Biological characteristics of molecular subtypes of ulcerative colitis characterized by ferroptosis and neutrophil infiltration.

Clinical ulcerative colitis (UC) is a heterogeneous condition. Moreover, medical interventions are nonspecific, and thus, treatment responses are inconsistent. The aim of this study was to explore the molecular subtypes and biological characteristics of UC based on ferroptosis and neutrophil gene sets. Multiple intestinal mucosa gene expression profiles of UC patients in the Gene Expression Omnibus (GEO) database were downloaded. Unsupervised clustering methods were used to identify potential molecular subtypes based on ferroptosis and neutrophil gene sets. Multiple immune infiltration algorithms were used to evaluate the biological characteristics of the molecular subtypes. Machine learning identifies hub genes for molecular subtypes and analyses their diagnostic efficacy for UC and predictive performance for drug therapy. The relevant conclusions were verified by clinical samples and animal experiments. Four molecular subtypes were identified according to the ferroptosis and neutrophil gene sets: neutrophil, ferroptosis, mixed and quiescent. The subtypes have different biological characteristics and immune infiltration levels. Multiple machine learning methods jointly identified four hub genes (FTH1, AQP9, STEAP3 and STEAP4). Receiver operating characteristic (ROC) curve analysis revealed that the four hub genes could be used as diagnostic markers for UC. The clinical response profile data of infliximab treatment patients showed that AQP9 and STEPA4 were reliable predictors of infliximab treatment response. In human samples the AQP9 and STEAP4 protein were shown to be increased in UC intestinal samples. In animal experiments, the ferroptosis and neutrophil phenotype were confirmed. Dual analysis of ferroptosis and neutrophil gene expression revealed four subgroups of UC patients. The molecular subtype-associated hub genes can be used as diagnostic markers for UC and predict infliximab treatment response.

Enantioselective synthesis of spirooxindole-pyran derivatives via a remote inverse-electron-demand Diels-Alder reaction of ß,γ-unsaturated amides.

Novel construction methods for obtaining 3,4'-pyran spirooxindole heterocyclic skeletons have always been the focus of attention. Herein, we report a highly enantioselective inverse-electron-demand oxa-Diels-Alder cycloaddition reaction of a ß,γ-unsaturated pyrazole amide and a N-diphenyl isatin-derived oxodiene using a bifunctional catalyst. In addition, large-scale experiments confirmed the reliability of the reaction. The resultant products of this study can be further transformed.

N-acetylcysteine Protects Against Myocardial Ischemia-Reperfusion Injury Through Anti-ferroptosis in Type 1 Diabetic Mice.

The hearts of subjects with diabetes are vulnerable to ischemia-reperfusion injury (IRI). In contrast, experimentally rodent hearts have been shown to be more resistant to IRI at the very early stages of diabetes induction than the heart of the non-diabetic control mice, and the mechanism is largely unclear. Ferroptosis has recently been shown to play an important role in myocardial IRI including that in diabetes, while the specific mechanisms are still unclear. Non-diabetic control (NC) and streptozotocin-induced diabetic (DM) mice were treated with the antioxidant N-acetylcysteine (NAC) in drinking water for 4 week starting at 1 week after diabetes induction. Mice were subjected to myocardial IRI induced by occluding the coronary artery for 30 min followed by 2 h of reperfusion, subsequently at 1, 2, and 5 week of diabetes induction. The post-ischemic myocardial infarct size in the DM mice was smaller than that in NC mice at 1 week of diabetes but greater than that in the NC mice at 2 and 5 week of diabetes, which were associated with a significant increase of ferroptosis at 2 and 5 week but a significant reduction of ferroptosis at 1 week of diabetes. NAC significantly attenuated post-ischemic ferroptosis as well as oxidative stress and reduced infarct size at 2 and 5 week of diabetes. Application of erastin, a ferroptosis inducer, reversed the cardioprotective effects of NAC. It is concluded that increased oxidative stress and ferroptosis are the major factors attributable to the increased vulnerability to myocardial IRI in diabetes and that attenuation of ferroptosis represents a major mechanism whereby NAC confers cardioprotection against myocardial IRI in diabetes.

