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Background: Progressive multifocal leukoencephalopathy (PML) is an often fatal disease of the central nervous system caused by opportunistic infection of John Cunningham Polyomavirus (JCV). There's still no antiviral therapeutic strategy which was generally recognized as effective. The prognosis may differ in patients with different pathological mechanisms and treatments. We aim to report the effectiveness of combined treatment of low-dose, long-term immunoglobulin and mirtazapine in a pathologically proved PML case., Case Presentation: A patient presented with progressive acalculia, right-left confusion and visual neglection was recorded. She received 10-year immunosuppressive therapy for dermatomyositis. White matter lesions located in bilateral parietal lobe and callosum area symmetrically in MR scanning. JC virus analysis and brain biopsy in left parietal lobe were performed. The number of JCV copies was 2595 in CSF and 282,809 in brain specimen. Abundant foamy macrophages and the lymphatic cells were obvious in immunohistochemistry staining. Few SV-40 positive JC infected cell and more CD4 + and CD68 + cells were predominant. Immunosuppressive drugs were terminated after being diagnosed as PML for positive JCV and pathological characteristics. In addition, immunoglobulin (5 g/day) and mirtazapine (45 mg/day) were used. JC virus in CSF decreased to 0 after treatment for 4 months and was still negative in June 2023. The clinical symptoms improved, and white matter lesions recovered significantly., Conclusions: We demonstrated that the combination treatment of IVIG and mirtazapine was effective in PML. Low-dose, long-term immunoglobulin might regulate the immune status in our case with controlled inflammatory reaction instead of destructive virus spreading. The therapy may be a prospective option for PML., (© 2024. The Author(s).)

Purpose: More accurate prediction of phenotype traits can increase the success of genomic selection in both plant and animal breeding studies and provide more reliable disease risk prediction in humans. Traditional approaches typically use regression models based on linear assumptions between the genetic markers and the traits of interest. Non-linear models have been considered as an alternative tool for modeling genomic interactions (i.e. non-additive effects) and other subtle non-linear patterns between markers and phenotype. Deep learning has become a state-of-the-art non-linear prediction method for sound, image and language data. However, genomic data is better represented in a tabular format. The existing literature on deep learning for tabular data proposes a wide range of novel architectures and reports successful results on various datasets. Tabular deep learning applications in genome-wide prediction (GWP) are still rare. In this work, we perform an overview of the main families of recent deep learning architectures for tabular data and apply them to multi-trait regression and multi-class classification for GWP on real gene datasets., Methods: The study involves an extensive overview of recent deep learning architectures for tabular data learning: NODE, TabNet, TabR, TabTransformer, FT-Transformer, AutoInt, GANDALF, SAINT and LassoNet. These architectures are applied to multi-trait GWP. Comprehensive benchmarks of various tabular deep learning methods are conducted to identify best practices and determine their effectiveness compared to traditional methods., Results: Extensive experimental results on several genomic datasets (three for multi-trait regression and two for multi-class classification) highlight LassoNet as a standout performer, surpassing both other tabular deep learning models and the highly efficient tree based LightGBM method in terms of both best prediction accuracy and computing efficiency., Conclusion: Through series of evaluations on real-world genomic datasets, the study identifies LassoNet as a standout performer, surpassing decision tree methods like LightGBM and other tabular deep learning architectures in terms of both predictive accuracy and computing efficiency. Moreover, the inherent variable selection property of LassoNet provides a systematic way to find important genetic markers that contribute to phenotype expression., (© 2024. The Author(s).)

Metal-organic frameworks (MOFs) are increasingly becoming an important choice for developing robust and efficient electrocatalysts; therefore, exploring the relationship between the structure, catalytic activity, and stability of MOFs is of great significance. MOFs 1 - 3 with different spatial configurations are designed and synthesized based on linear pyridine ligands, tetragonal carboxylic acid ligands, and triangular carboxylic acid ligands, while MOF 4 displays a three-dimensional (3D) supramolecule assembled through a mixed-ligand strategy. Compared with MOFs 1 - 3 , MOF 4 has the lowest overpotential of 106 mV (at 10 mA·cm -2 ) and a Tafel slope of 80.9 mV·dec -1 , as well as sturdy long-term stability in the process of oxygen evolution reaction (OER). The presence of dense metal clusters and μ 3 -O promotes the optimal catalytic performance of MOF 4 . Density functional theory (DFT) calculations of MOF 4 demonstrate that the process from O* to OOH* is the rate-determining step. This investigation further reveals the relationship between MOF structural composition and electrocatalytic OER performance and provides an effective strategy for the assembly of MOF-based electrocatalysts.

