fetal growth restriction from a small cohort.

OBJECTIVES: To identify the effect of distribution characteristic of macrophages on placental function and angiogenesis in pregnancies with preeclampsia (PE) in presence of fetal growth restriction (FGR) or preeclampsia without FGR. MATERIAL AND METHODS: The study tested the hypothesis that there was association between distribution characteristic of macrophage subsets (marked by CD68, CD163, respectively) and placental capillary development, leading to placental dysfunction in PE pregnancies with FGR (n = 36). Changes in placental parameters related with efficiency and angiogenesis and macrophage phenotypes (CD68 and CD163) were evaluated by immunohistochemistry. Pearson correlation analysis was performed to analysis the association between macrophage phenotype and placental function as well the CD34 staining, respectively. Additionally, the localization of CD68 and CD163 was assessed by using immunoflurorescence staining. RESULTS: Pearson correlation analysis had shown the positive association between CD68 expression and microvessel formation and the reverse linear relationship between CD163 staining and placental sufficiency in PE + FGR placenta. The co-localization of CD163 and CD34 may pointed to the compensatory role of CD163 distribution involved in prompting neovascularization. CONCLUSIONS: The association between disturbed distribution of macrophages and placental efficiency and angiogenesis were only found in PE with FGR not in PE pregnancies without FGR, underlying the discrepancy role of macrophage subsets depending on the clinical phenotype of PE pregnancies.

KIF20B and MET, hub genes of DIAPHs, predict poor prognosis and promote pancreatic cancer progression.

BACKGROUND: The DIAPHs (DIAPH1, DIAPH2, and DIAPH3) are members of the diaphanous subfamily of the formin family. KIF20B and MET, hub genes of DIAPHs, play crucial roles in cytoskeletal remodeling, cell migration, and adhesion. However, their combined prognostic and treatment value in pancreatic adenocarcinoma (PC) warrants further investigation. METHODS: Multiomics analysis tools were used to comprehensively assess the genomic expression and prognostic value of KIF20B and MET in PC. Immune cell infiltration, functional enrichment, single-cell RNA-seq (scRNA) analysis, potential therapeutic drugs, and nomograms were established and analyzed. CCK-8 levels, transwell assay, Co-IP assay, mass spectrometry, and western blotting were performed to assess the role of KIF20B and MET as modulators of ß-catenin and Lactate Dehydrogenase A (LDHA) in vitro. Xenograft tumor models were used to evaluate the anti-tumor effects in vivo. RESULTS: DIAPHs, KIF20B, and MET were overexpressed and functioned as poor prognostic markers of PC. Immunoinfiltration analysis revealed that pDC and NK cells were enriched with low expression levels of KIF20B and MET, whereas Th2 cells were enriched with high expression levels of these two genes. The copy number variations (CNVs) in KIF20B and MET were positively correlated with B cell and CD4 + T cell infiltration. Immunological checkpoints NT5E and CD44 were positively correlated with KIF20B and MET expression. Moreover, the nomogram constructed based on KIF20B and MET demonstrated predictive value for overall survival. scRNA-Seq analysis indicated that KIF20B and MET were enriched in endothelial, malignant, B, T, and CD8 + T cells, which correlated with glycolysis and the epithelial-mesenchymal transition (EMT). The interactions of KIF20B and MET with ß-catenin and LDHA were verified by Co-IP assay and mass spectrometry. Knockdown of KIF20B and MET downregulates ß-catenin and LDHA in vitro. Furthermore, dual knockdown of KIF20B and MET exhibited a synergistic suppressive effect on PC progression in vitro and in vivo. CONCLUSION: DIAPHs, KIF20B, and MET are promising candidates for the prognosis and treatment of PC. More importantly, downregulation of KIF20B and MET inhibited pancreatic cancer progression by regulating LDHA and EMT.

Risk factors for high-stage histological chorioamnionitis among pregnancies with cervical incompetence.

AIM: The study aimed to identify predictive risk factor to identify high-stage histological chorioamnionitis (HCA) in pregnancies with cervical incompetence (CIC). METHODS: A retrospective cohort study was conducted by including 116 pregnant women with cervical incompetence that required prophylactical and therapeutical cerclage. The histopathology examination on placenta was conducted with informed patient consent. All the cases included in this study were divided based on the severity degree of HCA. The demographic characteristic and the parameters related to maternal and fetal outcome were all analyzed. Besides, perioperative parameters of cerclage, including cervical length, cervical morphology, and laboratory indexes were also compared between two groups. Univariate and multivariate logistic regression analysis were used to determine the risk factor of severe chorioamnionitis. RESULTS: Severe HCA was significantly associated with cervical morphology, cerclage indication, cerclage type, and cervical length measured via ultrasound and vaginal examination. After adjusted for confounders, V-type funneling and short cervix was indicated as independent risk factors of severe HCA by multivariate logistic regression analysis, respectively. CONCLUSIONS: V-type funneling and short cervix may indicate the elevated risk of high-stage HCA. Due to the negative outcomes related with high-stage HCA, appropriate prenatal treatment would improve the pregnancy outcomes in cerclaged population. To facilitate postpartum treatment, placental histological examination should be routinely recommended to identify the high-stage HCA, especially in high risk pregnancies.

