Prior knowledge-guided multilevel graph neural network for tumor risk prediction and interpretation via multi-omics data integration.

The interrelation and complementary nature of multi-omics data can provide valuable insights into the intricate molecular mechanisms underlying diseases. However, challenges such as limited sample size, high data dimensionality and differences in omics modalities pose significant obstacles to fully harnessing the potential of these data. The prior knowledge such as gene regulatory network and pathway information harbors useful gene-gene interaction and gene functional module information. To effectively integrate multi-omics data and make full use of the prior knowledge, here, we propose a Multilevel-graph neural network (GNN): a hierarchically designed deep learning algorithm that sequentially leverages multi-omics data, gene regulatory networks and pathway information to extract features and enhance accuracy in predicting survival risk. Our method achieved better accuracy compared with existing methods. Furthermore, key factors nonlinearly associated with the tumor pathogenesis are prioritized by employing two interpretation algorithms (i.e. GNN-Explainer and IGscore) for neural networks, at gene and pathway level, respectively. The top genes and pathways exhibit strong associations with disease in survival analyses, many of which such as SEC61G and CYP27B1 are previously reported in the literature.

[Dynamic trajectory and cell communication of different cell clusters in malignant progression of glioblastoma].

OBJECTIVE: To delve deeply into the dynamic trajectories of cell subpopulations and the communication network among immune cell subgroups during the malignant progression of glioblastoma (GBM), and to endeavor to unearth key risk biomarkers in the GBM malignancy progression, so as to provide a more profound understanding for the treatment and prognosis of this disease by integrating transcriptomic data and clinical information of the GBM patients. METHODS: Utilizing single-cell sequencing data analysis, we constructed a cell subgroup atlas during the malignant progression of GBM. The Monocle2 tool was employed to build dynamic progression trajectories of the tumor cell subgroups in GBM. Through gene enrichment analysis, we explored the biological processes enriched in genes that significantly changed with the malignancy progression of GBM tumor cell subpopulations. CellChat was used to identify the communication network between the different immune cell subgroups. Survival analysis helped in identifying risk molecular markers that impacted the patient prognosis during the malignant progression of GBM. This method ological approach offered a comprehensive and detailed examination of the cellular and molecular dynamics within GBM, providing a robust framework for understanding the disease' s progression and potential therapeutic targets. RESULTS: The analysis of single-cell sequencing data identified 6 different cell types, including lymphocytes, pericytes, oligodendrocytes, macrophages, glioma cells, and microglia. The 27 151 cells in the single-cell dataset included 3 881 cells from the patients with low-grade glioma (LGG), 10 166 cells from the patients with newly diagnosed GBM, and 13 104 cells from the patients with recurrent glioma (rGBM). The pseudo-time analysis of the glioma cell subgroups indicated significant cellular heterogeneity during malignant progression. The cell interaction analysis of immune cell subgroups revealed the communication network among the different immune subgroups in GBM malignancy, identifying 22 biologically significant ligand-receptor pairs across 12 key biological pathways. Survival analysis had identified 8 genes related to the prognosis of the GBM patients, among which SERPINE1, COL6A1, SPP1, LTF, C1S, AEBP1, and SAA1L were high-risk genes in the GBM patients, and ABCC8 was low-risk genes in the GBM patients. These findings not only provided new theoretical bases for the treatment of GBM, but also offered fresh insights for the prognosis assessment and treatment decision-making for the GBM patients. CONCLUSION: This research comprehensively and profoundly reveals the dynamic changes in glioma cell subpopulations and the communication patterns among the immune cell subgroups during the malignant progression of GBM. These findings are of significant importance for understanding the complex biological processes of GBM, providing crucial new insights for precision medicine and treatment decisions in GBM. Through these studies, we hope to provide more effective treatment options and more accurate prognostic assessments for the patients with GBM.

Rapid detection of phenytoin sodium by partial-least squares and linear regression models combined with surface-enhanced Raman spectroscopy.