Propofol and salvianolic acid A synergistically attenuated cardiac ischemia-reperfusion injury in diabetic mice via modulating the CD36/AMPK pathway.

Background: Prevention of diabetic heart myocardial ischemia-reperfusion (IR) injury (MIRI) is challenging. Propofol attenuates MIRI through its reactive oxygen species scavenging property at high doses, while its use at high doses causes hemodynamic instability. Salvianolic acid A (SAA) is a potent antioxidant that confers protection against MIRI. Both propofol and SAA affect metabolic profiles through regulating Adenosine 5'-monophosphate-activated protein kinase (AMPK). The aim of this study was to investigate the protective effects and underlying mechanisms of low doses of propofol combined with SAA against diabetic MIRI. Methods: Diabetes was induced in mice by a high-fat diet followed by streptozotocin injection, and MIRI was induced by coronary artery occlusion and reperfusion. Mice were treated with propofol at 46 mg/kg/h without or with SAA at 10 mg/kg/h during IR. Cardiac origin H9c2 cells were exposed to high glucose (HG) and palmitic acid (PAL) for 24 h in the absence or presence of cluster of differentiation 36 (CD36) overexpression or AMPK gene knockdown, followed by hypoxia/reoxygenation (HR) for 6 and 12 h. Results: Diabetes-exacerbated MIRI is evidenced as significant increases in post-ischemic infarction with reductions in phosphorylated (p)-AMPK and increases in CD36 and ferroptosis. Propofol moderately yet significantly attenuated all the abovementioned changes, while propofol plus SAA conferred superior protection against MIRI to that of propofol. In vitro, exposure of H9c2 cells under HG and PAL decreased cell viability and increased oxidative stress that was concomitant with increased levels of ferroptosis and a significant increase in CD36, while p-AMPK was significantly reduced. Co-administration of low concentrations of propofol and SAA at 12.5 µM in H9c2 cells significantly reduced oxidative stress, ferroptosis and CD36 expression, while increasing p-AMPK compared to the effects of propofol at 25 µM. Moreover, either CD36 overexpression or AMPK silence significantly exacerbated HR-induced cellular injuries and ferroptosis, and canceled propofol- and SAA-mediated protection. Notably, p-AMPK expression was downregulated after CD36 overexpression, while AMPK knockdown did not affect CD36 expression. Conclusions: Combinational usage of propofol and SAA confers superior cellular protective effects to the use of high-dose propofol alone, and it does so through inhibiting HR-induced CD36 overexpression to upregulate p-AMPK.

Assessing the causal relationship between immune cell traits and depression by Mendelian randomization analysis.

BACKGROUND: Observational studies suggested that immune system disorder is associated with depression. However, the causal association has not been fully elucidated. Thus, we aim to assess the causality of the associations of immune cell profiles with risk of depression through Mendelian randomization analysis. METHODS: We extracted genetic variances of immune cell traits from a large publicly available genome-wide association study (GWAS) involving 3757 participants and depression from a GWAS containing 246,363 cases and 561,190 controls of European ancestry. Inverse variance weighting (IVW) was performed as the MR primary analysis. Simultaneously apply MR-Egger and weighted median as supplementary enhancements to the final result. We further performed heterogeneity and horizontal pleiotropy test to validate the main MR results. RESULTS: Five immunophenotypes were identified to be significantly associated with depression risk: CD27 on IgD-CD38dimB cell (OR = 1.019, 95 % CI = 1.010-1.028, P = 1.24 × 10-5), CD45RA-CD4+T cell Absolute Count (OR = 0.974, 95 % CI = 0.962-0.986, P = 3.88 × 10-5), CD40 on CD14-CD16+monocyte (OR = 0.987, 95 % CI = 0.981-0.993, P = 2.1 × 10-4), CD27 on switched memory B cell (OR = 1.015, 95 % CI = 1.006-1.023, P = 2.6 × 10-4), CD27 on IgD-CD38-B cell (OR = 1.017, 95 % CI = 1.008-1.027, P = 3.1 × 10-4). CONCLUSION: Our findings shed light on the intricate interaction pattern between the immune system and depression, offering a novel direction for researchers to investigate the underlying biological mechanisms of depression.

