Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

MTMR3 risk alleles enhance Toll Like Receptor 9-induced IgA immunity in IgA nephropathy.

Multiple genome-wide association studies (GWASs) have reproducibly identified the MTMR3/HORMAD2/LIF/OSM locus to be associated with IgA nephropathy (IgAN). However, the causal variant(s), implicated gene(s), and altered mechanisms remain poorly understood. Here, we performed fine-mapping analyses based on GWAS datasets encompassing 2762 IgAN cases and 5803 control individuals, and identified rs4823074 as the candidate causal variant that intersects the MTMR3 promoter in B-lymphoblastoid cells. Mendelian randomization studies suggested the risk allele may modulate disease susceptibility by affecting serum IgA levels through increased MTMR3 expression. Consistently, elevated MTMR3 expression in peripheral blood mononuclear cells was observed in patients with IgAN. Further mechanistic studies in vitro demonstrated that MTMR3 increased IgA production dependent upon its phosphatidylinositol 3-phosphate binding domain. Moreover, our study provided the in vivo functional evidence that Mtmr3-/- mice exhibited defective Toll Like Receptor 9-induced IgA production, glomerular IgA deposition, as well as mesangial cell proliferation. RNA-seq and pathway analyses showed that MTMR3 deficiency resulted in an impaired intestinal immune network for IgA production. Thus, our results support the role of MTMR3 in IgAN pathogenesis by enhancing Toll Like Receptor 9-induced IgA immunity.

Interleukin 4-driven reversal of self-reactive B cell anergy contributes to the pathogenesis of systemic lupus erythematosus.

OBJECTIVES: Reactivation of anergic autoreactive B cells (BND cells) is a key aetiological process in systemic lupus erythematosus (SLE), yet the underlying mechanism remains largely elusive. This study aimed to investigate how BND cells participate in the pathogenesis of SLE and the underlying mechanism. METHODS: A combination of phenotypical, large-scale transcriptome and B cell receptor (BCR) repertoire profiling were employed at molecular and single cell level on samples from healthy donors and patients with SLE. Isolated naïve B cells from human periphery blood were treated with anti-CD79b mAb in vitro to induce anergy. IgM internalisation was tracked by confocal microscopy and was qualified by flow cytometer. RESULTS: We characterised the decrease and disruption of BND cells in SLE patients and demonstrated IL-4 as an important cytokine to drive such pathological changes. We then elucidated that IL-4 reversed B cell anergy by promoting BCR recycling to the cell surface via STAT6 signalling. CONCLUSIONS: We demonstrated the significance of IL-4 in reversing B cell anergy and established the scientific rationale to treat SLE via blocking IL-4 signalling, also providing diagnostic and prognostic biomarkers to identify patients who are most likely going to benefit from such treatments.

Mutations in troABCD against Copper Overload in a copA Mutant of Streptococcus suis.

Streptococcus suis is a major swine pathogen that is increasingly recognized as a porcine zoonotic pathogen that threatens the health of both pigs and humans. Metal homeostasis plays a critical role during the process of bacterial infection. In this study, RNA sequencing was used to identify potential candidate genes involved in the maintenance of intracellular copper homeostasis. CopA was identified as the primary copper exporter in S. suis. The copA deletion mutant strain was found to be more sensitive to copper and accumulated more intracellular copper than the wild-type (WT) parent strain. In addition, adding manganese increased the ability of S. suis to resist copper, and the manganese transporter, TroABCD, was involved in tolerance to copper. The copA deletion mutant strain accumulated less copper when supplemented with manganese. Furthermore, when cultured with copper, the double deletion mutant (ΔcopAΔtroA) exhibited improved growth compared to the copA deletion mutant strain. In addition, the double deletion mutant (ΔcopAΔtroA) accumulated less copper than the copA deletion mutant strain. These data were consistent with a model wherein defective TroABCD resulted in decreased cellular copper accumulation and protected the strain against copper poisoning. IMPORTANCE Metal homeostasis plays a critical role during the process of bacterial infection. We identified three important potential candidate genes involved in maintenance of intracellular copper homeostasis. CopA was demonstrated to be the main copper exporter in Streptococcus suis, and manganese increased the tolerance of S. suis to copper. The double deletion mutant (ΔcopAΔtroA) improved growth ability over the copA deletion mutant strain in the presence of high concentrations of copper and accumulated less copper. These findings are consistent with a model wherein defective TroABCD resulted in decreased cellular accumulation of copper and protected the strain against copper poisoning.