Surface-enhanced Raman spectroscopy (SERS) for quantitative analysis is challenging owing to the unstable enhanced effect. However, it can be improved by combining it with chemometrics. In this study, we established a quantitative analysis method for phenytoin sodium (PS) based on partial least-squares (PLS) and linear regression (LR) models combined with SERS. Gold nanoparticles (AuNPs) were optimally enhanced substrates for PS. 180 PS samples in the concentration range of 0.98 - 980 µg mL-1 were used to establish a quantitative prediction model by PLS regression, and an accurate and robust prediction was achieved. Furthermore, we found that SERS peak intensity showed a good linear correlation with the concentration of PS in the concentration range of 1 - 80 µg mL -1. After using P-mercaptobenzoic acid as an internal standard, the accuracy and precision of the LR model were significantly improved compared with that of the model without an internal standard. In general, PLS chemometrics and LR model with internal standard which were combined with SERS in this paper provide new possible analytical methods for analytes to develop a rapid and sensitive quantitative analysis method.

Regulatory pattern of abnormal promoter CpG island methylation in the glioblastoma multiforme classification.

Glioblastoma (GBM) is characterized by extensive genetic and phenotypic heterogeneity. However, it remains unexplored primarily how CpG island methylation abnormalities in promoter mediate glioblastoma typing. First, we presented a multi-omics scale map between glioblastoma sample clusters constructed based on promoter CpG island (PCGI) methylation-driven genes, using datasets including methylation profiles, expression profiles, and single-cell sequencing data from multiple highly annotated public clinical cohorts. Second, we identified differences in the tumor microenvironment between the two glioblastoma sample clusters and resolved key signaling pathways between cell clusters at the single-cell level based on comprehensive comparative analyses to investigate the reasons for survival differences between two of these clusters. Finally, we developed a diagnostic map and a prediction model for glioblastoma, and compared theoretical differences of drug sensitivity between two glioblastoma sample clusters. In summary, this study established a classification system for dissecting promoter CpG island methylation heterogeneity in glioblastoma and provides a new perspective for the diagnosis and treatment of glioblastoma.

Pan-cancer analysis of the DNA methylation patterns of long non-coding RNA.

Long non-coding RNA (lncRNA) regulated by abnormal DNA methylation (ADM-lncRNA) emerges as a biomarker for cancer diagnosis and treatment. This study comprehensively described the methylation patterns of lncRNA in pan-cancer using the cancer data set in The Cancer Genome Atlas (TCGA). Based on the cancer heterogeneity of ADM-lncRNA in pan-cancer, we constructed a co-expression network of pan-cancer ADM-lncRNA (pADM-lncRNA) in 10 cancers, highlighting the combined action mode of abnormal DNA methylation, and indicating the internal connection among different cancers. Functional analysis revealed the pan-carcinogenic pathway of pADM-lncRNA and suggested potential factors for cancer heterogeneity and tumor immune microenvironment changes. Survival analysis showed the potential of pADM-lncRNA-mRNA co-expression pair as cancer biomarkers. Revealing the action mode of lncRNA and DNA methylation in cancer may help understand the key molecular mechanisms of cell carcinogenesis.

Engineered Thin Diffusion Layers for Anion-Exchange Membrane Electrolyzer Cells with Outstanding Performance.

Anion-exchange membrane electrolyzer cells (AEMECs) are one of the most promising technologies for carbon-neutral hydrogen production. Over the past few years, the performance and durability of AEMECs have substantially improved. Herein, we report an engineered liquid/gas diffusion layer (LGDL) with tunable pore morphologies that enables the high performance of AEMECs. The comparison with a commercial titanium foam in the electrolyzer indicated that the engineered LGDL with thin-flat and straight-pore structures significantly improved the interfacial contacts, mass transport, and activation of more reaction sites, leading to outstanding performance. We obtained a current density of 2.0 A/cm2 at 1.80 V with an efficiency of up to 81.9% at 60 °C under 0.1 M NaOH-fed conditions. The as-achieved high performance in this study provides insight to design advanced LGDLs for the production of low-cost and high-efficiency AEMECs.