MOF-based materials, as bifunctional catalysts for electrocatalytic water splitting, play an important role in the application and development of clean fuel hydrogen energy. This study presents a series of novel 3D Co-based MOFs with layered networks, including [Co(4,4'-bipy) 0.5 (aip)(CH 3 OH)·H 2 O] n ( Co-MOF 1 ), [Co 2 (1,3'-bit)(aip) 2 (CH 3 OH)·H 2 O] n ( Co-MOF 2 ), [Co(4,4'-bipb)(aip)] n ( Co-MOF 3 ), and [Co 2 (4,4'-bipe)(aip) 2 ·1.5H 2 O] n ( Co-MOF 4 ). Their single-crystal structures of Co-MOFs 1-4 are characterized and analyzed before being applied in alkaline solutions for water decomposition (OER and HER). The electrocatalytic tests indicate that Co-MOFs 1-4 exhibit a good performance. Notably, Co-MOF 4 exhibits great behavior which has low overpotentials of 94 and 188 mV (OER) as well as 185 and 352 mV (HER) at the currents of 10 and 100 mA cm -2 , respectively. In comparison with Co-MOFs 1-3 , Co-MOF 4 has the lowest Tafel slopes, highest ECSA, and smallest resistance. The immanent qualities, such as distinct interwoven long chain layered structure, unsaturated coordination modes, and synergistic catalytic qualities among Co ions, contribute to explaining the results. The fundamentals provide valuable information for the investigation of innovative MOF-based bifunctional electrocatalysts for overall water splitting.

Introduction: IVT use declined globally in 2020 due to the Corona Virus Disease 2019 (COVID-19) pandemic, but it increased in South China. This study was conducted to evaluate the association of establishing Stroke Prevention Centers (SPCs) at primary hospitals with IVT increase in South China., Materials and Methods: We conducted a longitudinal observational study across 336 hospitals in 114 areas in South China during 2020-2022. Data regarding certified stroke centers, IVT volumes, and IVT rates were collected. Correlations between IVT rates and the number or density of stroke centers were accessed. IVT use was compared among areas with different levels of stroke centers or on different certification process., Results: During 2020-2022, there were 83, 125, and 152 stroke centers, with 26, 65, and 92 SPCs, respectively. IVT therapies were 12,795, 17,266, and 20,411, representing a 29.8% increase/year (all p  < 0.001). IVT rates increased from 7.2% in 2020 to 8.8% and 10.4% in 2021 and 2022, demonstrating a 22.2% increase/year (all p  < 0.001). IVT rates correlated with the number and density of SPCs (all p  < 0.05). IVT rates were higher in areas equipped with SPCs than in those without stroke centers (all p  < 0.05). IVT rates consistently increased during the SPC certification process from 1 year before through the certification and subsequent maintenance (both p  < 0.05)., Discussion and Conclusion: Well-organised SPCs and IVT therapy demonstrated substantial increase during the 3-year period. Certification of SPCs at primary hospitals is associated with improved IVT therapy in South China even with city lockdown during COVID-19 pandemic., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Discontinuation of the deep medullary veins (DMVs) may be an early imaging marker for identifying cognitive impairment caused by cerebral small vessel disease (CSVD). However, this method lacks mechanistic exploration. We aimed to investigate whether the DMV score is related to CSVD imaging markers and cognitive impairment in patients with CSVD., Methods: This retrospective study included patients with CSVD who completed DMV score and cognition (e.g., MMSE, MoCA) assessments, and underwent MRI scanning (T2-FLAIR for white matter hyperintensities (WMH) volume, T1-weighted MRI for brain parenchymal fractions (BPF) analysis, and SWI for assessment of DMV score). The CSVD imaging markers were quantitatively assessed using the AccuBrain® system. We assessed the diagnostic value of neuroimaging biomarkers for detecting CSVD-related cognitive impairment. In addition, we explored the relationship between the DMV score, CSVD imaging markers, and cognition using mediation analysis., Results: Ninety-four patients with CSVD were divided into a cognitive impairment group (n = 39) and a non-cognitive impairment group (n = 55). Higher DMV scores, larger WMH volumes, and smaller BPF were observed in the cognitive impairment group than those in the non-cognitive impairment group. Receiver operating characteristics (ROC) analysis revealed that the discovery value of the integration of patient age, BPF, whole WMH volume, and DMV score for cognitive impairment was 0.742, with a sensitivity and specificity of 79.5 % and 61.5 %, respectively. Mediation analysis showed mediation by WMH and BPF in the relationship between DMV score and cognitive impairment (all P < 0.05)., Limitations: This study did not evaluate the DMV score in subregions according to DMV anatomy., Conclusions: The DMV score is significantly associated with cognitive impairment in patients with CSVD, and this association is mediated through WMH and BPF., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hyperlipidemia (HLP) is a prevalent metabolic disorder and a significant risk factor for cardiovascular disease. According to recent discoveries, super-enhancers (SEs) play a role in the increased expression of genes that encode important regulators of both cellular identity and the progression of diseases. However, the underlying function of SEs in the development of HLP is still unknown. We performed an integrative analysis of data on H3K27ac ChIP-seq and RNA sequencing obtained from liver tissues of mice under a low-fat diet (LFD) and high-fat diet (HFD) from GEO database. The rank ordering of super enhancers algorithm was employed for the computation and identification of SEs. A total of 1,877 and 1,847 SEs were identified in the LFD and HFD groups, respectively. The SE inhibitor JQ1 was able to potently reverse lipid deposition and the increased intracellular triglyceride and total cholesterol induced by oleic acid, indicating that SEs are involved in regulating lipid accumulation. Two hundred seventy-eight were considered as HFD-specific SEs (HSEs). GO and KEGG pathway enrichment analysis of the upregulated HSEs-associated genes revealed that they were mainly involved in lipid metabolic pathway. Four hub genes, namely Cd36, Pex11a, Ech1, and Cidec, were identified in the HSEs-associated protein-protein interaction network, and validated with two other datasets. Finally, we constructed a HSEs-specific regulatory network with Cidec and Cd36 as the core through the prediction and verification of transcription factors. Our study constructed a HSEs-associated regulatory network in the pathogenesis of HLP, providing new ideas for the underlying mechanisms and therapeutic targets of HLP., Competing Interests: Declaration of competing interests The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cerebral small vessel disease (SVD) may be associated with an increased risk of depressive symptoms. Serum uric acid (SUA), an antioxidant, may be involved in the occurrence and development of depressive symptoms, but the mechanism remains unknown. Moreover, the relationship between structural brain networks and SUA has not been explored. This study examined the relationship between SUA and depressive symptoms in patients with SVD using graph theory analysis. We recruited 208 SVD inpatients and collected fasting blood samples upon admission. Depressive symptoms were assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24). Magnetic resonance imaging was used to evaluate SVD, and diffusion tensor images were used to analyze structural brain networks using graph theory. Patients with depressive symptoms (n = 34, 25.76%) compared to those without (334.53 vs 381.28 μmol/L, p  = 0.017) had lower SUA levels. Graph theoretical analyses showed a positive association of SUA with betweenness centrality, nodal efficiency, and clustering coefficients and a negative correlation with the shortest path length in SVD with depressive symptoms group. HAMD scores were significantly associated with nodal network metrics in the right cerebral hemisphere. Our findings suggested that lower SUA levels are significantly associated with disrupted structural brain networks in the right cerebral hemisphere of patients with SVD who have depressive symptoms., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Hypertension is a leading cause of cerebral small vessel disease (CSVD) and vascular dementia in elderly individuals. We aimed to assess cerebral perfusion and dynamic changes in brain structure in stroke-prone renovascular hypertensive rats (RHRSPs) with different durations of hypertension and to investigate whether they have pathophysiological features similar to those of humans with CSVD. The RHRSP model was established using the two-kidney, two-clip (2k2c) method, and the Morris water maze (MWM) test, MRI, immunohistochemistry, and biochemical analysis were performed at multiple time points for up to six months following the 2k2c operation. Systolic blood pressure was significantly greater in the RHRSP group than in the sham-operated group at week 4 post-surgery and continued to increase over time, leading to cognitive decline by week 20. Arterial spin labeling revealed cerebral hypoperfusion in the RHRSP group at 8 weeks, accompanied by vascular remodeling and decreased vessel density. Diffusion tensor imaging and Luxol fast blue staining indicated that white