REDH: A database of RNA editome in hematopoietic differentiation and malignancy.

BACKGROUND: The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking. METHODS: We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases. RESULTS: We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control. CONCLUSIONS: REDH is accessible at http://www.redhdatabase.com/ . This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

Research on the Adsorption Law of HFAD Agents on the Surface of Porous Media during Hydraulic Fracturing-Assisted Oil Displacement in Low-Permeability Reservoirs.

Adsorption loss of surfactants in porous media is one of the key factors affecting their application in low-permeability reservoirs. The hydraulic fracturing-assisted oil displacement (HFAD) technology can effectively reduce the adsorption loss of surfactants in porous media. However, the adsorption laws of HFAD agents (surfactants) during the HFAD process are still unclear. It was studied based on physical simulation experiments in this paper. The results showed that 0.3% SY-D as the HAFD agent achieved the best effect, which could reduce the oil-water interfacial tension to 0.0239 mN/m and increase the wettability index to 0.7492. In the high-pressure injection process of HFAD technology, the injection pressure and core permeability are positively correlated with the dynamic saturation adsorption capacity of the HFAD agent on the surface of porous media and the ambient temperature is negatively correlated with it. The higher the injection pressure and the larger the core permeability, the lower the dynamic saturation adsorption capacity of the HFAD agent on the porous media surface. In addition, since adsorption is an exothermic process, increasing the temperature has an inhibitory effect on adsorption. The higher the temperature, the slower the adsorption process of the HFAD agent on porous media. Among the three influencing factors, permeability has the greatest influence on the dynamic saturation adsorption capacity of the HFAD agent on the surface of core porous media, followed by injection pressure, and temperature has the least influence on it. Therefore, when implementing HFAD technology for the reservoir with low permeability, it can be considered to increase the injection pressure of HFAD technology to reduce the dynamic saturation adsorption capacity so as to increase the effective concentration of the agent. The research results have certain guiding significance for the application of HFAD technology in the field.

LcSAO1, an Unconventional DOXB Clade 2OGD Enzyme from Ligusticum chuanxiong Catalyzes the Biosynthesis of Plant-Derived Natural Medicine Butylphthalide.

Butylphthalide, a prescription medicine recognized for its efficacy in treating ischemic strokes approved by the State Food and Drug Administration of China in 2005, is sourced from the traditional botanical remedy Ligusticum chuanxiong. While chemical synthesis offers a viable route, limitations in the production of isomeric variants with compromised bioactivity necessitate alternative strategies. Addressing this issue, biosynthesis offers a promising solution. However, the intricate in vivo pathway for butylphthalide biosynthesis remains elusive. In this study, we examined the distribution of butylphthalide across various tissues of L. chuanxiong and found a significant accumulation in the rhizome. By searching transcriptome data from different tissues of L. chuanxiong, we identified four rhizome-specific genes annotated as 2-oxoglutarate-dependent dioxygenase (2-OGDs) that emerged as promising candidates involved in butylphthalide biosynthesis. Among them, LcSAO1 demonstrates the ability to catalyze the desaturation of senkyunolide A at the C-4 and C-5 positions, yielding the production of butylphthalide. Experimental validation through transient expression assays in Nicotiana benthamiana corroborates this transformative enzymatic activity. Notably, phylogenetic analysis of LcSAO1 revealed that it belongs to the DOXB clade, which typically encompasses genes with hydroxylation activity, rather than desaturation. Further structure modelling and site-directed mutagenesis highlighted the critical roles of three amino acid residues, T98, S176, and T178, in substrate binding and enzyme activity. By unraveling the intricacies of the senkyunolide A desaturase, the penultimate step in the butylphthalide biosynthesis cascade, our findings illuminate novel avenues for advancing synthetic biology research in the realm of medicinal natural products.

Mechanism of Low Chemical Agent Adsorption by High Pressure for Hydraulic Fracturing-Assisted Oil Displacement Technology: A Study of Molecular Dynamics Combined with Laboratory Experiments.