Assessing the Causal Relationship between Genetically Determined Inflammatory Cytokines and Parkinson's Disease Risk: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Observational studies have suggested an association between inflammatory cytokines and Parkinson's disease (PD). This Mendelian randomization (MR) was conducted to further assess the causal correlations between inflammatory cytokines and PD. Methods: Genetic instruments associated with inflammatory cytokines were extracted from a large summary genome-wide association studies (GWAS) involving 8,293 European participants. Summary-level statistics for PD were obtained from a large-sample GWAS containing 17 studies that involved European participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted (IVW) method. Results: The IVW method indicated that basic fibroblast growth factor (FGFBasic), interleukin-2 (IL-2), and macrophage migration inhibitory factor (MIF) may be suggestively associated with the risk of PD (OR: 0.71, 95%CI: 0.52-0.96, P = 0.027; OR: 1.18, 95%CI: 1.01-1.38, P = 0.041; and OR: 1.23, 95%CI: 1.04-1.46, P = 0.018). In the reverse direction, monokine induced by interferon gamma (MIG), beta nerve growth factor (bNGF), interleukin-17 (IL-17), and interferon gamma (IFNg) are suggested to be the consequences of PD. Conclusion: Our MR analysis indicated that suggestive associations between circulating levels of FGFBasic, IL-2, and MIF and PD risk. In addition, MIG, bNGF, IL-17, and IFNg are more likely to be involved in the development of downstream PD.

Comparative Analysis of the Mitochondrial Genomes of Chloropidae and Their Implications for the Phylogeny of the Family.

Chloropidae, commonly known as grass flies, represent the most taxonomically diverse family of Diptera Carnoidea, comprising over 3000 described species worldwide. Previous phylogenetic studies of this family have predominantly relied on morphological characters, with mitochondrial genomes being reported in a few species. This study presents 11 newly sequenced mitochondrial genomes (10 Chloropidae and 1 Milichiidae) and provides the first comprehensive comparative analysis of mitochondrial genomes for Chloropidae. Apart from 37 standard genes and the control region, three conserved intergenic sequences across Diptera Cyclorrhapha were identified in all available chloropid mitochondrial genomes. Evolutionary rates within Chloropidae exhibit significant variation across subfamilies, with Chloropinae displaying higher rates than the other three subfamilies. Phylogenetic relationships based on mitochondrial genomes were inferred using maximum likelihood and Bayesian methods. The monophyly of Chloropidae and all four subfamilies is consistently strongly supported, while subfamily relationships within Chloropidae remain poorly resolved, possibly due to rapid evolution.

ROS-Responsive Bola-Lipid Nanoparticles as a Codelivery System for Gene/Photodynamic Combination Therapy.

