PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis.

BACKGROUND: Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms. METHODS: We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan et al, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network. RESULTS: Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort. CONCLUSIONS: This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.

Novel inflammatory and insulin resistance indices provide a clue in cerebral amyloid angiopathy.

This study investigated the correlation of newly identified inflammatory and insulin resistance indices with cerebral amyloid angiopathy (CAA), and explored their potential to differentiate CAA from hypertensive arteriopathy (HA). We retrospectively analyzed 514 consecutive patients with cerebral small vessel disease (CSVD)-related haemorrhage, comparing the differences in novel inflammatory and insulin resistance indices between patients with CAA and HA. Univariate regression, LASSO and multivariate regression were used to screen variables and construct a classification diagnosis nomogram. Additionally, these biomarkers were explored in patients with mixed haemorrhagic CSVD. Inflammatory indices were higher in CAA patients, whereas insulin resistance indices were higher in HA patients. Further analysis identified neutrophil-to-lymphocyte ratio (NLR, OR 1.17, 95% CI 1.07-1.30, P < 0.001), and triglyceride-glucose index (TyG, OR = 0.56, 95% CI 0.36-0.83, P = 0.005) as independent factors for CAA. Therefore, we constructed a CAA prediction nomogram without haemorrhagic imaging markers. The nomogram yielded an area under the curve (AUC) of 0.811 (95% CI 0.764-0.865) in the training set and 0.830 (95% CI 0.718-0.887) in the test set, indicating an ability to identify high-risk CAA patients. These results show that CSVD patients can be phenotyped using novel inflammatory and insulin resistance indices, potentially allowing identification of high-risk CAA patients without haemorrhagic imaging markers.

Bioinformatics investigation of adaptive immune-related genes in peri-implantitis and periodontitis: Characteristics and diagnostic values.

BACKGROUND: Peri-implantitis and periodontitis have similar immunological bioprocesses and inflammatory phenotypes. In the inflammatory process, the adaptive immune cells can drive the development of disease. This research investigated the differences and diagnostic significance of peri-implantitis and periodontitis in adaptive immune responses. METHODS: We acquired four GEO datasets of gene expressions in surrounding tissues in healthy person, healthy implant, periodontitis, and peri-implantitis patients. The structural characteristics and enrichment analyses of differential expression genes were examined. The adaptive immune landscapes in peri-implantitis and periodontitis were then evaluated using single sample gene set enrichment analysis. The STRING database and Cytoscape were used to identify adaptive hub genes, and the ROC curve was used to verify them. Finally, qRT-PCR method was used to verify the expression level of Hub gene in activated T cells on the titanium-containing or titanium-free culture plates. RESULTS: At the transcriptome level, the data of healthy implant, peri-implantitis and periodontitis were highly dissimilar. The peri-implantitis and periodontitis both exhibited adaptive immune response. Except for the activated CD4+T cells, there was no significant difference in other adaptive immune cells between peri-implantitis and periodontitis. In addition, correlation analysis showed that CD53, CYBB, and PLEK were significantly positively linked with activated CD4+T cells in the immune microenvironment of peri-implantitis, making them effective biomarkers to differentiate it from periodontitis. CONCLUSIONS: Peri-implantitis has a uniquely immunogenomic landscape that differs from periodontitis. This study provides new insights and ideas into the activated CD4+T cells and hub genes that underpin the immunological bioprocess of peri-implantitis.

Clearance dysfunction of trans-barrier transport and lymphatic drainage in cerebral small vessel disease: Review and prospect.

Cerebral small vessel disease (CSVD) causes 20%-25% of stroke and contributes to 45% of dementia cases worldwide. However, since its early symptoms are inconclusive in addition to the complexity of the pathological basis, there is a rather limited effective therapies and interventions. Recently, accumulating evidence suggested that various brain-waste-clearance dysfunctions are closely related to the pathogenesis and prognosis of CSVD, and after a comprehensive and systematic review we classified them into two broad categories: trans-barrier transport and lymphatic drainage. The former includes blood brain barrier and blood-cerebrospinal fluid barrier, and the latter, glymphatic-meningeal lymphatic system and intramural periarterial drainage pathway. We summarized the concepts and potential mechanisms of these clearance systems, proposing a relatively complete framework for elucidating their interactions with CSVD. In addition, we also discussed recent advances in therapeutic strategies targeting clearance dysfunction, which may be an important area for future CSVD research.