Changes of intestinal microbiota and microbiota-based treatments in IBD.

Inflammatory bowel disease (IBD) has gained increasing attention from researchers in terms of its pathophysiology as a global disease with a growing incidence. Although the exact etiology of IBD is still unknown currently, various studies have made us realize that it is related to the dysbiosis of intestinal microbiota and the link between the two may not just be a simple causal relationship, but also a dynamic and complicated one. The intestinal microbiota has been confirmed to be closely related to the occurrence, development, and treatment of IBD. Therefore, this review focuses on the changes in the structure, function, and metabolites of intestinal bacteria, fungi, and viruses in influencing IBD, as well as various approaches to IBD treatment by changing disordered intestinal microbiota. Ultimately, more clinical studies will be needed to focus on the efficacy of intestinal microbiota-based treatments in IBD, because of the existence of both advantages and disadvantages.

Circ_0005397 enhances hepatocellular carcinoma progression through miR-1283/HEG1.

INTRODUCTION AND OBJECTIVES: Circular RNA (circRNA) has been confirmed to be an important regulator for the progression of hepatocellular carcinoma (HCC). However, the role and regulatory mechanism of circ_0005397 in HCC are not completely clear. PATIENTS AND METHODS: Fifty HCC patients were included in this study. Reverse transcription-qPCR analysis was used to appraise circ_0005397, microRNA (miR)-1283, HEG homolog 1 (HEG1) mRNA expression levels, while western blot was used to identify HEG1, PCNA, Bax and Bcl-2 protein expression levels. Furthermore, cell proliferation, apoptosis, migration, invasion and angiogenesis were judged through cell counting kit-8 assay, EdU assay, Caspase3 activity test, flow cytometry, transwell assay and tube formation experiment. Dual-luciferase reporter assay and RIP assay were used to verify the targeting relationship between miR-1283 and circ_0005397 or HEG1. Finally, the effect of circ_0005397 on HCC tumor development was detected by mice experiments in vivo. RESULTS: Circ_0005397 was highly expressed in HCC tissues and cells, in HCC cell lines. Circ_0005397 silencing inhibited proliferation, migration, invasion and angiogenesis, while induced apoptosis in HCC cells. Circ_0005397 could sponge miR-1283, and miR-1283 could target HEG1. MiR-1283 inhibitor incompletely counteracted the effect of si-circ_0005397 on HCC cell progression, while HEG1 overexpression partially overturned the effect of miR-1283 on HCC cell progression. Circ_0005397 regulated the expression of HEG1 through targeting miR-1283. Moreover, circ_0005397 silencing blocked the growth of HCC tumors in vivo. CONCLUSIONS: Circ_0005397 regulated HEG1 by targeting miR-1283, thereby promoting HCC development.

Interaction between GALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy.

BACKGROUND: Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established. METHODS: To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis. RESULTS: We discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; ß=0.26, P=1.20×10-9); the locus we identified at GALNT12 (rs7856182; ß=0.73, P=2.38×10-9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10-2) and disease risk (P=6.55×10-3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls. CONCLUSIONS: Our data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.

Identification and Validation of Ferroptosis-Related DNA Methylation Signature for Predicting the Prognosis and Guiding the Treatment in Cutaneous Melanoma.