matter disintegration and demyelination gradually progressed in the corpus callosum and that myelin basic protein levels decreased. Eight weeks after surgery, blood-brain barrier (BBB) leakage into the corpus callosum was observed. The albumin leakage area was negatively correlated with the myelin sheath area (r=-0.88, p<0.001). RNA-seq analysis revealed downregulation of most angiogenic genes and upregulation of antiangiogenic genes in the corpus callosum of RHRSPs 24 weeks after surgery. RHRSPs developed cerebral hypoperfusion, BBB disruption, spontaneous white matter damage, and cognitive impairment as the duration of hypertension increased. RHRSPs share behavioral and neuropathological characteristics with CSVD patients, making them suitable animal models for preclinical trials related to CSVD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Progressive infarction (PI) has a negative effect on functional prognosis. Our study aimed to develop and validate a risk score for predicting PI in patients with anterior circulation single subcortical infarction (ACSSI)., Methods: Between January 2020 and October 2022, we retrospectively enrolled 638 eligible patients with ACSSI. Two-thirds of the eligible patients were randomly allocated to the training cohort (n = 425). Another resampling sample was formed through the bootstrap method and was used as the validation group (n = 425). Multivariate logistic regression analysis was used to identify the independent factors associated with PI. Each factor was then point assigned based on β-coefficient and a risk scoring system was developed. This scoring system was internally validated through 1000-bootstrap resamplings. The C-statistic and Hosmer-Lemeshow test were used to assess model discrimination and calibration., Results: PI occurred in 121 patients, accounting for 19.0% of the total patients. A 7-point NTS score system based on the initial NIHSS score, triglyceride-glucose index, and the number of infarct slices on axial diffusion-weighted imaging was developed. The NTS score showed good discrimination and calibration in the training cohort (C-statistic = 0.686; p value of Hosmer-Lemeshow test = 0.797) and validation cohort (C-statistic = 0.681; p value of Hosmer-Lemeshow test = 0.451). The three risk levels for predicting PI in the training and validation cohorts based on NTS score were as follows: low (0-2, 9.6% vs. 9.3%), intermediate (3-5, 28.2% vs. 26.7%), and high risk (6-7, 60.2% vs. 57.4%)., Interpretation: The NTS score is a valid and convenient risk score for predicting PI in ACSSI patients., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Ischemic stroke causes secondary neurodegeneration in the thalamus ipsilateral to the infarction site and impedes neurological recovery. Axonal degeneration of thalamocortical fibers and autophagy overactivation are involved in thalamic neurodegeneration after ischemic stroke. However, the molecular mechanisms underlying thalamic neurodegeneration remain unclear. Sterile /Armadillo/Toll-Interleukin receptor homology domain protein (SARM1) can induce Wallerian degeneration. Herein, we aimed to investigate the role of SARM1 in thalamic neurodegeneration and autophagy activation after photothrombotic infarction. Neurological deficits measured using modified neurological severity scores and adhesive-removal test were ameliorated in Sarm1 -/- mice after photothrombotic infarction. Compared with wild-type mice, Sarm1 -/- mice exhibited unaltered infarct volume; however, there were markedly reduced neuronal death and gliosis in the ipsilateral thalamus. In parallel, autophagy activation was attenuated in the thalamus of Sarm1 -/- mice after cerebral infarction. Thalamic Sarm1 re-expression in Sarm1 -/- mice increased thalamic neurodegeneration and promoted autophagy activation. Auotophagic inhibitor 3-methyladenine partially alleviated thalamic damage induced by SARM1. Moreover, autophagic initiation through rapamycin treatment aggravated post-stroke neuronal death and gliosis in Sarm1 -/- mice. Taken together, SARM1 contributes to secondary thalamic neurodegeneration after cerebral infarction, at least partly through autophagy inhibition. SARM1 deficiency is a potential therapeutic strategy for secondary thalamic neurodegeneration and functional deficits after stroke., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Currently, ischemic stroke is the leading cause of death in China. To compare regional differences of ischemic stroke, we analyzed the clinical characteristics of patients with ischemic stroke in four regionally representative hospitals in China., Methods: We conducted a retrospective study at four tertiary hospitals in east China, with regionally