Causal Effects of Blood Metabolites and Obstructive Sleep Apnea: A Mendelian Randomization Study.

BACKGROUND: Obstructive sleep apnea (OSA) is one of the most common forms of sleep-disordered breathing. Studies have shown that certain changes in metabolism play an important role in the pathophysiology of OSA. However, the causal relationship between these metabolites and OSA remains unclear. AIMS: We use a mendelian randomization (MR) approach to investigate the causal associations between the genetic liability to metabolites and OSA. METHODS: We performed a 2-sample inverse-variance weighted mendelian randomization analysis to evaluate the causal effects of genetically determined 486 metabolites on OSA. Multiple sensitivity analyses were performed to assess pleiotropy. We used multivariate mendelian randomization analyses to assess confounding factors and mendelian randomization Bayesian model averaging to rank the significant biomarkers by their genetic evidence. We also conducted a metabolic pathway analysis to identify potential metabolic pathways. RESULTS: We identified 14 known serum metabolites (8 risk factors and 6 protective factors) and 12 unknown serum metabolites associated with OSA. These 14 known metabolites included 8 lipids( 1-arachidonoylglycerophosphoethanolamine, Tetradecanedioate, Epiandrosteronesulfate, Acetylca Glycerol3-phosphate, 3-dehydrocarnitine, Margarate17:0, Docosapentaenoaten3;22:5n3), 3 Aminoacids (Isovalerylcarnitine,3-methyl-2-oxobutyrate,Methionine), 2 Cofactors and vitamins [Bilirubin(E,ZorZ,E),X-11593--O-methylascorbate], 1Carbohydrate(1,6-anhydroglucose). We also identified several metabolic pathways that involved in the pathogenesis of OSA. CONCLUSION: MR (mendelian randomization) approach was performed to identify 6 protective factors and 12 risk factors for OSA in the present study. 3-Dehydrocarnitine was the most significant risk factors for OSA. Our study also confirmed several significant metabolic pathways that were involved in the pathogenesis of OSA. Valine, leucine and isoleucine biosynthesis metabolic pathways were the most significant metabolic pathways that were involved in the pathogenesis of OSA.

Correlation between neutrophil gelatinase phase lipocalin and cerebral small vessel disease.

Background: Cerebral small vessel disease (CSVD) is common in the elderly population. Neutrophil gelatinase-associated lipocalin (NGAL) is closely related to cardiovascular and cerebrovascular diseases. NGAL causes pathological changes, such as damage to the vascular endothelium, by causing inflammation, which results in other related diseases. The purpose of this study was to investigate whether serum NGAL levels could predict disease severity in patients with CSVD. Methods: The patients with CSVD who visited the Department of Neurology at the First Affiliated Hospital of Zhengzhou University between January 2018 and June 2022 were prospectively included. The total CSVD burden score was calculated using whole-brain magnetic resonance imaging (MRI), and the patients were divided into a mild group (total CSVD burden score < 2 points) and a severe group (total CSVD burden score ≥ 2 points). Age, sex, height, smoking and alcohol consumption history, medical history, and serological results of patients were collected to perform the univariate analysis. Multivariate logistic regression was used to analyze the risk factors that affect CSVD severity. The multiple linear regression method was used to analyze which individual CSVD markers (periventricular white matter hyperintensities, deep white matter hyperintensities, lacune, and cerebral microbleed) play a role in the association between total CSVD burden score and NGAL. Results: A total of 427 patients with CSVD (140 in the mild group and 287 in the severe group) were included in the study. A multivariate logistic regression analysis showed that the following factors were significantly associated with CSVD severity: male sex [odds ratio(OR), 1.912; 95% confidence interval (CI), 1.150-3.179], age (OR, 1.046; 95% CI, 1.022-1.070), history of cerebrovascular disease (OR, 3.050; 95% CI, 1.764-5.274), serum NGAL level (OR, 1.005; 95% CI, 1.002-1.008), and diabetes (OR, 2.593; 95% CI, 1.424-4.722). A multivariate linear regression shows that periventricular white matter hyperintensities and cerebral microbleed are associated with serum NGAL concentrations (P < 0.05). Conclusion: Serum NGAL level is closely related to CSVD severity and is a risk factor for the burden of CSVD brain damage. Serum NGAL has high specificity in reflecting the severity of CSVD.

Smoking, Coffee Consumption, Alcohol Intake, and Obstructive Sleep Apnea: A Mendelian Randomization Study.