The nonviral delivery systems that combine genes with photosensitizers for multimodal tumor gene/photodynamic therapy (PDT) have attracted much attention. In this study, a series of ROS-sensitive cationic bola-lipids were applied for the gene/photosensitizer codelivery. Zn-DPA was introduced as a cationic headgroup to enhance DNA binding, while the hydrophobic linking chains may facilitate the formation of lipid nanoparticles (LNP) and the encapsulation of photosensitizer Ce6. The length of the hydrophobic chain played an important role in the gene transfection process, and 14-TDZn containing the longest chains showed better DNA condensation, gene transfection, and cellular uptake. 14-TDZn LNPs could well load photosensitizer Ce6 to form 14-TDC without a loss of gene delivery efficiency. 14-TDC was used for codelivery of p53 and Ce6 to achieve enhanced therapeutic effects on the tumor cell proliferation inhibition and apoptosis. Results showed that the codelivery system was more effective in the inhibition of tumor cell proliferation than individual p53 or Ce6 monotherapy. Mechanism studies showed that the production of ROS after Ce6 irradiation could increase the accumulation of p53 protein in tumor cells, thereby promoting caspase-3 activation and inducing apoptosis, indicating some synergistic effect. These results demonstrated that 14-TDC may serve as a promising nanocarrier for gene/PDT combination therapy.

Tantalum Particles Promote M2 Macrophage Polarization and Regulate Local Bone Metabolism via Macrophage-Derived Exosomes Influencing the Fates of BMSCs.

In this study, the regulatory role and mechanisms of tantalum (Ta) particles in the bone tissue microenvironment are explored. Ta particle deposition occurs in both clinical samples and animal tissues following porous Ta implantation. Unlike titanium (Ti) particles promoting M1 macrophage (Mϕ) polarization, Ta particles regulating calcium signaling pathways and promoting M2 Mϕ polarization. Ta-induced M2 Mϕ enhances bone marrow-derived mesenchymal stem cells (BMSCs) proliferation, migration, and osteogenic differentiation through exosomes (Exo) by upregulating miR-378a-3p/miR-221-5p and downregulating miR-155-5p/miR-212-5p. Ta particles suppress the pro-inflammatory and bone resorption effects of Ti particles in vivo and in vitro. In a rat femoral condyle bone defect model, artificial bone loaded with Ta particles promotes endogenous Mϕ polarization toward M2 differentiation at the defect site, accelerating bone repair. In conclusion, Ta particles modulate Mϕ polarization toward M2 and influence BMSCs osteogenic capacity through Exo secreted by M2 Mϕ, providing insights for potential bone repair applications.

First-Principles High-Throughput Inverse Design of Direct Momentum-Matching Band Alignment van der Waals Heterostructures Utilizing Two-Dimensional Indirect Semiconductors.

Two-dimensional (2D) van der Waals (vdW) heterostructures have attracted widespread attention in photocatalysis. Herein, we employ a novel strategy utilizing first-principles high-throughput inverse design of 2D Z-scheme heterojunctions for photocatalysis. This approach is anchored in high-throughput screening conditions, which are fundamentally based on the characteristics of carrier mechanisms influenced significantly by Z-scheme heterojunctions. A pivotal element of our screening process is the integration of the indirect-to-direct bandgap transition with momentum-matching band alignment in k-space, guiding us to combine two 2D indirect bandgap monolayers into direct Z-scheme heterojunctions characterized by pronounced interlayer excitons. Various stacking modes introduce extra and distinct degrees of freedom that can be useful for tuning the properties of heterostructures, encompassing factors such as components, stacking patterns, and sequences. We demonstrate that various stacking modes can facilitate the indirect-to-direct bandgap transition and the emergence of interlayer excitons. These findings provide exciting opportunities for designing Z-scheme heterojunctions in photocatalysis.

Pomelo (Citrus grandis (L.) Osbeck) sponge layers as a potential source of soluble dietary fiber: Evaluation of its physicochemical, structural and functional properties.

