N-glycosylation of SCAP exacerbates hepatocellular inflammation and lipid accumulation via ACSS2-mediated histone H3K27 acetylation.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a widely expressed membrane glycoprotein that acts as an important modulator of lipid metabolism and inflammatory stress. N-glycosylation of SCAP has been suggested to modulate cancer development, but its role in NASH is poorly understood. In this study, the N-glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and N-glycosylation sites mutated SCAP were constructed to investigate the N-glycosylation role of SCAP in regulating inflammation and lipid accumulation as well as the underlying mechanisms. The hepatic SCAP protein levels were significantly increased in C57BL/6J mice fed with western diet and sweet water (WD+SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation. In vitro, the enhanced N-glycosylation increased the protein stability of SCAP and hence increased its total protein levels, while the ablation of N-glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, the presence of SCAP N-glycosylation increased not only the SREBP1-mediated acetyl-CoA synthetase 2 (ACSS2) transcription but also the AMPK-mediated S659 phosphorylation of ACCS2 protein, causing the enhanced ACSS2 levels in nucleus and hence increasing the histone H3K27 acetylation (H3K27ac), which is a key epigenetic modification associated with NASH. Modulating ACSS2 expression or its location in cytoplasm abolished the effects of SCAP N-glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP N-glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes.

Two Mixed-Ligand Co(II) Complexes as Luminescent Materials and Loaded with Temozolomide-gel Particles in Nursing Against Glioma.

By employing a mixed-ligand strategy, we synthesized two new coordination polymers (CPs) featuring Co(II): {Co(H2L)(bib)]·2H2O}n (1) and {Co(L)(bib)2]·2H2O}n (2), where H4L represents 5-(3,5-dicarboxybenzyloxy) isophthalic acid, and bib denotes 1,4-bis(1-imidazolyl)benzene. These CPs were obtained through the reaction of H4L, a flexible carboxylic acid ligand, with Co(NO3)2·6H2O in various solvent mixtures, along with the N-donor co-ligand bib. Complexes 1 and 2 are formed through distinct coordination modes, resulting in their distinct structural features and excellent fluorescent properties. Based on ligand-centered fluorescence emission and the blue shift (CP 1) along with red shift (CP 2) characteristics, both complexes show promise for applications in fields such as blue fluorescence sensing materials and luminescent materials. After successfully synthesizing two CPs, CP 1 was chosen as the carrier for loading temozolomide (TMZ). Subsequently, leveraging the unique advantages of hydrogels, we developed a novel metal gel formulation loaded with TMZ. The inhibitory effect of this formulation on the growth of glioblastoma was evaluated. Our results demonstrate a significant suppression of glioblastoma cell proliferation by this system, providing an effective avenue for glioblastoma treatment.

Comparison of bio-beads combined with Pseudomonas edaphica and three phosphate materials for lead immobilization: Performance, mechanism and plant growth.

Phosphate materials (PMs) combine with phosphate solubilizing bacteria play an essential roles in lead (Pb) immobilization, but their resulting ability to reduce Pb bioavailability may vary depending on PMs used. In this study, Pseudomonas edaphica GAU-665 and three PMs: tricalcium phosphate, calcium phytate and nano-hydroxyapatite were respectively encapsulated into bio-beads by sodium alginate, which immobilization efficiency of Pb2+ were 99.11%, 97.76% and 99.02% at initial Pb2+ concentration of 200 mg L-1, respectively. The Pb2+ immobilization performance of bio-beads under different conditions and their organic acids secreted were examined. Most Pb2+ was immobilized by bio-beads through combined functions of adsorption, precipitation, ion exchange and biomineralization, accompanied by the formation of more stable compounds such as Pb3(PO4)2, Pb5(PO4)3OH and Pb5(PO4)3Cl. Meanwhile, pot experimental results indicated that the inoculation of CPhy (calcium phytate) bio-beads with PSB have highest biomass and root growth of oat (Avena sativa L.) in Pb-stressed compared with CK, which increased the content of chlorophyll b (167.51%) in shoot. In addition, the CPhy bio-beads enhance the peroxidase, catalase activities and reduce the malondialdehyde content to alleviating lead physiological toxicity in oat, which reductions the Pb accumulation in shoot (52.06%) and root (81.04%), and increased the residual fraction of Pb by 165.80% in soil. These findings suggest the bio-beads combined with P. edaphica GAU-665 and calcium phytate is an efficient Pb immobilization material and provided feasible way to improve safety agricultural production and Pb-contaminated soil remediation.