Cutaneous melanoma (CM) is one of the most aggressive skin tumors with a poor prognosis. Ferroptosis is a newly discovered form of regulated cell death that is closely associated with cancer development and immunotherapy. The aim of this study was to establish and validate a ferroptosis-related gene (FRG) DNA methylation signature to predict the prognosis of CM patients using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. A reliable four-FRG DNA methylation prognostic signature was constructed via Cox regression analysis based on TCGA database. Kaplan-Meier analysis showed that patients in the high-risk group tended to have a shorter overall survival (OS) than the low-risk group in both training TCGA and validation GEO cohorts. Time-dependent receiver operating characteristic (ROC) analysis showed the areas under the curve (AUC) at 1, 3, and 5 years were 0.738, 0.730, and 0.770 in TCGA cohort and 0.773, 0.775, and 0.905 in the validation cohort, respectively. Univariate and multivariate Cox regression analyses indicated that the signature was an independent prognostic indicator of OS in patients with CM. Immunogenomic profiling showed the low-risk group of patients had a higher immunophenoscore, and most immune checkpoints were negatively associated with the risk signature. Functional enrichment analysis revealed that immune response and immune-related pathways were enriched in the low-risk group. In conclusion, we established and validated a four-FRG DNA methylation signature that independently predicts prognosis in CM patients. This signature was strongly correlated with the immune landscape, and may serve as a biomarker to guide clinicians in making more precise and personalized treatment decisions for CM patients.

Shared genetic study gives insights into the shared and distinct pathogenic immunity components of IgA nephropathy and SLE.

An autoimmune component has been suggested to play a role in pathogenesis of IgA nephropathy (IgAN). And genetic studies have reported the shared susceptibility loci between IgAN and the prototype autoimmune disease systemic lupus erythematosus (SLE). This study was designed to systemically identify and annotate the shared susceptibility genes between IgAN and SLE. We first conducted an imputation-based genome-wide association analysis in 1180 IgAN cases and 899 controls, 1639 SLE cases and 2410 controls. Then we integrated blood expression quantitative trait loci (eQTL) databases and gene expression data to prioritize the potentially functional genes. The results showed that a total of 1928 SNPs mapping to 14 loci were identified to be shared genes between IgAN and SLE. Conditional analysis prioritized 18 independent SNPs, among which alleles of 4 SNPs in HLA and 7 SNPs in non-HLA loci were risk for SLE were protective alleles for IgAN. Most of the shared SNPs and their proxies (r2 ≥ 0.8 in Asians) (181/184, 98.37%) in non-HLA loci were located in non-coding regions. By analyzing two publicly independent blood-eQTL databases, four genes UBE2L3, FCGR2B, ANXA6, and BLK, which seemed to be restricted to PBMC or its subsets were prioritized. Among them only UBE2L3 showed consistent direction between SLE and IgAN, while the others showed opposite directions. Differential gene analysis showed that UBE2L3 was highly expressed in both SLE and IgAN, while FCGR2B and BLK showed marginal significance in SLE and IgAN, respectively. By exploring the pleiotropy of shared genes between IgAN and SLE, our results provide important clues for understanding the shared role of plasmablasts but the distinct role of B cells in pathogenesis of these two diseases.

High-Energy Metal-Organic Frameworks with a Dicyanamide Linker for Hypergolic Fuels.

In this study, a hypergolic linker (dicyanamide, DCA) and a high-energy nitrogen-rich ligand (1,5-diaminotetrazole, DAT) were applied to construct high-energy metal-organic frameworks (HEMOFs) with hypergolic property. Three novel metal-organic frameworks (MOFs) were synthesized via a mild method with fascinating 2D polymeric architectures, and they could ignite spontaneously upon contact with white fuming nitric acid (WFNA). The gravimetric energy densities of the three HEMOFs all exceeded 26.2 kJ·g-1. The cupric MOF exhibits the highest gravimetric and volumetric energy density of 27.5 kJ·g-1 and 51.3 kJ·cm-3, respectively. By adjusting the metal cations, high-energy ligands and hypergolic linkers can improve the performance of hypergolic MOFs. This work provides a strategy for manufacturing MOFs as potential high-energy hypergolic fuels.

Effect of follicle cell autophagy on gonadal development of triploid female rainbow trout (Oncorhynchus mykiss).

Autophagy is a cellular process which occurs in eukaryotic cells. To study the mechanism regulating polyploid fish growth and development is of significance in genetic, because of its growth advantages and economic values. This study focused on triploid female rainbow trout (RBT) which discusses the effects of autophagy on gonadal development of polyploid fish. Autophagy-related genes of RBT lc3b, atg12, atg4b, gabarap1, and bcl2 were cloned, and autophagy gene expressions in gonads were analyzed at different developmental period. Gonadal ultrastructures were observed under transmission electron microscopy. To detect autophagy protein expression and localization, antibodies of RBT-LC3B and RBT-ATG12 were produced. Results showed clear evidence that autophagy-related genes were highly expressed during 200-300 days post fertilization (dpf), in which autophagosome structures were identified. In this stage, the conversion of LC3B-I to LC3B-II was greater than those in other stages. Immunolabeling-manifested autophagy occurred intensively in the cytoplasm of follicular cells. The morphology of follicular cells was gradually changed, leading to gonadal fibrosis and regression. This autophagic research is a new study area on gonadal development of polyploid fish.