The regulatory pattern of target gene expression by aberrant enhancer methylation in glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor with grim prognosis. Aberrant DNA methylation is an epigenetic mechanism that promotes GBM carcinogenesis, while the function of DNA methylation at enhancer regions in GBM remains poorly described. RESULTS: We integrated multi-omics data to identify differential methylation enhancer region (DMER)-genes and revealed global enhancer hypomethylation in GBM. In addition, a DMER-mediated target genes regulatory network and functional enrichment analysis of target genes that might be regulated by hypomethylation enhancer regions showed that aberrant enhancer regions could contribute to tumorigenesis and progression in GBM. Further, we identified 22 modules in which lncRNAs and mRNAs synergistically competed with each other. Finally, through the construction of drug-target association networks, our study identified potential small-molecule drugs for GBM treatment. CONCLUSIONS: Our study provides novel insights for understanding the regulation of aberrant enhancer region methylation and developing methylation-based biomarkers for the diagnosis and treatment of GBM.

Pharmacokinetics and tissue distribution study of hupehenenine in rats: A novel isosteroid alkaloid isolated from Bulbus Hupehensis Fritillariae.

Hupehenenine is a novel isosteroid alkaloid that was first isolated from Bulbus Hupehensis Fritillariae. The inhibitory proliferation effect of hupehenenine and its three related alkaloid derivatives, including o-caproyl-hupehenenine, o-(2-furanoyl)-hupehenenine, and Δ5(6) -isopeimine on human lung cancer cell line, human chronic myeloid leukemia cell line, and human thyroid duct cancer cell line in vitro, has been identified. This study first developed a sensitive HPLC-MS/MS method for the simultaneous quantification of hupehenenine and three alkaloid derivatives in rat plasma and tissues. The developed method was validated, and it was linear over the concentration range of 1-800 ng/mL for all analytes with R2 ≥ 0.9939 and 0.9972, respectively, in rat plasma and rat liver homogenate. The lower limit of quantitation was 1 ng/mL for all analytes. The intra-day and inter-day precision and accuracy were satisfactory. This validated method was successfully applied to investigate the pharmacokinetics and tissue distribution of hupehenenine in rats. In pharmacokinetic study, the maximum plasma concentration of rats exists gender difference. Tissue distribution study showed that hupehenenine has good affinity for multiple tissues but is unable to cross the blood-brain barrier. These results may provide a useful reference for further research of hupehenenine and its three related alkaloid derivatives.

Author Correction: Eliminating dissolution of platinum-based electrocatalysts at the atomic scale.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Eliminating dissolution of platinum-based electrocatalysts at the atomic scale.

A remaining challenge for the deployment of proton-exchange membrane fuel cells is the limited durability of platinum (Pt) nanoscale materials that operate at high voltages during the cathodic oxygen reduction reaction. In this work, atomic-scale insight into well-defined single-crystalline, thin-film and nanoscale surfaces exposed Pt dissolution trends that governed the design and synthesis of durable materials. A newly defined metric, intrinsic dissolution, is essential to understanding the correlation between the measured Pt loss, surface structure, size and ratio of Pt nanoparticles in a carbon (C) support. It was found that the utilization of a gold (Au) underlayer promotes ordering of Pt surface atoms towards a (111) structure, whereas Au on the surface selectively protects low-coordinated Pt sites. This mitigation strategy was applied towards 3 nm Pt3Au/C nanoparticles and resulted in the elimination of Pt dissolution in the liquid electrolyte, which included a 30-fold durability improvement versus 3 nm Pt/C over an extended potential range up to 1.2 V.

Genome­wide DNA methylation regulation analysis of long non­coding RNAs in glioblastoma.

Glioblastoma (GBM) is a malignant brain tumor associated with high mortality. Long non­coding RNAs (lncRNAs) are increasingly being recognized as its modulators. However, it remains mostly unexplored how lncRNAs are mediated by DNA methylation in GBM. The present study integrated multi­omics data to analyze the epigenetic dysregulation of lncRNAs in GBM. Widely aberrant methylation in the lncRNA promoters was observed, and the lncRNA promoters exhibited a more hypomethylated pattern in GBM. By combining transcriptional datasets, it was possible identify the lncRNAs whose transcriptional changes might be associated with the aberrant promoter methylation. Then, a methylation­mediated lncRNA regulatory network and functional enrichment analysis of aberrantly methylated lncRNAs showed that lncRNAs with different methylation patterns were involved in diverse GBM progression­related biological functions and pathways. Specifically, four lncRNAs whose increased expression may be regulated by the corresponding promoter hypomethylation were evaluated to have an excellent diagnostic effect and clinical prognostic value. Finally, through the construction of drug­target association networks, the present study identified potential therapeutic targets and small­molecule drugs for GBM treatment. The present study provides novel insights for understanding the regulation of lncRNAs by DNA methylation and developing cancer biomarkers in GBM.