Changes in serum sodium concentration during hemodialysis is a predictor of mortality and cardio-cerebrovascular event.

BACKGROUND: Previous study consistently showed that lower serum sodium (SNa) was associated with a greater risk of mortality in hemodialysis (HD) patients. However, few studies have focused on the change in SNa (ΔSNa = post-HD SNa - pre-HD SNa) during an HD session. METHODS: In a retrospective cohort of maintenance HD adults, all-cause mortality and cardio-cerebrovascular event (CCVE) were followed up for a medium of 82 months. Baseline pre-HD SNa and ΔSNa were collected; time-averaged pre-HD SNa and ΔSNa were computed as the mean values within 1-year, 2-year and 3-year intervals after enrollment. Cox proportional hazards models were used to evaluate the relationships of pre-HD and ΔSNa with outcomes. RESULTS: Time-averaged pre-HD SNa were associated with all-cause mortality (2-year pre-HD SNa: HR [95% CI] 0.86 [0.74-0.99], p = 0.042) and CCVE (3-year pre-HD SNa: HR [95% CI] 0.83 [0.72-0.96], p = 0.012) with full adjustment. Time-averaged ΔSNa also demonstrated an association with all-cause mortality (3-year ΔSNa: HR [95% CI] 1.26 [1.03-1.55], p = 0.026) as well as with CCVE (3-year ΔSNa: HR [95% CI] 1.51 [1.21-1.88], p = <0.001) when fully adjusted. Baseline pre-HD SNa and ΔSNa didn't exhibit association with both outcomes. CONCLUSIONS: Lower time-averaged pre-HD SNa and higher time-averaged ΔSNa were associated with a greater risk of all-cause mortality and CCVE in HD patients.

The efficacy and safety of continuous intravenous tirofiban for acute ischemic stroke patients treated by endovascular therapy: a meta-analysis.

Introduction: Tirofiban is a non-peptide selective glycoprotein IIb/IIIa receptor inhibitor with a short half-life. The research assesses the efficacy and safety of continuous intravenous tirofiban in patients with acute ischemic stroke (AIS) undergoing endovascular therapy (ET). Methods: A systematic search of Pubmed, Embase, Web of Science, and Cochrane Library databases is conducted from inception until January 26, 2024. Eligible studies are included based on predefined selection criteria. Efficacy outcomes (favorable functional outcome and excellent functional outcome) and safety outcomes (symptomatic intracranial hemorrhage [sICH], any intracranial hemorrhage [ICH], and 90-day mortality) are calculated using odds ratios (OR) and 95% confidence intervals (CI). Results: A total of 4,329 patients from 15 studies are included in the analysis. The results indicate a significant trend toward favorable functional outcomes in the tirofiban group (OR, 1.24; 95% CI, 1.09-1.42; p = 0.001). In terms of safety outcomes, tirofiban does not increase the risk of sICH (OR, 0.90; 95% CI, 0.71-1.13; p = 0.35) or any ICH (OR, 0.97; 95% CI, 0.70-1.34; p = 0.85), but it significantly decreases 90-day mortality (OR, 0.75; 95% CI, 0.64-0.88; p = 0.0006). A subgroup analysis suggests that continuous intravenous tirofiban demonstrates better efficacy (OR, 1.24; 95% CI, 1.09-1.42; p = 0.001) for patients with AIS undergoing rescue ET with even better results when used in combination with intra-arterial and intravenous administration (OR, 1.25; 95% CI, 1.07-1.451; p = 0.005). Conclusion: Continuous intravenous tirofiban is effective and safe for patients with AIS undergoing rescue ET, particularly when combined with intra-arterial tirofiban. Systematic review registration: PROSPERO, identifier CRD42023385695.

Efficient hydrogenation of diethyl malonate to 1,3-propanediol over CuGa/SiO2 bimetallic catalysts.