representative patients. The associated factors include hypertension, diabetes mellitus, coronary heart disease, hyperlipidemia and a combination of these factors. The standardized ratio (SR), estimated as the observed number divided by the expected number, computed as the sum of predicted probabilities from a multivariable logistic regression model derived using data from all other cities, was used to compare to average levels., Results: A total of 34,707 patients were included. The number of patients increased with age in all four hospitals and patients were predominantly male. The number of ischemic stroke cases with related factors increased with age, except for hyperlipidemia. There was no significant gender difference when multiple related factors existed simultaneously. Coronary heart disease had a more significant impact on ischemic stroke in Qingdao Municipal Hospital and the First Hospital of Qinhuangdao, while hyperlipidemia had a significant influence on ischemic stroke in the First Hospital of Qinhuangdao., Conclusions: At four hospitals in east China, with the increase of age, the risk factors associated with ischemic stroke increased, and the distribution of ischemic stroke-related factors showed regional differences., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Converting CO 2 to valuable chemicals and fuels is a viable method to establish a carbon-neutral energy cycle in the environment. Metal-organic frameworks (MOFs), characterized by dispersed active sites, high porosity, etc., have displayed a great application prospect in the electrochemical/chemical CO 2 reduction reaction (CO 2 RR) process. Herein, we proposed a one-step production to establish a series of pillar-layered porous MOFs, [Co 2 (L)(bimb)] n (MOF 1 ) and [Co 4 (L) 2 (bidpe) 2 ] n (MOF 2 ) [H 4 L = 5'-(4-carboxyphenyl)-(1,1':2',1″-terphenyl)-4,4',4″-tricarboxylic, bimb = 1,4-bis(imidazol-1-yl)-butane, bidpe = 4'-bis(imidazolyl) diphenyl ether], for preferential conversion of CO 2 via ligand adjustment and increase of active sites' density. According to single-crystal X-ray diffraction studies, [Co 2 (L)(bimb)] n exhibits pillar-layered binuclear 3D frameworks with a 2,4,6-linked 3-nodes new topology structure, while [Co 4 (L) 2 (bidpe) 2 ] n displays pillar-layered tetranuclear interspersed networks with a 4,6-linked 2-nodes fsc topology structure through a ligand adjustment strategy. Meanwhile, the pillar-layered structure of the MOFs with abundant active sites is conducive to mass diffusion and benefits the conversion of CO 2 . MOFs 1 - 2 exhibit good electrocatalytic activity for CO 2 RR in 0.5 M KHCO 3 solution. Especially, the current density of MOF 2 generated at -0.90 V (vs. RHE) reaches -81.6 mA·cm -2 , which is 3.1 times higher than that under an Ar atmosphere. In addition, MOFs 1 - 2 can be used as a heterogeneous catalyst for chemical conversion of CO 2 . The results are expected to provide inspiration for rational design to develop stable and high-efficiency MOF-based electrocatalysts for CO 2 RR.

Tissue transglutaminase (TG2) is a widely distributed multifunctional protein involved in a broad range of cellular and metabolic functions carried out in a variety of cellular compartments. In addition to transamidation, TG2 also functions as a Gα signaling protein, a protein disulfide isomerase (PDI), a protein kinase, and a scaffolding protein. In the nucleus, TG2 modifies histones and transcription factors. The PDI function catalyzes the trimerization and activation of heat shock factor-1 in the nucleus and regulates the oxidation state of several mitochondrial complexes. Cytosolic TG2 modifies proteins by the addition of serotonin or other primary amines and in this way affects cell signaling. Modification of protein-bound glutamines reduces ubiquitin-dependent proteasomal degradation. At the cell membrane, TG2 is associated with G protein-coupled receptors (GPCRs), where it functions in transmembrane signaling. TG2 is also found in the extracellular space, where it functions in protein cross-linking and extracellular matrix stabilization. Of particular importance in transglutaminase research are recent findings concerning the role of TG2 in gene expression, protein homeostasis, cell signaling, autoimmunity, inflammation, and hypoxia. Thus, TG2 performs a multitude of functions in multiple cellular compartments, making it one of the most versatile cellular proteins. Additional evidence links TG2 with multiple human diseases including preeclampsia, hypertension, cardiovascular disease, organ fibrosis, cancer, neurodegenerative diseases, and celiac disease. In conclusion, TG2 provides a multifunctional and multisite response to physiological stress.