This study investigates the influence of physical parameters such as porosity, permeability, pore-throat radius, and specific surface area/volume on the adsorption capacity of surfactants in the pore surface of reservoirs. In the meantime, the hydraulic fracturing-assisted oil displacement (HFAD) technique can effectively improve the permeability and porosity of pores in the reservoir, which may affect the adsorption capacity of surfactants in low-permeability reservoirs. This may help to reduce the adsorption loss of surfactants in low-permeability reservoirs. Based on physical simulation methods, dynamic adsorption experiments were conducted to clarify the dynamic saturation adsorption capacity effect of high-pressure and low-pressure displacement agents by the HFAD technique. In addition, the molecular dynamics simulation method was used to study the effect of high-pressure conditions of HFAD on the adsorption capacity of surfactants on weakly lipophilic silica walls. Under the condition of high injection pressure by the HFAD technique, the fluid flow velocity and the initial kinetic energy of molecules increase, while the absolute value of the electrostatic potential energy in the system decreases. In addition, the van der Waals potential energy increases. In other words, the smaller the gravitational attraction experienced by the surfactant molecules during adsorption, the greater the repulsive force. Under the dual action of electrostatic force and van der Waals forces, the absolute values of the adsorption energy and the free energy decrease. The adsorption capacity of the surfactant molecules is weakened. Moreover, the decrease in adsorption capacity has little effect on the improvement of wettability, indicating that the adsorption of the surfactant reduced by HFAD technology is mostly ineffective adsorption.

Macrophage-specific deletion of MIC26 (APOO) mitigates advanced atherosclerosis by increasing efferocytosis.

BACKGROUND AND AIMS: Recent studies have suggested that MIC26 (apolipoprotein O, APOO), a novel mitochondrial inner membrane protein, is involved in inflammation. Thus, the role of macrophage MIC26 in acute inflammation and chronic inflammatory disease atherosclerosis was investigated. METHODS: Macrophage-specific MIC26 knockout mice (MIC26LysM) were generated by crossing Apooflox/flox and LysMcre+/- mice. An endotoxemia mouse model was generated to explore the effects of macrophage MIC26 deficiency on acute inflammation, while an atherosclerosis mouse model was constructed by crossing MIC26LysM mice with Apoe-/- mice and challenged with a Western diet. Atherosclerotic plaques, primary macrophage function, and mitochondrial structure and function were analyzed. RESULTS: MIC26 knockout did not affect the median survival time and post-injection serum interleukin 1ß concentrations in mice with endotoxemia. Mice with MIC26 deficiency in an Apoe-/- background had smaller atherosclerotic lesions and necrotic core than the control group. In vitro studies found that the loss of MIC26 did not affect macrophage polarization, apoptosis, or lipid handling capacity, but increased efferocytosis (the ability to clear apoptotic cells). An in situ efferocytosis assay of plaques also showed that the ratio of macrophage-associated apoptotic cells to free apoptotic cells was higher in the MIC26-deficient group than in the control group, indicating increased efferocytosis. In addition, an in vivo thymus efferocytosis assay indicated that MIC26 deletion promoted efferocytosis. Mechanistically, the loss of MIC26 resulted in an abnormal mitochondrial inner membrane structure, increased mitochondrial fission, and decreased mitochondrial membrane potential. Loss of MIC26 reduced mitochondria optic atrophy type 1 (OPA1) protein, and OPA1 silencing in macrophages promoted efferocytosis. Overexpression of OPA1 abolished the increase in efferocytosis produced by MIC26 deficiency. CONCLUSIONS: Macrophage MIC26 deletion alleviated advanced atherosclerosis and necrotic core expansion by promoting efferocytosis. This mechanism may be related to the increased mitochondrial fission caused by reduced mitochondrial OPA1.

Age-associated augmented renal clearance and low BMI trigger suboptimal vancomycin trough concentrations in children with haematologic diseases: data of 1453 paediatric patients from 2017 to 2022.