Cu catalysts with different compositions and different Cu and promoter contents were prepared by precipitation-gel method and studied for the selective hydrogenation of syngas or biomass-based diethyl malonate (DEM) to valuable 1,3-propanediol (1,3-PDO). The Ga-promoted 70Cu6Ga/SiO2 catalyst was found to exhibit the highest catalytic performance, achieving 100% DEM conversion and 76.6% 1,3-PDO selectivity under reaction conditions of 160 °C and 8 MPa H2. The 70Cu6Ga/SiO2 bimetallic catalyst also presented obviously better stability than that of the monometallic 70Cu/SiO2 catalyst in a continuous flow reactor over 180 h time-on stream. Characterization results showed that the incorporation of Ga increased the interaction between Cu and Ga species, hindered the full reduction of Cu2+ species, and thus increased the proportion of Cu+ and the number of Lewis acidic sites on the catalyst surface. The synergistic effect between Cu0 and Cu+ enhanced the adsorption and activation of ester carbonyl groups and their subsequent hydrogenation, eventually contributed to the outstanding performances of the CuGa/SiO2 bimetallic catalysts.

Association Between CYP24A1 Polymorphisms and Bladder Cancer Risk in the Chinese Han Population.

In this cohort of 217 bladder cancer patients and 484 healthy controls, we explored the association between CYP24A1 variants (rs2762934, rs1570669, rs6068816, rs2296241) and bladder cancer risk in the Chinese Han population. Utilizing the Agena MassARRAY system, we genotyped four selected CYP24A1 polymorphisms. Logistic regression revealed a significant association of rs2762934 and rs1570669 with elevated bladder cancer risk, while rs6068816 exhibited a protective effect. Bioinformatics analysis of CYP24A1 expression in normal and cancerous bladder tissues indicated higher expression in normal tissue. In conclusion, our findings highlight the potential role of CYP24A1 variants in bladder cancer susceptibility.

Dysregulations of amino acid metabolism and lipid metabolism in urine of children and adolescents with major depressive disorder: a case-control study.

RATIONALE: The mechanisms underlying major depressive disorder (MDD) in children and adolescents are unclear. Metabolomics has been utilized to capture metabolic signatures of various psychiatric disorders; however, urinary metabolic profile of MDD in children and adolescents has not been studied. OBJECTIVES: We analyzed urinary metabolites in children and adolescents with MDD to identify potential biomarkers and metabolic signatures. METHODS: Here, liquid chromatography-mass spectrometry was used to profile metabolites in urine samples from 192 subjects, comprising 80 individuals with antidepressant-naïve MDD (AN-MDD), 37 with antidepressant-treated MDD (AT-MDD) and 75 healthy controls (HC). We performed orthogonal partial least squares discriminant analysis to identify differential metabolites and employed logistic regression and receiver operating characteristic analysis to establish a diagnostic panel. RESULTS: In total, 143 and 71 differential metabolites were identified in AN-MDD and AT-MDD, respectively. These were primarily linked to lipid metabolism, molecular transport, and small molecule biochemistry. AN-MDD additionally exhibited dysregulated amino acid metabolism. Compared to HC, a diagnostic panel of seven metabolites displayed area under the receiver operating characteristic curves of 0.792 for AN-MDD, 0.828 for AT-MDD, and 0.799 for all MDD. Furthermore, the urinary metabolic profiles of children and adolescents with MDD significantly differed from those of adult MDD. CONCLUSIONS: Our research suggests dysregulated amino acid metabolism and lipid metabolism in the urine of children and adolescents with MDD, similar to results in plasma metabolomics studies. This contributes to the comprehension of mechanisms underlying children and adolescents with MDD.

A data-adaptive methods in detecting exogenous methyltransferase accessible chromatin in human genome using nanopore sequencing.

MOTIVATION: Identifying chromatin accessibility is one of the key steps in studying the regulation of eukaryotic genomes. The combination of exogenous methyltransferase and nanopore sequencing provides an strategy to identify open chromatin over long genomic ranges at the single-molecule scale. However, endogenous methylation, non-open-chromatin-specific exogenous methylation and base-calling errors limit the accuracy and hinders its application to complex genomes. RESULTS: We systematically evaluated the impact of these three influence factors, and developed a model-based computational method, methyltransferase accessible genome region finder(MAGNIFIER), to address the issues. By incorporating control data, MAGNIFIER attenuates the three influence factors with data-adaptive comparison strategy. We demonstrate that MAGNIFIER is not only sensitive to identify the open chromatin with much improved accuracy, but also able to detect the chromatin accessibility of repetitive regions that are missed by NGS-based methods. By incorporating long-read RNA-seq data, we revealed the association between the accessible Alu elements and non-classic gene isoforms. AVAILABILITY: Freely avaliable on web at https://github.com/Goatofmountain/MAGNIFIER. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

[Characteristics of Epiphytic Bacterial Community on Submerged Macrophytes in Water Environment Supplemented with Reclaimed Water].