Pomelo sponge layer (PSL) had been considered as a potential source of soluble dietary fiber (SDF), while they were mostly disposed of as waste. To promote high-value utilization of pomelo wastes, this study extracted SDF from PSL of six varieties of pomelo, and their physicochemical, structural and functional properties were investigated. Results indicated that all PSL-SDFs showed good physicochemical and functional properties. Among them, PSL-SDF from grapefruit (GRSDF) showed better water holding capacity and swelling capacity, whereas Shatian pomelo PSL-SDF and Guanxi pomelo PSL-SDF had the highest thermal stability and oil holding capacity, respectively. Furthermore, compared with other PSL-SDFs, GRSDF displayed the lowest hydrolysis degree coupled with the best antioxidant and probiotic growth-promoting abilities. Finally, the correlation analysis showed that multiple beneficial effects of PSL-SDFs were markedly associated with their molecular weight and the concentrations of total phenolic, total flavonoids, rhamnose, galacturonic acid, glucose and arabinose. Collectively, these findings contributed to a better understanding of the physicochemical and functional properties of SDFs extracted from different PSLs, which provided a scientific basis for the development of PSL-SDFs into functional foods.

Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia.

OBJECTIVE: Idiopathic infantile hypercalcemia (IIH) is a rare disorder of PTH-independent hypercalcemia. CYP24A1 and SLC34A1 gene mutations cause two forms of hereditary IIH. In this study, the clinical manifestations and molecular aspects of six new Chinese patients were investigated. METHODS: The clinical manifestations and laboratory study of six patients with idiopathic infantile hypercalcemia were analyzed retrospectively. RESULTS: Five of the patients were diagnosed with hypercalcemia, hypercalciuria, and bilateral medullary nephrocalcinosis. Their clinical symptoms and biochemical abnormalities improved after treatment. One patient presented at age 11 years old with arterial hypertension, hypercalciuria and nephrocalcinosis, but normal serum calcium. Gene analysis showed that two patients had compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant, and three patients had a monoallelic SLC34A1 variant. Four novel CYP24A1 variants (c.116G > C, c.287T > A, c.476G > A and c.1349T > C) and three novel SLC34A1 variants (c.1322 A > G, c.1697_1698insT and c.1726T > C) were found in these patients. CONCLUSIONS: A monoallelic variant of CYP24A1 or SLC34A1 gene contributes to symptomatic hypercalcemia, hypercalciuria and nephrocalcinosis. Manifestations of IIH vary with onset age. Hypercalcemia may not necessarily present after infancy and IIH should be considered in patients with nephrolithiasis either in older children or adults.

Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.

Hexanucleotide repeat expansions in the C9orf72 gene are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Due to the lack of trunk neuromuscular organoids (NMOs) from ALS patients' induced pluripotent stem cells (iPSCs), an organoid system was missing to model the trunk spinal neuromuscular neurodegeneration. With the C9orf72 ALS patient-derived iPSCs and isogenic controls, we used an NMO system containing trunk spinal cord neural and peripheral muscular tissues to show that the ALS NMOs could model peripheral defects in ALS, including contraction weakness, neural denervation, and loss of Schwann cells. The neurons and astrocytes in ALS NMOs manifested the RNA foci and dipeptide repeat proteins. Acute treatment with the unfolded protein response inhibitor GSK2606414 increased the glutamatergic muscular contraction 2-fold and reduced the dipeptide repeat protein aggregation and autophagy. This study provides an organoid system for spinal neuromuscular pathologies in ALS and its application for drug testing.

The 90-Day Survival Threshold: A Pivotal Determinant of Long-Term Prognosis in HBV-ACLF Patients - Insights from a Prospective Longitudinal Cohort Study.

This work aims to explore the long-term prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). In this prospective study, eligible inpatients with HBV-ACLF are enrolled and followed up from December 2012 to February 2023, for clinical events, laboratory tests at least every 6 months. Overall, the survival rates at 28 days, 90 days, 1 year, 5 years, and 8 years are 64.7%, 48.8%, 46.1%, 43.8%, and 42.2%, respectively. Among the 8-year mortality and liver transplant cases, ACLF survivors (who survived over 90 days) accounted for 7.8% (9/115). Among 101 patients who survived for more than 90 days, 97.9% of patients achieve virologic response at 1 year. For HBeAg-positive patients, the HBeAg seroconversion are 25.5%, 63.6%, and 76.9% at 1, 5, and 8 years, respectively. Alanine aminotransferase, aspartate aminotransferase, total bilirubin, INR, white blood cell count, and albumin levels gradually improve within the first year. Fibrosis biomarkers APRI, FIB-4 and Chitinase-3-like protein 1 (CHI3L1) levels decreases within the first 5 years. The Cox proportional hazards regression reveal that high total bilirubin (HR = 1.008, p = 0.021) is the independent risk factor for 8-year survival of ALCF survivors. The 90-day period following of HBV-ACLF represented a critical juncture for long-term prognosis, revealing favorable outcomes beyond this timeframe.