BACKGROUND: It is usually difficult for the trough concentration of vancomycin to reach the recommended lower limit of 10 mg/L per the label dose in the paediatric population. Moreover, children with haematologic diseases who suffer from neutropenia are more likely to have lower exposure of vancomycin, and the risk factors have been poorly explored. METHOD: We reviewed and analysed the initial trough concentration of vancomycin and synchronous cytometry and biochemical parameters in the blood of 1453 paediatric patients with haematologic diseases over a 6 year period, from 2017 to 2022. RESULTS: Forty-five percent of the enrolled children had vancomycin trough concentrations below 5 mg/L after receiving a dose of 40 mg/kg/day, and the multiple regression showed that age (OR = 0.881, 95% CI 0.855 to 0.909, P < 0.001), BMI (OR = 0.941, 95% CI 0.904 to 0.980, P = 0.003) and the glomerular filtration rate (OR = 1.006, 95% CI 1.004 to 1.008, P < 0.001) were independent risk factors. A total of 79.7% of the children experienced augmented renal clearance, which was closely correlated to age-associated levels of serum creatinine. The vancomycin trough concentration was higher in children with aplastic anaemia than in those with other haematologic diseases due to a higher BMI and a lower glomerular filtration rate. CONCLUSION: Age-associated augmented renal clearance and low BMI values contributed to suboptimal trough concentrations of vancomycin in children with haematologic diseases, and the effects of long-term use of cyclosporine and glucocorticoids need to be taken into account.

Burden of Lung Cancer in China, 1990-2019: Findings from the Global Burden of Disease Study 2019.

BACKGROUND: Lung cancer is one of the most common malignant tumors in the world. It has become an increasingly important public health problem in China. In this study, we systematically assessed the lung cancer situation in China from 1990 to 2019 and provided an epidemiological knowledge base for the revision of health policies. The relevant data were extracted from the Global Burden of Disease (GBD) database. METHODS: Based on GBD 2019 data, we evaluated the incidence, prevalence, and death rates of lung cancer in China and their change trends from 1990 to 2019, making comparisons by gender and age. RESULTS: The age-standardized incidence and death rates (ASIR and ASDR, respectively) of lung cancer in China were higher than the average levels in Asia, Africa, Europe, and Oceania and also higher than those of neighboring Asian countries. Lung cancer rose from the seventh leading cause of death in 1990 to the fourth leading one in 2019, indicating that the disease burden of lung cancer is increasing. In 2019, the incidence, prevalence, and death rates of lung cancer were all higher in men than in women across all age groups. All three indices were lower in men and women <50 years old than in men and women >50 years. From 1990 to 2019, the ASIR, age-standardized prevalence rate (ASPR), and ASDR showed trends of increase (P < .05), and the rise in the ASPR (average annual percentage change [AAPC] = 1.9) was greater than those in the ASIR (AAPC = 1) and ASDR (AAPC = .8). CONCLUSIONS: From 1990 to 2019, the incidence, prevalence, and death rates of lung cancer continued to increase in China. To reduce this burden, prevention and management of known risk factors should be promoted through national policies.

Multiomics comparison among populations of three plant sources of Amomi Fructus.

Amomi Fructus (Sharen, AF) is a traditional Chinese medicine (TCM) from three source species (or varieties), including Wurfbainia villosa var. villosa (WVV), W. villosa var. xanthioides (WVX), or W. longiligularis (WL). Among them, WVV has been transplanted from its top-geoherb region, Guangdong, to its current main production area, Yunnan, for >50 years in China. However, the genetic and transcriptomic differentiation among multiple AF source species (or varieties) and between the origin and transplanted populations of WVV is unknown. In our study, the observed overall higher expression of terpenoid biosynthesis genes in WVV than in WVX provided possible evidence for the better pharmacological effect of WVV. We also screened six candidate borneol dehydrogenases (BDHs) that potentially catalyzed borneol into camphor in WVV and functionally verified them. Highly expressed genes at the P2 stage of WVV, Wv05G1424 and Wv05G1438, were capable of catalyzing the formation of camphor from (+)-borneol, (-)-borneol and DL-isoborneol. Moreover, the BDH genes may experience independent evolution after acquiring the ancestral copies, and the following tandem duplications might account for the abundant camphor content in WVV. Furthermore, four populations of WVV, WVX, and WL are genetically differentiated, and the gene flow from WVX to WVV in Yunnan contributed to the greater genetic diversity in the introduced population (WVV-JH) than in its top-geoherb region (WVV-YC), which showed the lowest genetic diversity and might undergo genetic degradation. In addition, terpene synthesis (TPS) and BDH genes were selected among populations of multiple AF source species (or varieties) and between the top- and non-top-geoherb regions, which might explain the difference in metabolites between these populations. Our findings provide important guidance for the conservation, genetic improvement, and industrial development of the three source species (or varieties) and for identifying top-geoherbalism with molecular markers, and proper clinical application of AF.

Interlukin-4 weakens resistance to stress injury and megakaryocytic differentiation of hematopoietic stem cells by inhibiting Psmd13 expression.