Biofilms attached to submerged macrophytes play an important role in improving the water quality of the water environment supplemented with reclaimed water. In order to explore the effects of reclaimed water quality and submerged macrophyte species on the characteristics of an epiphytic bacterial community, different types of submerged macrophytes were selected as research objects in this study. 16S rRNA high-throughput sequencing technology was used on the epiphytic bacteria and the surrounding environmental samples to analyze the bacterial community structure and functional genes. The results showed that approximately 20%-35% of the nitrogen and phosphorus nutrients were absorbed and utilized in the water environment supplemented with reclaimed water. However, the COD, turbidity, and chroma of the downstream water were significantly increased. The bacterial community of the biofilms attached to submerged macrophytes was significantly different from that in the surrounding environment (soil, sediment, and water body) and in the activated sludge that was treated by reclaimed water. In terms of bacterial community diversity, the richness and diversity were significantly lower than those of soil and sediment but higher than those of plankton bacteria in water. In terms of bacterial community composition, dominant genera and corresponding abundances were also different from those of other samples. The main dominant bacterial genera were Sphingomonas, Aeromonas, Pseudomonas, and Acinetobacter, accounting for 7%-40%, respectively. Both macrophyte species and the quality of reclaimed water (BOD5, TN, NH4+-N, and TP) could affect the bacterial community. However, the effect of water quality of the bacterial community was greater than that of macrophytes species. Additionally, the quality of reclaimed water also affected the abundance of functional genes in the bacterial community, and the relative abundance of nitrogen and phosphorus cycling functional genes was higher in areas with higher nitrogen and phosphorus concentrations.

Inactivation of ERK1/2 in cancer-associated hepatic stellate cells suppresses cancer-stromal interaction by regulating extracellular matrix in fibrosis.

The ERK1/2 pathway is involved in epithelial-mesenchymal transformation and cell cycle of tumor cells in hepatocellular carcinoma (HCC). In the present study, we investigated the involvement of ERK1/2 activation on hepatic stellate cells (HSCs). We identified ERK1/2 phosphorylation in activated HSCs of HCC samples. We found that tumor cells promoted the migration and invasion capacity of HSCs by activating ERK1/2 phosphorylation. Using high throughput transcriptome sequencing analysis, we found that ERK1/2 inhibition altered genes significantly correlated to signaling pathways involved in extracellular matrix remodeling. We screened genes and demonstrated that the ERK1/2 inhibition-related gene set significantly correlated to cancer-associated fibroblast infiltration in TCGA HCC tumor samples. Moreover, inhibition of ERK1/2 suppressed tumor cell-induced enhancement of HSC migration and invasion by regulating expression of fibrosis markers FAP, FN1 and COL1A1. In a tumor cell and HSC splenic co-transplanted xenograft mouse model, inhibition of ERK1/2 suppressed liver tumor formation by downregulating fibrosis, indicating ERK1/2 inhibition suppresses tumor-stromal interactions in vivo. Taken together, our data indicate that inhibition of ERK1/2 in tumor-associated HSCs suppresses tumor-stromal interactions and progression. Furthermore, inhibition of ERK1/2 may be a potential target for HCC treatment.

The diversity of peripheral blood T cells and myeloid-derived suppressor cells in patients with idiopathic membranous nephropathy.

OBJECTIVE: Membranous nephropathy is a leading cause of adult-onset nephrotic syndrome. Peripheral T cells and myeloid-derived suppressor cells (MDSCs) are closely associated with autoimmune diseases, while their exact roles and interaction in these processes are unclear. Here, we studied the roles of T cells, MDSCs, and their subsets in patients with idiopathic membranous nephropathy (IMN). MATERIALS AND METHODS: 35 IMN patients and 30 healthy controls were included in this retrospective study. Flow cytometry was performed to determine the phenotype of human T cells and MDSCs in peripheral blood mononuclear cells (PBMCs). Anti-PLA2R was measured by ELISA. Values ≥ 20 RU/mL were defined as positive and < 14 RU/mL as negative. RESULTS: A higher ratio of CD4/CD8 T cells with a lower proportion of Tregs, a remarkably lower proportion of G-MDSCs (but not M-MDSCs), lower frequency of PD-L2+G-MDSCs, and higher frequency of PD-L1+M-MDSCs were found in IMN patients compared to healthy controls. The ratio of CD4/CD8 T cells was higher, and the frequencies of PD-1+CD4+ T cells, CTLA-4+CD4+ T cells, PD-1+Tregs, and CTLA-4+Tregs were lower in PBMCs of PLA2R-positive IMN patients compared to PLA2R-negative IMN patients. CONCLUSION: Tregs and G-MDSCs were reduced in the circulation of the IMN patients, which may promote understanding of the crucial functions that are mediated by these cells in the pathogenesis of IMN.