The improvement of the shear stress and oscillatory shear index of coronary arteries during Enhanced External Counterpulsation in patients with coronary heart disease.

BACKGROUND: Enhanced External Counterpulsation (EECP) can chronically relieve ischemic chest pain and improve the prognosis of coronary heart disease (CHD). Despite its role in mitigating heart complications, EECP and the mechanisms behind its therapeutic nature, such as its effects on blood flow hemodynamics, are still not fully understood. This study aims to elucidate the effect of EECP on significant hemodynamic parameters in the coronary arterial tree. METHODS: A finite volume method was used in conjunction with the inlet pressure wave (surrogated by the measured aortic pressure) before and during EECP and outlet flow resistance, assuming the blood as newtonian fluid. The time-average wall shear stress (TAWSS) and oscillatory shear index (OSI) were determined from the flow field. RESULTS: Regardless of the degree of vascular stenosis, hemodynamic conditions and flow patterns could be improved during EECP. In comparison with the original tree, the tree with a severe stenosis (75% area stenosis) demonstrated more significant improvement in hemodynamic conditions and flow patterns during EECP, with surface area ratio of TAWSS risk area (SAR-TAWSS) reduced from 12.3% to 6.7% (vs. SAR-TAWSS reduced from 7.2% to 5.6% in the original tree) and surface area ratio of OSI risk area (SAR-OSI) reduced from 6.8% to 2.5% (vs. SAR-OSI of both 0% before and during EECP in the original tree because of mild stenosis). Moreover, it was also shown that small ratio of diastolic pressure (D) and systolic pressure (S) (D/S) could only improve the hemodynamic condition mildly. The SAR-TAWSS reduction ratio significantly increased as D/S became larger. CONCLUSIONS: A key finding of the study was that the improvement of hemodynamic conditions along the LMCA trees during EECP became more significant with the increase of D/S and the severity degree of stenoses at the bifurcation site. These findings have important implications on EECP as adjuvant therapy before or after percutaneous coronary intervention (PCI) in patients with diffuse atherosclerosis.

Sex-specific and opposite modulatory aspects revealed by PPI network and pathway analysis of ischemic stroke in humans.

BACKGROUND: Ischemic Stroke (IS) is a major disease which greatly threatens human health. Recent studies showed sex-specific outcomes and mechanisms of cerebral ischemic stroke. This study aimed to identify the key changes of gene expression between male and female IS in humans. METHODS: Gene expression dataset GSE22255, including peripheral blood samples, was downloaded from the Gene Expression Omnibus (GEO) dataset. Differentially Expressed Genes (DEGs) with a LogFC>1, and a P-value <0.05 were screened by BioConductor R package and grouped in female, male and overlap DEGs for further bioinformatic analysis. Gene Ontology (GO) functional annotation, Protein-Protein Interaction (PPI) network, "Molecular Complex Detection" (MCODE) modules, CytoNCA (cytoscape network centrality analysis) essential genes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway interrelation analysis were performed. RESULTS: In a total of 54,665 genes, 185 (73 ups and 112 downs) DEGs in the female dataset, 461 DEGs (297 ups and 164 downs) in the male dataset, within which 118 DEGs overlapped (7 similar changes in female and male, 111 opposite changes in female and male) were obtained from the GSE22255 dataset. Female, male and overlapping DEGs enriched for similar cellular components and molecular function. Male DEGs enriched for divergent biological processes from female and overlapping DEGs. Sex-specific and overlapping DEGs were put into the PPI network. Overlapping genes such as IL6, presented opposite changes and were mainly involved in cytokine-cytokine receptor interactions, the TNF-signalling pathway, etc. CONCLUSION: The analysis of sex-specific DEGs from GEO human blood samples showed that not only specific but also opposite DEG alterations in the female and male stroke genome wide dataset. The results provided an overview of sex-specific mechanisms, which might provide insight into stroke and its biomarkers and lead to sex-specific prognosis and treatment strategies in future clinical practice.