Thrombocytopenia is a major and fatal complication in patients with acute myeloid leukemia (AML), which results from disrupted megakaryopoiesis by leukemic niche and blasts. Our previous research revealed that elevated interleukin-4 (IL-4) in AML bone marrow had adverse impact on multiple stages throughout megakaryopoiesis including hematopoietic stem cells (HSCs), but the specific mechanism remains unknown. In the present study, we performed single-cell transcriptome analysis and discovered activated oxidative stress pathway and apoptosis pathway in IL-4Rαhigh versus IL-4Rαlow HSCs. IL-4 stimulation in vitro led to apoptosis of HSCs and down-regulation of megakaryocyte-associated transcription factors. Functional assays displayed higher susceptibility of IL-4Rαhigh HSCs to tunicamycin and irradiation-induced apoptosis, demonstrating their vulnerability to endoplasmic reticulum (ER) stress injury. To clarify the downstream signaling of IL-4, we analyzed the transcriptomes of HSCs from AML bone marrow and found a remarkable down-regulation of the proteasome component Psmd13, whose expression was required for megakaryocytic-erythroid development but could be inhibited by IL-4 in vitro. We knocked down Psmd13 by shRNA in HSCs, and found their repopulating capacity and megakaryocytic differentiation were severely compromised, with increased apoptosis in vivo. In summary, our study uncovered a previous unrecognized regulatory role of IL-4-Psmd13 signaling in anti-stress and megakaryocytic differentiation capability of HSCs.

Computer-assisted rescue of the inferior mesenteric artery in a child with a giant ganglioneuroblastoma: A case report.

BACKGROUND: Ganglioneuroblastoma (GNB) is a peripheral neuroblastoma (NB) with malignant degree between highly malignant NB and benign ganglioma (GN). Pathology is the gold standard of diagnosis. Although GNB is not uncommon in children, biopsy alone may lead to an inaccurate diagnosis, especially for giant tumors. However, surgical resection may be associated with significant complications. Here, we report a case of computer-assisted surgical resection of a giant GNB in a child and successful rescue of the inferior mesenteric artery. CASE SUMMARY: A 4-year-old girl was admitted to our department for a giant retroperitoneal lesion, which was considered to be an NB by her local hospital. The symptoms of the girl disappeared spontaneously without treatment. On physical examination, a mass of about 10 cm × 7 cm could be palpated in her abdomen. Ultrasonography and contrast-enhanced computed tomography performed in our hospital also showed an NB, and there was a very thick blood vessel inside the tumor. However, aspiration biopsy revealed GN. Surgical resection is the best treatment option for this giant benign tumor. For precise preoperative evaluation, three-dimensional reconstruction was performed. It was clear that the tumor was close to the abdominal aorta. The superior mesenteric vein was pushed forward, and the inferior mesenteric artery passed through the tumor. Because GN generally does not invade blood vessels, we split the tumor with a CUSA knife during the operation and found that there was indeed a straight and intact vascular sheath. Arterial pulsation was observed in the completely exposed inferior mesenteric artery. The pathologists interpreting the tissue finally diagnosed it as a mixed GNB (GNBi), which is more malignant than GN. However, both GN and GNBi usually have a good prognosis. CONCLUSION: This was a case of successful surgical resection of a giant GNB, and aspiration biopsy underestimated the pathological staging of the tumor. Preoperative three-dimensional reconstruction assisted with the radical resection of the tumor and rescue of the inferior mesenteric artery.

Ruxolitinib improves hematopoietic regeneration by restoring mesenchymal stromal cell function in acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we used a haplo-MHC-matched transplantation aGVHD murine model and performed single-cell RNA-Seq of nonhematopoietic BM cells. Transcriptional analysis showed that BM mesenchymal stromal cells (BMSCs) were severely affected, with a reduction in cell ratio, abnormal metabolism, compromised differentiation potential, and defective hematopoiesis-supportive function, all of which were validated by functional assays. We found that ruxolitinib, a selective JAK1/2 inhibitor, ameliorated aGVHD-related hematopoietic dysfunction through a direct effect on recipient BMSCs, resulting in improved proliferation ability, adipogenesis/osteogenesis potential, mitochondria metabolism capacity, and crosstalk with donor-derived hematopoietic stem/progenitor cells. By inhibiting the JAK2/STAT1 pathway, ruxolitinib maintained long-term improvement of aGVHD BMSC function. Additionally, ruxolitinib pretreatment in vitro primed BMSCs to better support donor-derived hematopoiesis in vivo. These observations in the murine model were validated in patient samples. Overall, our findings suggest that ruxolitinib can directly restore BMSC function via the JAK2/STAT1 pathway and, in turn, improve the hematopoietic dysfunction caused by aGVHD.