In Situ Visualization of RNA-Specific Sialylation on Living Cell Membranes to Explore N-Glycosylation Sites.

The small RNAs on living cell membranes were recently found to be N-glycosylated and terminated with sialic acids, although the glycosylation sites and potential functions remain unclear. Herein, we designed a second-generation hierarchical coding strategy (HieCo 2) for in situ visualization of cell surface RNA-specific sialylation. After covalently binding DNA codes to sialic acids and then binding a DNA code to a target RNA via sequence specificity, cascade decoding processes were performed with subsequent signal amplification that enabled sensitive in situ visualization of low-abundance Y5 RNA-specific sialic acids on living cell membranes. The proposed strategy unveils the number of glycosylation sites on a single RNA and reveals the binding preference of glycosylated RNAs to different sialic acid binding-immunoglobulin lectin-type receptors, demonstrating a new route for exploration of the glycosylated RNA-related biological and pathological processes.

Identifying plasma metabolic characteristics of major depressive disorder, bipolar disorder, and schizophrenia in adolescents.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.

Mechanistic Investigation of Calcium Channel Regulation-Associated Genes in Pulmonary Arterial Hypertension and Signatures for Diagnosis.

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disorder with complex causes. Calcium channel blockers have long been used in its treatment. Our study aimed to validate experimental results showing increased calcium ion concentration in PAH patients. We investigated the impact of genes related to calcium channel regulation on PAH development and developed an accurate diagnostic model. Clinical trial data from serum of 18 healthy individuals and 18 patients with PAH were retrospectively analyzed. Concentrations of calcium and potassium ions were determined and compared. Datasets were retrieved, selecting genes associated with calcium ion release. R packages processed the datasets, filtering 174 common genes, and conducting Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Six hub genes were identified, and nomogram and logistic regression prediction models were constructed. Random forest filtered cross genes, and a diagnostic model was developed and validated using an artificial neural network. The 174 intersection genes related to calcium ions showed significant correlations with biological processes, cellular components, and molecular functions. Six key genes were obtained by constructing a protein-protein interaction network. A diagnostic model with high accuracy (> 90%) and diagnostic capability (AUC = 0.98) was established using a neural network algorithm. This study validated the experimental results, identified key genes associated with calcium ions, and developed a highly accurate diagnostic model using a neural network algorithm. These findings provide insights into the role of calcium release genes in PAH and demonstrate the potential of the diagnostic model for clinical application. However, due to limitations in sample size and a lack of prognosis data, the regulatory mechanisms of calcium ions in PAH patients and their impact on the clinical prognosis of PAH patients still need further exploration in the future.

Efficacy and safety of nalbuphine for epidural labor analgesia at high altitude: An observational study.

Xining is located at the eastern edge of the Qinghai-Tibet Plateau, with an average altitude of >7000 feet (>2000 m). Nalbuphine is a kappa-opioid receptor agonist that can provide analgesia with fewer side effects than other opioid analgesics. This study aimed to evaluate pain control, side effects, and neonatal outcomes from combining nalbuphine with sufentanil and ropivacaine in 600 women during epidural anesthesia while giving birth at a high altitude in Xining, China. A total of 600 parturients receiving epidural labor analgesia were randomly divided into 2 groups, each group 300 parturients. The nalbuphine group received nalbuphine, sufentanil, and ropivacain, the control group only received sufentanil and ropivacain. The analgesic effect was evaluated through the Visual Analogue Scale scores. Neonatal outcomes were mainly evaluated through the Apgar Scores. Compared to the control group, the nalbuphine group showed lower Visual Analogue Scale scores at all time points after analgesia (P < .05). In comparison with the control group, parturients in the nalbuphine group showed lower incidence rates of fever at delivery, 24-hour postpartum bleeding, and pruritus (P < .05). However, between the 2 groups, there were no statistically significant differences in the remaining maternal and infant outcomes and neonatal outcomes (P > .05). Moreover, no adverse effects on neonatal outcomes were observed. The findings from this study support findings from previous studies that nalbuphine provided safe epidural analgesia without significant side effects for the mother and infant, and showed both safety and efficacy when used during labor at high altitude.