Unusually High Concentration of Alkyl Ammonium Hydroxide in the Cation-Hydroxide-Water Coadsorbed Layer on Pt.

Interactions between a catalyst and electrolyte have paramount importance for the performance of electrochemical devices. Here, we present the cation-hydroxide-water coadsorption on the Pt surface by a rotating disk electrode and neutron reflectometry. The rotating disk electrode experiments show that the current density of Pt rapidly dropped at hydrogen oxidation potentials due to tetramethylammonium hydroxide (TMAOH)-water coadsorption. Subsequent neutron reflectometry in 0.1 M TMAOD/D2O reveals that the thickness of the coadsorbed layer increased to 18 Å after 10.5 h exposure at 0.1 V vs reverse hydrogen electrode (RHE). The scattering length density analysis revealed that the TMAOD to water ratio in the coadsorbed layer was 4.5, which was significantly higher than the reportedly highest TMAOH concentration in aqueous solution. Finally, we discuss the potential impact of the coadsorbed layer on the performance and durability of alkaline membrane fuel cells, which sheds light on the material design of high-performance alkaline electrochemical devices.

cPKCßII is significant to hypoxic preconditioning in mice cerebrum.

Stroke causes significant morbidity and mortality worldwide, for which no satisfactory preventive option currently exists. Hypoxic preconditioning (HPC) is a protective strategy for cerebral ischemic stroke. To this end, we have identified, Conventional protein kinase C (cPKC)BetaII to play an important role in HPC. Pathway analysis and protein-protein interaction network building and functional proteomic exploration was used to identify 38 proteins in 6 Kyoto Encyclopedia of Genes and Genomes pathways that interact with cPKCBetaII in brains subjected to HPC. The role of the oxidative phosphorylation pathway was confirmed by experimental validation, and the demonstration that the activity of the complex I and complex V and expression and activity of Ndufv2 and ATP5d was increased. Ndufv2 was co-localized with PKCBetaII in neurons rather than glial cells. Together, these data show that Ndufv2 and the oxidative phosphorylation pathway play an important role in cPKCBetaII-related HPC mediated signalling, likely as an adaptive neuroprotective mechanism.

Comparison and analysis of lncRNA-mediated ceRNA regulation in different molecular subtypes of glioblastoma.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with a poor prognosis. A molecular level classification of GBM can provide insight into accurate patient-specific treatment. Competitive endogenous RNAs (ceRNAs), such as long non-coding RNAs (lncRNAs), play an essential role in the development of tumors and are associated with survival. However, the pattern of lncRNA-mediated ceRNA (LMce) crosstalk in different GBM subtypes is still unclear. In this study, we present a computational cascade to construct LMce networks of different GBM subtypes and investigate the lncRNA-mRNA regulations among them. Our results showed that although most lncRNAs and mRNAs in the different GBM subtype networks were the same, the regulation relationships of these RNAs were different among subtypes. 42.5%, 50.9%, 43.5% and 65.0% lncRNA-mRNA regulatory pairs were classic (CL)-, mesenchymal (MES)-, proneural (PN)- and neural (NE)-specific. In addition, our study identified 61, 132, 24 and 16 modules in which lncRNAs and mRNAs synergically competed with each other for miRNAs as CL-, MES-, PN- and NE-specific. CL- and MES-specific modules were mainly involved in biological functions such as cell proliferation, apoptosis and migration, while PN- and NE-specific modules were mainly related to DNA damage and cell cycle dysregulation. Survival analysis demonstrated that some modules could be potential prognostic markers of patients of CL and MES subtypes. This study uncovered the LMce interaction patterns in different GBM subtypes, identified subtype-specific modules with distinct biological functions, and revealed the potential prognostic markers of patients of different GBM subtypes. These results might contribute to the discovery of the GBM prognostic biomarkers and development of a more accurate therapeutic process.

Phenyl Oxidation Impacts the Durability of Alkaline Membrane Water Electrolyzer.