BACKGROUND: Previous studies revealed that obstructive sleep apnea (OSA) and smoking, alcohol consumption, and coffee intake are closely related. This study aimed to evaluate the causal effect between these factors and OSA. METHODS: The published genome-wide association study data (GWAS) provided genetic tools. We conducted a univariable two-sample Mendelian Randomization (MR) to estimate the causal effect between smoking initiation, never smoking, alcohol consumption, coffee intake, and coffee consumption with the risk of incidence OSA. Inverse variance weighting (IVW) was used as the main method for effect evaluation, and other MR methods were used for sensitivity analysis. After adjusting for body mass index (BMI), hypertension, and diabetes respectively by multivariable MR (MVMR), we further evaluate the causal effect of these factors on OSA. RESULTS: Under univariable MR analysis, we observed that smoking initiation was associated with an increased risk of incidence OSA (OR 1.326, 95% CI 1.001-1.757, p =0.049). Never smoking was associated with decreased risk of OSA (OR 0.872, 95% CI 0.807-0.942, p <0.001). Coffee intake and coffee consumption was associated with an increased incidence of OSA (OR 1.405, 95% CI 1.065-1.854, p =0.016) and (OR 1.330, 95% CI 1.013-1.746, p =0.040). Further multivariate MR showed that the causal relationship between never smoking and OSA existed but not coffee consumption, after adjusting for diabetes and hypertension. However, the all results did not support causality after adjusting for BMI. CONCLUSION: This two-sample MR study showed that genetically predicted smoking and higher coffee intake are causally associated with an increased risk of OSA.

Association of Blood Lipid Profile Components with White Matter Hyperintensity Burden in Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) refers to a common cerebrovascular disease and white matter hyperintensities (WMHs) constitute a typical feature of CSVD. However, there has not been a large number of studies investigating the relationship between lipid profile components and WMHs. METHODS: Altogether, 1019 patients with CSVD were enrolled at the First Affiliated Hospital of Zhengzhou University between April 2016 to December 2021. Baseline data were collected for all patients, including demographic characteristics and clinical data. WMH volumes were evaluated by two experienced neurologists using the MRIcro software. Multivariate regression analysis was used to investigate the relationship among the severity of WMHs, blood lipids and common risk factors. RESULTS: Altogether, 1019 patients with CSVD were enrolled, including 255 in the severe WMH group and 764 in the mild WMH group. After including age, sex and blood lipids to construct a multivariate logistic regression equation, we observed that the severity of WMHs was independently predicted by low-density lipoprotein (LDL), homocysteine level and history of cerebral infarction. CONCLUSION: We used WMH volume, a highly accurate measure, to assess its relationship with lipid profiles. The WMH volume increased with a decrease in LDL. This relationship was more significant, especially among the subgroups of patients aged <70 years and men. Patients with cerebral infarction and higher homocysteine levels were more likely to have higher WMH volumes. Our study has provided a reference for clinical diagnosis and therapy, especially for discussing the role of blood lipid profiles in the pathophysiology of CSVD.

Evidence-based nursing reduces complications and negative emotions and improves limb function in patients undergoing hip arthroplasty.

OBJECTIVE: This retrospective study primarily analyzed the influence of evidence-based nursing (EBN) on postoperative complications (POCs), negative emotions (NEs) and limb function of patients undergoing hip arthroplasty (HA). METHODS: The research participants were 109 patients undergoing HA in Honghui Hospital, Xi'an Jiaotong University from September 2019 to September 2021. Among them, 52 patients who received routine nursing intervention were set as a control group, and 57 patients that received EBN were set as the research group. The POCs (infection; pressure sores, PS; lower extremity deep venous thrombosis, LEDVT), NEs (Hamilton Anxiety/Depression Scale, HAMA/HAMD), limb function (Harris Hip Score, HHS), pain intensity (Visual Analogue Scale, VAS), quality of life (QoL; Short-Form 36 Item Health Survey, SF-36) and sleep quality (Pittsburgh Sleep Quality Index, PSQI) were compared. Finally, the risk factors of complications in patients undergoing HA were identified by Logistic regression. RESULTS: The incidence of POCs such as infection, PS and LEDVT was markedly lower in the research group than that in the control group. The postinterventional HAMA and HAMD scores of the research group were obviously lower than the baseline (before intervention) and those of the control group. The research group also exhibited obviously higher scores in various dimensions of the HHS and SF-36 than the baseline and control group. Moreover, the post-interventional VAS and PSQI scores of the research group were markedly reduced compared with the baseline and those of the control group. Factors including drinking history, place of residence and nursing modality were found to be not associated with an increased risk of complications in patients undergoing HA. CONCLUSION: EBN can lower the incidence of POCs, mitigate NEs and pain perception, and enhance limb function, QoL and sleep quality in patients undergoing HA, so it is worth popularizing.