Cuproptosis-related DNA methylation signature predict prognosis and immune microenvironment in cutaneous melanoma.

The prognosis for Cutaneous Melanoma (CM), a skin malignant tumor that is extremely aggressive, is not good. A recently identified type of controlled cell death that is intimately related to immunotherapy and the development of cancer is called cuproptosis. Using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, we developed and validated a DNA-methylation located in cuproptosis death-related gene prognostic signature (CRG-located DNA-methylation prognostic signature) to predict CM's prognosis. Kaplan-Meier analysis of our TCGA and GEO cohorts showed that high-risk patients had a shorter overall survival. The area under the curve (AUC) for the TCGA cohort was 0.742, while for the GEO cohort it was 0.733, according to the receiver operating characteristic (ROC) analysis. Furthermore, this signature was discovered as an independent prognostic indicator over CM patients based on Cox-regression analysis. Immunogenomic profiling indicated that majority immune-checkpoints got an opposite relationship with the signature, and patients in the group at low risk got higher immunophenoscore. Several immune pathways were enriched, according to functional enrichment analysis. In conclusion, a prognostic methylation signature for CM patients was established and confirmed. Because of its close relationship to the immune landscape, this signature may help clinicians make more accurate and individualized choices regarding therapy.

Radiomics Model of Dynamic Contrast-Enhanced MRI for Evaluating Vessels Encapsulating Tumor Clusters and Microvascular Invasion in Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: To develop and validate a clinical-radiomics model of dynamic contrast-enhanced MRI (DCE-MRI) for the preoperative discrimination of Vessels encapsulating tumor clusters (VETC)- microvascular invasion (MVI) and prognosis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: 219 HCC patients from Institution 1 were split into internal training and validation groups, with 101 patients from Institution 2 assigned to external validation. Histologically confirmed VETC-MVI pattern categorizing HCC into VM-HCC+ (VETC+/MVI+, VETC-/MVI+, VETC+/MVI-) and VM-HCC- (VETC-/MVI-). The regions of intratumor and peritumor were segmented manually in the arterial, portal-venous and delayed phase (AP, PP, and DP, respectively) of DCE-MRI. Six radiomics models (intratumor and peritumor in AP, PP, and DP of DCE-MRI) and one clinical model were developed for assessing VM-HCC. Establishing intra-tumoral and peri-tumoral models through combining intratumor and peritumor features. The best-performing radiomics model and the clinical model were then integrated to create a Combined model. RESULTS: In institution 1, pathological VM-HCC+ were confirmed in 88 patients (training set: 61, validation set: 27). In internal testing, the Combined model had an AUC of 0.85 (95% CI: 0.76-0.93), which reached an AUC of 0.75 (95% CI: 0.66-0.85) in external validation. The model's predictions were associated with early recurrence and progression-free survival in HCC patients. CONCLUSIONS: The clinical-radiomics model offers a non-invasive approach to discern VM-HCC and predict HCC patients' prognosis preoperatively, which could offer clinicians valuable insights during the decision-making phase.

A cluster of type I interferon-regulated genes associates with disease activity and prognosis in patients with IgA nephropathy.