A Galectin-9-Driven CD11chigh Decidual Macrophage Subset Suppresses Uterine Vascular Remodeling in Preeclampsia.

BACKGROUND: Preeclampsia is a serious disease of pregnancy that lacks early diagnosis methods or effective treatment, except delivery. Dysregulated uterine immune cells and spiral arteries are implicated in preeclampsia, but the mechanistic link remains unclear. METHODS: Single-cell RNA sequencing and spatial transcriptomics were used to identify immune cell subsets associated with preeclampsia. Cell-based studies and animal models including conditional knockout mice and a new preeclampsia mouse model induced by recombinant mouse galectin-9 were applied to validate the pathogenic role of a CD11chigh subpopulation of decidual macrophages (dMφ) and to determine its underlying regulatory mechanisms in preeclampsia. A retrospective preeclampsia cohort study was performed to determine the value of circulating galectin-9 in predicting preeclampsia. RESULTS: We discovered a distinct CD11chigh dMφ subset that inhibits spiral artery remodeling in preeclampsia. The proinflammatory CD11chigh dMφ exhibits perivascular enrichment in the decidua from patients with preeclampsia. We also showed that trophoblast-derived galectin-9 activates CD11chigh dMφ by means of CD44 binding to suppress spiral artery remodeling. In 3 independent preeclampsia mouse models, placental and plasma galectin-9 levels were elevated. Galectin-9 administration in mice induces preeclampsia-like phenotypes with increased CD11chigh dMφ and defective spiral arteries, whereas galectin-9 blockade or macrophage-specific CD44 deletion prevents such phenotypes. In pregnant women, increased circulating galectin-9 levels in the first trimester and at 16 to 20 gestational weeks can predict subsequent preeclampsia onset. CONCLUSIONS: These findings highlight a key role of a distinct perivascular inflammatory CD11chigh dMφ subpopulation in the pathogenesis of preeclampsia. CD11chigh dMφ activated by increased galectin-9 from trophoblasts suppresses uterine spiral artery remodeling, contributing to preeclampsia. Increased circulating galectin-9 may be a biomarker for preeclampsia prediction and intervention.

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.

ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G0-G1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53-mutant tumors but not in TP53-WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53-mutant, but not in TP53-WT, PDXs. In plasmid-based reporter assays, GBM43 (TP53-mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor-mediated radiosensitization.

Hierarchical and dynamic graph attention network for drug-disease association prediction.

In the realm of biomedicine, the prediction of associations between drugs and diseases holds significant importance. Yet, conventional wet lab experiments often fall short of meeting the stringent demands for prediction accuracy and efficiency. Many prior studies have predominantly focused on drug and disease similarities to predict drug-disease associations, but overlooking the crucial interactions between drugs and diseases that are essential for enhancing prediction accuracy. Hence, in this paper, a resilient and effective model named Hierarchical and Dynamic Graph Attention Network (HDGAT) has been proposed to predict drug-disease associations. Firstly, it establishes a heterogeneous graph by leveraging the interplay of drug and disease similarities and associations. Subsequently, it harnesses the capabilities of graph convolutional networks and bidirectional long short-term memory networks (Bi-LSTM) to aggregate node-level information within the heterogeneous graph comprehensively. Furthermore, it incorporates a hierarchical attention mechanism between convolutional layers and a dynamic attention mechanism between nodes to learn embeddings for drugs and diseases. The hierarchical attention mechanism assigns varying weights to embeddings learned from different convolutional layers, and the dynamic attention mechanism efficiently prioritizes inter-node information by allocating each node with varying rankings of attention coefficients for neighbour nodes. Moreover, it employs residual connections to alleviate the over-smoothing issue in graph convolution operations. The latent drug-disease associations are quantified through the fusion of these embeddings ultimately. By conducting 5-fold cross-validation, HDGAT's performance surpasses the performance of existing state-of-the-art models across various evaluation metrics, which substantiates the exceptional efficacy of HDGAT in predicting drug-disease associations.