Ultrafine PdCo bimetallic nanoclusters confined in N-doped porous carbon for the efficient semi-hydrogenation of alkynes.

Semi-hydrogenation of alkynes to prepare alkenes is an important reaction in the petrochemical and fine chemical industries. The use of conventional Pd nanoparticle-based catalysts is limited by alkyne over-hydrogenation and low Pd utilization. In this study, a nitrogen-doped mesoporous carbon material (m-NC), which was rich in defect sites after Zn volatilization, was fabricated by the carbonization of ZIF-8. Ultrafine PdCo bimetallic nanoclusters with Co atom-modified Pd active site electronic and compositional structure were highly dispersed and confined in m-NC. As-obtained Pd0.43Co1/m-NC was used for the semi-hydrogenation of alkynes and it exhibited high selectivity with high conversion under mild reaction conditions. Pd0.43Co1/m-NC also exhibited excellent stability in leaching tests and maintained its catalytic activity for at least nine reaction cycles. The highly dispersed active sites in Pd0.43Co1/m-NC served as the active sites for the catalytic semi-hydrogenation of alkynes; as a regulator, the second metal Co effectively improved selectivity, and m-NC endowed the catalyst with excellent stability. The research work presented here may provide a foundation for the design of highly active, selective, and stable Pd-based bimetallic catalysts for selective hydrogenation.

Prediction of Symptoms on Admission with Early Neurological Deterioration in Single Small Subcortical Infarct.

BACKGROUND: Early neurological deterioration (END) often occurs during hospitalization in single small subcortical infarct (SSSI). While, symptoms on admission were rarely reported about its performance on predicting the risk of END. OBJECTIVES: The objective of this study is to explore the relationship between symptoms on admission and END in SSSI. METHODS: Patients with SSSI in the lenticulostriate artery (LSA) territory presenting within 72 hours of stroke onset were screened prospectively. Clinical characteristics, including symptoms on admission, laboratory tests and imaging findings, were collected. Based on the body regions involved including spherical face (SF), upper limb (UL) or lower limb (LL), symptoms on admission were classified into single spherical face (sSF) and any involvement of limbs (AL). END was defined as ≥2 points increase in total National Institutes of Health Stroke Scale (NIHSS) score or ≥ 1 point increase in motor score within 72 hours after admission. Multivariate logistic regression was used to analyze factors associated with END. RESULTS: Out of 5,832 ischemic stroke patients in the database, 394 patients were finally enrolled in analysis. 65 patients (16.5%) developed END. Multivariable logistic regression revealed that symptoms with LL (OR 2.337, 95% CI 1.041-5.246), UL (OR 2.936, 95% CI 1.349-6.390) were both associated with END, while the involvement of SF (OR 0.447, 95% CI 0.249-0.804) showed the opposite result. Further analysis found that symptoms with AL (OR 3.958, 95% CI 1.355-11.565) showed a higher risk of END compared to sSF after adjustment. CONCLUSION: Our results discovered that symptoms with AL carried a higher risk of END than those involving sSF in SSSI.

Concentrated Growth Factors Promote hBMSCs Osteogenic Differentiation in a Co-Culture System With HUVECs.

Osteogenesis is a complex physiologic process that occurs during bone regeneration. This process requires several growth factors that act on bone marrow-derived mesenchymal stem cells (BMSCs). Concentrated growth factor (CGF) is a new-generation platelet-rich derivative that is an appealing autologous material for application in tissue repair and bone regenerative medicine because it contains a variety of fibrin and growth factors. In this study, the effects of CGF on the proliferation and osteogenic differentiation of hBMSCs and human umbilical vein endothelial cells (HUVECs) were explored with in vitro cell co-culture experiments. HBMSCs and HUVECs were directly co-cultured at the ratio of 1:2 under different concentrations (0, 2, 5, 10, 20%) of CGF for 7 days. Alkaline phosphatase (ALP) staining and quantitative reverse transcription polymerase chain reaction were used to detect the effects of CGF on the expression of osteogenic genes (ALP, osteocalcin [OCN], type I collagen [COL-1], Runt-related transcription factor 2 [RUNX2]) and connexin 43 (CX43). RNA sequencing was used to explore potential regulated genes and signaling pathways that affect the osteogenesis of co-cultured hBMSCs exposed to CGF. The results showed higher expressions of ALP, COL-1, RUNX2, OCN, and CX43 in the direct co-culture group containing 10% CGF compared to the direct co-culture group without CGF and the indirect co-culture group. In summary, 10% CGF can significantly promote osteogenesis in hBMSCs directly co-cultured with HUVECs. Intercellular communication between the direct co-culture of hBMSCs and HUVECs through CX43 may be one of the main regulatory mechanisms.