The exact pathogenesis of IgA nephropathy (IgAN) is complex and so far, not well defined. Since it has been shown that microbial infections could induce high levels of type I interferon (IFN-I) and there is an evident link between mucosal infection and gross hematuria in IgAN, we hypothesized that IFN-I may play a role in the pathogenic process. In this study, we investigated the type I interferon status in IgAN based on the expression of 17 IFN-regulated genes (IRGs) in whole blood from 59 IgAN patients in a cross-sectional study, of which 34 patients followed longitudinally. Analysis of the IFN-score showed that there was a significant elevated IFN-score in the IgAN patients compared with healthy controls (n = 28, p = 9.80 × 10-3), and we observed an elevated IFN-score in the group with less tubular atrophy/interstitial fibrosis (p = 1.07 × 10-2) and with a lower proportion of mesangial hypercellularity (p = 1.23 × 10-2). In the longitudinal analysis, Cox regression analysis revealed that a higher IFN level was associated with a better renal outcome in IgAN after adjustments for gender and age (hazard ratio, 0.90; 95 % confidence interval, 0.81 to 0.97; p = 4.20 × 10-2). In conclusion, our finding suggested that IFN score may represent a novel type of biomarker in IgAN, which requires further exploration on its mechanism and therapeutic targeting.

Unveiling biomarkers and therapeutic targets in IgA nephropathy through large-scale blood transcriptome analysis.

INTRODUCTION: IgA nephropathy (IgAN) is the most prevalent form of glomerulonephritis. Unfortunately, molecular biomarkers for IgAN derived from omics studies are still lacking. This research aims to identify critical genes associated with IgAN through large-scale blood transcriptome analysis. METHODS: We constructed novel blood transcriptome profiles from peripheral blood mononuclear cells (PBMCs) of 53 Chinese IgAN patients and 28 healthy individuals. Our analysis included GO, KEGG, and GSEA for biological pathways. We analyzed immune cell profiles with CIBERSORT and constructed PPI networks with STRING, visualized in Cytoscape. Key differentially expressed genes (DEGs) were identified using CytoHubba and MCODE. We assessed the correlation between gene expressions and clinical data to evaluate clinical significance and identified hub genes through machine learning, validated with an open-access dataset. Potential drugs were explored using the CMap database. RESULTS: We identified 333 DEGs between IgAN patients and healthy controls, mainly related to immune response and inflammation. Key pathways included NK cell mediated cytotoxicity, complement and coagulation cascades, antigen processing, and B cell receptor signaling. Cytoscape revealed 16 clinically significant genes (including KIR2DL1, KIR2DL3, VISIG4, C1QB, and C1QC, associated with sub-phenotype and prognosis). Machine learning identified two hub genes (KLRC1 and C1QB) for a diagnostic model of IgAN with 0.92 accuracy, validated at 1.00 against the GSE125818 dataset. Sirolimus, calcifediol, and efaproxiral were suggested as potential therapeutic agents. CONCLUSION: Key DEGs, particularly VISIG4, KLRC1, and C1QB, emerge as potential specific markers for IgAN, paving the way for future targeted personalized treatment options.

Understanding Use Intention of mHealth Applications Based on the Unified Theory of Acceptance and Use of Technology 2 (UTAUT-2) Model in China.

The COVID-19 pandemic has significantly impacted the healthcare industry, especially public health resources and resource allocation. With the change in people's lifestyles and increased demand for medical and health care in the post-pandemic era, the Internet and home healthcare have rapidly developed. As an essential part of Internet healthcare, mobile health (mHealth) applications help to fundamentally address the lack of medical resources and meet people's healthcare needs. In this mixed-method study, we conducted in-depth interviews with 20 users in China (mean age = 26.13, SD = 2.80, all born in China) during the pandemic, based on the unified theory of acceptance and use of technology 2 (UTAUT-2) mode, and identified four dimensions of user needs in mHealth scenarios: convenience, control, trust, and emotionality. Based on the interview results, we adjusted the independent variables, deleted the hedonic motivation and the habit, and added the perceived trust and perceived risk as the variables. Using a structural equation model (SEM), we designed the questionnaire according to the qualitative results and collected data from 371 participants (above 18 years old, 43.9% male) online to examine the interrelationships these variables. The results show that performance expectancy (ß = 0.40, p < 0.001), effort expectancy (ß = 0.40, p < 0.001), social influence (ß = 0.14, p < 0.05), facilitating condition (ß = 0.15, p < 0.001), and perceived trust (ß = 0.31, p < 0.001) had positive effects on use intention. Perceived risk (ß = -0.31, p < 0.001) harmed use intention, and price value (ß = 0.10, p > 0.5) had no significant effects on use intention. Finally, we discussed design and development guidelines that can enhance user experience of mHealth applications. This research combines the actual needs and the main factors affecting the use intention of users, solves the problems of low satisfaction of user experience, and provides better strategic suggestions for developing mHealth applications in the future.