The durability of alkaline anion exchange membrane (AEM) electrolyzers is a critical requirement for implementing this technology in cost-effective hydrogen production. Here, we report that the electrochemical oxidation of the adsorbed phenyl group (found in the ionomer) on oxygen evolution catalysts produces phenol, which may cause performance deterioration in AEM electrolyzers. In-line 1H NMR kinetic analyses of phenyl oxidation in a model organic cation electrolyte shows that catalyst type significantly impacts the phenyl oxidation rate at an oxygen evolution potential. Density functional theory calculations show that the phenyl adsorption is a critical factor determining the phenyl oxidation. This research provides a path for the development of more durable AEM electrolyzers with components that can minimize the adverse impact induced by the phenyl group oxidation, such as the development of novel ionomers with fewer phenyl moieties or catalysts with less phenyl-adsorbing character.

Binary Transition-Metal Oxide Hollow Nanoparticles for Oxygen Evolution Reaction.

Low-cost transition metal oxides are actively explored as alternative materials to precious metal-based electrocatalysts for the challenging multistep oxygen evolution reaction (OER). We utilized the Kirkendall effect allowing the formation of hollow polycrystalline, highly disordered nanoparticles (NPs) to synthesize highly active binary metal oxide OER electrocatalysts in alkali media. Two synthetic strategies were applied to achieve compositional control in binary transition metal oxide hollow NPs. The first strategy is capitalized on the oxidation of transition-metal NP seeds in the presence of other transition-metal cations. Oxidation of Fe NPs treated with Ni (+2) cations allowed the synthesis of hollow oxide NPs with a 1-4.7 Ni-to-Fe ratio via an oxidation-induced doping mechanism. Hollow Fe-Ni oxide NPs also reached a current density of 10 mA/cm2 at 0.30 V overpotential. The second strategy is based on the direct oxidation of iron-cobalt alloy NPs which allows the synthesis of hollow Fe xCo100- x-oxide NPs where x can be tuned in the range between 36 and 100. Hollow Fe36Co64-oxide NPs also revealed the current density of 10 mA/cm2 at 0.30 V overpotential in 0.1 M KOH.

Clinical features of acute acquired comitant esotropia in the Chinese populations.

Acute acquired comitant esotropia (AACE) is an unusual presentation of esotropia that occurs after infancy. This study was aimed to study the clinical features and the differences between children and adult patients with AACE in the Chinese populations.This was a retrospective analysis of patients diagnosed with AACE over 4 years; 69 patients (25 females and 44 males) were identified. The patients were divided into 3 groups: < 10 year-old (n = 6, 8.7%), 10-18 year-old (n = 23, 33.3%), and ≥18 year-old (n = 40, 58.0%). Patients underwent medical history, brain and orbital computed tomography, and ophthalmological and orthoptic examinations.The refractions of AACE patients varied among age groups: patients < 10 year-old had mild hypermetropia, while older children and adults showed moderate-to-high myopia (P < .001). The mean angles of esotropia were significantly larger in young children compared with older children and adults (P = .005). There was no significant difference in binocularity detected by either synoptophore or TNO stereoscopic testing among different disease durations. Stereopsis detected by synoptophore and TNO testing showed no significant difference at duration within half a year, but the stereopsis measured by TNO was significantly worse than that detected by synoptophore with extending disease duration (P < .05).AACE seems to occur mostly in older children and adults in the Chinese population. Younger children with AACE seem to demonstrate a common trait of mild hypermetropic refractive errors, while myopia can be seen in older children and adult patients. The duration from onset to treatment of esotropia does not affect the preoperative binocularity.

Control of Architecture in Rhombic Dodecahedral Pt-Ni Nanoframe Electrocatalysts.

Platinum-based alloys are known to demonstrate advanced properties in electrochemical reactions that are relevant for proton exchange membrane fuel cells and electrolyzers. Further development of Pt alloy electrocatalysts relies on the design of architectures with highly active surfaces and optimized utilization of the expensive element, Pt. Here, we show that the three-dimensional Pt anisotropy of Pt-Ni rhombic dodecahedra can be tuned by controlling the ratio between Pt and Ni precursors such that either a completely hollow nanoframe or a new architecture, the excavated nanoframe, can be obtained. The excavated nanoframe showed ∼10 times higher specific and ∼6 times higher mass activity for the oxygen reduction reaction than Pt/C, and twice the mass activity of the hollow nanoframe. The high activity is attributed to enhanced Ni content in the near-surface region and the extended two-dimensional sheet structure within the nanoframe that minimizes the number of buried Pt sites.