Contribution of ApoB-100/SORT1-Mediated Immune Microenvironment in Regulating Oxidative Stress, Inflammation, and Ferroptosis After Spinal Cord Injury.

This study aims to explore the impacts of ApoB-100/SORT1-mediated immune microenvironment during acute spinal cord injury (SCI), and to investigate the potential mechanism. CB57BL/6 mice underwent moderate thoracic contusion injury to establish the SCI animal model, and received ApoB-100 lentivirus injection to interfere ApoB-100 level. Functional recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) score and footprint analysis. Transmission electron microscopy was applied to observe the ultrastructure of the injured spinal cord tissue. Hematoxylin-eosin (HE) staining and Perls staining were conducted to assess histological changes and iron deposition. Biochemical factor and cytokines were detected using their commercial kits. M1/M2 macrophage markers were detected by immunofluorescence assay in vivo and by flow cytometry in vitro. HT22 neurons were simulated by lipopolysaccharide (LPS), followed by incubation with polarized macrophage medium to simulate the immune microenvironment of injured spinal cord in vitro. The local immune microenvironment is changed in SCI mice, accompanied with the occurrence of oxidative stress and the elevation of both M1 and M2 macrophages. Knockdown of ApoB-100 ameliorates oxidative stress and lipid disorder, and inhibits inflammation and ferroptosis in SCI mice. Importantly, knockdown of ApoB-100 can partly restrict M1 macrophages but does not change M2 macrophage proportion in SCI mice. Further, M1 macrophages are observed to attenuate the inflammatory response, oxidative stress, and ferroptosis levels of LPS-induced HT22 cells, which is further strengthened by SORT1 knockdown. Blockage of ApoB-100/SORT1-mediated immune microenvironment plays a protective role against SCI via inhibiting oxidative stress, inflammation, lipid disorders, and ferroptosis, providing novel insights of the targeted therapy of SCI.

Chemical profile and difference analysis of four parts of Strobilanthes sarcorrhiza by ultrafast flow liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry and multivariate statistical analysis.

Strobilanthes sarcorrhiza (CTS) is a medicinal plant with various pharmacological effects such as tonifying kidney and anti-inflammatory. However, the chemical composition and difference of its four parts (leaves, stems, rhizomes, and root tubers) have been rarely reported. In this study, ultrafast flow liquid chromatography coupled with quadrupole-time-of-flight MS was applied to analyze the chemical profile of CTS and identify 55 compounds, including terpenoids, phenylethanol glycosides, fatty acid derivatives, chain glycosides, flavonoid glycosides, and others. Among these compounds, 34 compounds were first identified in CTS. They were mainly terpenoids, phenylethanol glycosides, fatty acid derivatives, and so forth. Multivariate statistical analysis, such as principal component analysis and orthogonal partial least squares-discriminant analysis were also used to evaluate the difference in chemical compounds from the four parts of CTS. The results showed that phenylethanol glycosides were the main compounds of the underground parts, while terpenoids were the main compounds of the aboveground parts. This study revealed the chemical diversity and similarity of CTS and suggested that the rhizomes could be used as an alternative medicinal part to improve the resource utilization of CTS.