Adolescent male rats show altered gut microbiota composition associated with depressive-like behavior after chronic unpredictable mild stress: Differences from adult rats.

Accumulating evidence reveals the metabolism and neurotransmitter systems are different in major depressive disorder (MDD) between adolescent and adult patients; however, much is still unknown from the gut microbiome perspective. To minimize confounding factors such as geographical location, ethnicity, diet, and drugs, we investigated the gut microbial differences between adolescent and adult male Sprague-Dawley rats. We exposed the adolescent rats to chronic unpredictable mild stress (CUMS) for 3 weeks and assessed their behavior using the sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST). We collected and sequenced fecal samples after the behavioral tests and compared them with our previous data on adult rats. Both adolescent and adult CUMS rats exhibited reduced sucrose preference in SPT, reduced total distance in OFT, and increased immobility time in FST. Moreover, compared to their respective controls, the adolescent CUMS rats had distinct amplicon sequence variants (ASVs) mainly in the Muribaculaceae family, Bacteroidetes phylum, while the adult CUMS rats had those in the Lachnospiraceae family, Firmicutes phylum. In the adolescent group, the Muribaculaceae negatively correlated with FST and positively correlated with SPT and OFT. In the adult group, the different genera in the Lachnospiraceae showed opposite correlations with FST. Furthermore, the adolescent CUMS rats showed disrupted microbial functions, such as "Xenobiotics biodegradation and metabolism" and "Immune system", while the adult CUMS rats did not. These results confirmed the gut microbiota differences between adolescent and adult rats after CUMS modeling and provided new insight into the age-related influence on depression models.

Negative prognostic impact of Co-mutations in TGFß and TP53 pathways in surgically resected rectal tumors following neoadjuvant chemoradiotherapy.

BACKGROUND: Preoperative neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is a common approach for treating patients with locally advanced rectal cancer. Nevertheless, the mutational profile and its prognostic impact in surgically resected tumor specimens after nCRT remains to be clarified. METHODS: The comprehensive analysis of mutational landscape was retrospectively conducted by target regions sequencing approach that covered 150 tumor-related genes. Univariate and multivariate logistic regression and Cox regression was used to examine the association of mutation status in genes and pathways with pathological response and prognosis. Data from Memorial Sloan Kettering Cancer Center (MSK) cohort was used for comparison with our results. RESULTS: The top five commonly mutated genes in resected rectal tumor tissue samples following nCRT were TP53 (42%), APC (31%), KRAS (27%), PIK3CA (14%) and FBXW7 (11%). Mutations in the WNT pathway, which was mainly represented by APC mutation, were found to be significantly associated with tumor regression grade (TRG) 3. In our cohort, co-mutations in the receptor tyrosine kinase (RTK)/RAS and WNT pathways were found to be independently associated with reduced risk of recurrent and significantly associated with longer disease-free survival (DFS). In both our cohort and the MSK cohort, co-mutations in the TGF-ß and TP53 pathways were significantly associated with worse DFS. CONCLUSIONS: Resected rectal tumor samples from patients without complete pathological response can be appropriately used to detect mutations. Co-mutations in the TGF-ß and TP53 pathways may provide more prognostic information beyond commonly used clinical factors.

Network pharmacology prediction, molecular docking and in vitro experiment explored the potential mechanism of Gaoyuan'an capsule in improving hypoxia tolerance.