Facile preparation of ultrafine Pd nanoparticles anchored on covalent triazine frameworks catalysts for efficient N-alkylation.

The fabrication of stable and efficient catalysts for green and economic catalytic transformation is significant. Here, highly stable covalent triazine frameworks (CTF-1) were used as the supporting material for anchoring ultrafine Pd nanoparticles (NPs) via a facile impregnation process and a one-pot calcination-reduction strategy. The widespread dispersion of ultrafine Pd NPs was a result of the abundant high nitrogen-content triazine groups of CTF-1 that endowed the catalyst Pd@CTF-1 with high catalytic activity. The catalytic performance of Pd@CTF-1 was demonstrated by the one-pot N-alkylation of benzaldehyde with aniline (or nitrobenzene) under mild reaction conditions, and Pd@CTF-1 exhibited a wide range of general applicability for N-alkylation reactions. The reaction mechanism for the N-alkylation reaction was also studied in detail. In addition, the Pd@CTF-1 catalyst exhibited high thermal and chemical stability, maintaining good catalytic efficiency after multiple reaction cycles. This study provides new insights for the fabrication of organic supporting materials with highly dispersed active catalytic sites that can lead to excellent catalytic performance for efficient, economical, and green reactions.

Construction of a sandwich-like UiO-66-NH2@Pt@mSiO2 catalyst for one-pot cascade reductive amination of nitrobenzene with benzaldehyde.

Heterogeneous noble metal-based catalysts with stable, precise structures and high catalytic performance are of great research interest for sustainable catalysis. Herein, we designed the novel sandwich-like metal-organic-framework composite nanocatalyst UiO-66-NH2@Pt@mSiO2 using UiO-66-NH2@Pt as the core, and mesoporous SiO2 as the shell. The obtained UiO-66-NH2@Pt@mSiO2 catalyst shows a well-defined structure and interface, and the protection of the mSiO2 shell can efficiently prevent Pt NPs from aggregating and leaching in the reaction process. In the one-pot cascade reaction of nitroarenes and aromatic aldehydes to secondary amines, UiO-66-NH2@Pt@mSiO2 shows excellent catalytic performance due to acid catalytic sites provided by UiO-66-NH2 and Pt hydrogenation catalytic sites. Furthermore, the porous structure of the UiO-66-NH2@Pt@mSiO2 catalyst also enhances reactant diffusion and improves the reaction efficiency. This work provides a new avenue to meticulously design well-defined nanocatalysts with superior catalytic performance and stability for challenging reactions.

Atomically Dispersed Co Clusters Anchored on N-doped Carbon Nanotubes for Efficient Dehydrogenation of Alcohols and Subsequent Conversion to Carboxylic Acids.

The catalytic dehydrogenation of readily available alcohols to high value-added carbonyl compounds is a research hotspot with scientific significance. Most of the current research about this reaction is performed with noble metal-based homogeneous catalysts of high price and poor reusability. Herein, highly dispersed Co-cluster-decorated N-doped carbon nanotubes (Co/N-CNTs) were fabricated via a facile strategy and used for the dehydrogenation of alcohols with high efficiency. Various characterization techniques confirmed the presence of metallic Co clusters with almost atomic dispersion, and the N-doped carbon supports also enhanced the catalytic activity of Co clusters in the dehydrogenation reaction. Aldehydes as dehydrogenation products were further transformed in situ to carboxylic acids through a Cannizzaro-type pathway under alkaline conditions. The reaction pathway of the dehydrogenation of alcohols was clearly confirmed by theoretical calculations. This work should provide an effective and simple approach for the accurate design and synthesis of small Co-clusters catalysts for the efficient dehydrogenation-based transformation of alcohols to carboxylic acids under mild reaction conditions.