Cupric coordination compounds with multiple anions: a promising strategy for the regulation of energetic materials.

To seek new high energetic materials, N-methylene-C-bridged nitrogen-rich heterocycle 1-((4,5-diamino-4H-1,2,4-triazol-3-yl)methyl)-1H-1,2,4-triazol-3,5-diamine (DATMTDA) (2) was first synthesized, and two copper coordination compounds ([Cu12(OH)4(ClO4)4(H2O)4(DATMTDA)12](ClO4)16·12H2O (3) and [Cu3(OH)(ClO4)(DATMTDA)3](ClO4)3(NO3) (4)) based on 2 were formed by introducing different anions. These compounds were characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction analysis. The crystal structures of compounds 3 and 4 are similar and crystallize in monoclinic systems with the P21/c space group, while the central copper atoms show different coordination behaviors. However, the structure of compounds 3 and 4 is analogous to a three dimensional structure owing to the O atom of OH-, forming coordinate bonds with three copper cations. The NBO charge of 2 was calculated using density functional theory to understand its coordination modes. The Hirshfeld surface calculation reveals that 3 and 4 have strong intermolecular interactions. The thermal decomposition processes, non-isothermal kinetics, and enthalpies of formation and sensitivities of these compounds were investigated. By introducing one NO3- of compound 4 to replace one ClO4- in compound 3, compound 4 shows lower density and lower decomposition peak temperature but lower sensitivity and a higher formation enthalpy than compound 3. The complex 4 possesses an outstanding catalytic effect for the decomposition of AP than that of complex 3. The results illustrate the possibility of introducing various anions into energetic coordination compounds for the regulation of energetic materials.

Twenty-four-hour ambulatory blood pressure variability and association with ischemic stroke subtypes in the subacute stage.

Background and purpose: Blood pressure (BP) variability (BPV) increases the risk of cerebral disease in both hemorrhagic and ischemic strokes. However, whether BPV is associated with different types of ischemic stroke remains unclear. In this study, we explored the relationship between BPV and ischemic stroke subtypes. Methods: We enrolled consecutive patients aged 47-95 years with ischemic stroke in the subacute stage. We categorized them into four groups based on their artery atherosclerosis severity, brain magnetic resonance imaging markers, and disease history: large-artery atherosclerosis, branch atheromatous disease, small-vessel disease, and cardioembolic stroke. Twenty-four-hour ambulatory blood pressure monitoring was performed, and the mean systolic blood pressure/diastolic blood pressure, standard deviation, and coefficient of variation were calculated. A multiple logistic regression model and random forest were used to test the relationship between BP and BPV in the different types of ischemic stroke. Results: A total of 286 patients, including 150 men (73.0 ± 12.3 years) and 136 women (77.8 ± 9.6 years) were included in the study. Of these, 86 (30.1%) patients had large-artery atherosclerosis, 76 (26.6%) had branch atheromatous disease, 82 (28.7%) had small-vessel disease, and 42 (14.7%) had cardioembolic stroke. There were statistically significant differences in BPV between subtypes of ischemic stroke in 24-h ambulatory blood pressure monitoring. The random forest model showed that BP and BPV were important features associated with ischemic stroke. Multinomial logistic regression analysis demonstrated that systolic blood pressure levels; systolic blood pressure variability at 24 h, daytime and nighttime; and nighttime diastolic blood pressure were independent risk factors for large-artery atherosclerosis after adjustment for confounders. When compared to branch atheromatous disease and small-vessel disease, nighttime diastolic blood pressure and standard deviation of diastolic blood pressure were significantly associated with patients in the cardioembolic stroke group. However, a similar statistical difference was not seen in patients with large-artery atherosclerosis. Conclusion: The results of this study indicate a discrepancy in blood pressure variability among different ischemic stroke subtypes during the subacute stage. Higher systolic blood pressure and systolic blood pressure variability during the 24 h, daytime, and nighttime, and nighttime diastolic blood pressure were independent predictors for large-artery atherosclerosis stroke. Increased nighttime diastolic BPV was an independent risk factor for cardioembolic stroke.