BACKGROUND: Tibetan medicine Gaoyuan'an capsule (GYAC) is widely used to prevent pulmonary edema at high altitude, but the specific mechanism has not been explored. In this study, we analyzed the mechanism of GYAC in hypoxia tolerance, and provided a new idea for the prevention and treatment of altitude disease. METHODS: The effective components and corresponding targets of GYAC were screened out by the Chinese herbal medicine network database, and the key targets of hypoxia tolerance were retrieved by Genecards, OMIM and PubMed database. Cytoscape 3.7.2 was used to construct GYAC ingredient-target-hypoxia tolerance-related target network. GO function annotation and KEGG enrichment analysis were performed to predict the pathways in which target genes may be involved, and molecular docking was used to verify the binding ability of the compound to target genes. In vitro, the above results were further verified by molecular experiment. RESULTS: We found that GYAC can improve hypoxia tolerance by regulating various target genes, including IL6, IFNG, etc. The main regulatory pathways were HIF-1 signaling pathway. Molecular docking showed that the affinity between luteolin and target genes (IL6, IFNG) were better. In vitro, we observed that hypoxia can inhibit cell viability and promote apoptosis of H9C2 cell. And hypoxia can promote the expression of LDH. After the addition of luteolin, the decrease of cell viability, the increase of cell apoptosis, LDH release and the decrease of mitochondrial membrane potential were inhibited. Besides, inflammatory related factors (IL-6, IL-10, IL-2, IFNG and VEGFA) expression were also inhibited hypoxic cell models. CONCLUSIONS: The results of network pharmacology and molecular docking showed that luteolin, a monomeric component of GYAC, played a role in hypoxia tolerance through a variety of target genes, such as IL6, IFNG. What's more, we have discovered that luteolin can reduce the inflammatory response in cardiac myocytes, thereby alleviating mitochondrial damage, and ultimately enhancing the hypoxia tolerance of H9C2 cardiomyocytes.

Reconfiguration of Structural and Functional Connectivity Coupling in Patient Subgroups With Adolescent Depression.

Importance: Adolescent major depressive disorder (MDD) is associated with serious adverse implications for brain development and higher rates of self-injury and suicide, raising concerns about its neurobiological mechanisms in clinical neuroscience. However, most previous studies regarding the brain alterations in adolescent MDD focused on single-modal images or analyzed images of different modalities separately, ignoring the potential role of aberrant interactions between brain structure and function in the psychopathology. Objective: To examine alterations of structural and functional connectivity (SC-FC) coupling in adolescent MDD by integrating both diffusion magnetic resonance imaging (MRI) and resting-state functional MRI data. Design, Setting, and Participants: This cross-sectional study recruited participants aged 10 to 18 years from January 2, 2020, to December 28, 2021. Patients with first-episode MDD were recruited from the outpatient psychiatry clinics at The First Affiliated Hospital of Chongqing Medical University. Healthy controls were recruited by local media advertisement from the general population in Chongqing, China. The sample was divided into 5 subgroup pairs according to different environmental stressors and clinical characteristics. Data were analyzed from January 10, 2022, to February 20, 2023. Main Outcomes and Measures: The SC-FC coupling was calculated for each brain region of each participant using whole-brain SC and FC. Primary analyses included the group differences in SC-FC coupling and clinical symptom associations between SC-FC coupling and participants with adolescent MDD and healthy controls. Secondary analyses included differences among 5 types of MDD subgroups: with or without suicide attempt, with or without nonsuicidal self-injury behavior, with or without major life events, with or without childhood trauma, and with or without school bullying. Results: Final analyses examined SC-FC coupling of 168 participants with adolescent MDD (mean [mean absolute deviation (MAD)] age, 16.0 [1.7] years; 124 females [73.8%]) and 101 healthy controls (mean [MAD] age, 15.1 [2.4] years; 61 females [60.4%]). Adolescent MDD showed increased SC-FC coupling in the visual network, default mode network, and insula (Cohen d ranged from 0.365 to 0.581; false discovery rate [FDR]-corrected P < .05). Some subgroup-specific alterations were identified via subgroup analyses, particularly involving parahippocampal coupling decrease in participants with suicide attempt (partial η2 = 0.069; 90% CI, 0.025-0.121; FDR-corrected P = .007) and frontal-limbic coupling increase in participants with major life events (partial η2 ranged from 0.046 to 0.068; FDR-corrected P < .05). Conclusions and Relevance: Results of this cross-sectional study suggest increased SC-FC coupling in adolescent MDD, especially involving hub regions of the default mode network, visual network, and insula. The findings enrich knowledge of the aberrant brain SC-FC coupling in the psychopathology of adolescent MDD, underscoring the vulnerability of frontal-limbic SC-FC coupling to external stressors and the parahippocampal coupling in shaping future-minded behavior.