Unfavorable venous outflow (VO) is associated with cerebral edema, which represents microvascular dysfunction. This study estimated the relationship between VO and microvascular function in acute ischemic stroke patients. We retrospectively included 102 MCA/ICA occluded patients with anterior circulation infarction who underwent reperfusion therapy between July 2017 and April 2022. Unfavorable VO was defined as a cortical vein opacification score of 0-3 and favorable VO as that of 4-6. The clinical characteristics, collateral status, microvascular integrity, and outcomes were compared between patients with favorable and unfavorable VO. Multivariate analysis and receiver operator characteristic (ROC) analysis were used. The patients with unfavorable VO had higher extravascular-extracellular volume fraction (Ve) in the infarct core and a lower percentage of robust arterial collateral circulation. ROC analysis revealed that Ve in the infarct core predicts unfavorable VO (AUC = 0.67, sensitivity = 65.08%, specificity = 69.23%). The higher Ve in the infarct core (odds ratio = 1.011, 95% CI = 1.000-1.021, P =  0.046) and poor arterial collateral flow (odds ratio = 0.102, 95% CI = 0.032-0.327, P  < 0.001) were independent predictors of unfavorable VO. This suggests that microvascular dysfunction may be one of the mechanisms underlying impaired VO., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Chronic hypertension is a major risk factor for cognitive impairment, which can promote neuroinflammation and neuronal loss in the central nervous system. Transforming growth factor β-activated kinase 1 (TAK1) is a key molecular component in determining cell fate and can be activated by inflammatory cytokines. This study aimed to investigate the role of TAK1 in mediating neuronal survival in the cerebral cortex and hippocampus under chronic hypertensive conditions. To that end, we used stroke-prone renovascular hypertension rats (RHRSP) as chronic hypertension models. Adeno-associated virus (AAV) designed to overexpress or knock down TAK1 expression were injected into the lateral ventricles of rats and the subsequent effects on cognitive function and neuronal survival under chronic hypertensive conditions were assessed. We found that, TAK1 knockdown in RHRSP markedly increased neuronal apoptosis and necroptosis and induced cognitive impairment, which could be reversed by Nec-1s, an inhibitor of receptor interacting protein kinase 1 (RIPK1). In contrast, overexpression of TAK1 in RHRSP significantly suppressed neuronal apoptosis and necroptosis and improved cognitive function. Further knockdown of TAK1 in sham-operated rats received similar phenotype with RHRSP. The results have been verified in vitro. In this study, we provide in vivo and in vitro evidence that TAK1 improves cognitive function by suppressing RIPK1-driven neuronal apoptosis and necroptosis in rats with chronic hypertension.

Background: Developing Internet+home care (IHC) services is a promising way to address the problems related to population aging, which is an important global issue. However, IHC services are in their infancy in China. Limited studies have investigated the willingness and demand of nurses in municipal hospitals to provide IHC services., Objective: This study aims to investigate the willingness and demand of nurses in municipal hospitals in China to provide IHC services and analyze the factors to promote IHC development in China., Methods: This cross-sectional study used multistage sampling to recruit 9405 nurses from 10 hospitals in 5 regions of China. A self-designed questionnaire with good reliability and validity was used to measure nurses' willingness and demand for providing IHC services. Data analysis used the chi-square test, Welch t test, binary logistic regression analysis, and multiple linear regression analysis., Results: Nurses were highly willing to provide IHC services and preferred service distances of <5 km and times from 8 AM to 6 PM. An individual share >60% was the expected service pay sharing. Job title, educational level, monthly income, and marital status were associated with nurses' willingness to provide IHC services in binary logistic regression analysis. Supervising nurses were 1.177 times more likely to express a willingness to provide IHC services than senior nurses. Nurses with a bachelor's degree had a 1.167 times higher likelihood of expressing willingness to provide IHC services than those with a junior college education or lower. Married nurses were 1.075 times more likely to express a willingness than unmarried nurses. A monthly income >¥10,000 increased the likelihood of nurses' willingness to provide IHC services, by 1.187 times, compared with an income <¥5000. Nurses' total mean demand score for IHC services was 17.38 (SD 3.67), with the highest demand being privacy protection. Multiple linear regression analysis showed that job title, monthly income, and educational level were associated with nurses' demand for IHC services. Supervising nurses (B=1.058, P<.001) and co-chief nurses or those with higher positions (B=2.574, P<.001) reported higher demand scores than senior nurses. Monthly incomes of ¥5000 to ¥10,000 (B=0.894, P<.001) and >¥10,000 (B=1.335, P<.001), as well as a bachelor's degree (B=0.484, P=.002) and at least a master's degree (B=1.224, P=.02), were associated with higher demand scores compared with a monthly income <¥5000 and junior college education or lower, respectively., Conclusions: Nurses in municipal hospitals showed a high willingness and demand to provide IHC services, with differences in willingness and demand by demographic characteristics. Accordingly, government and hospitals should regulate the service period, service distance, and other characteristics according to nurses' willingness and demand and establish relevant laws and regulations to ensure the steady and orderly development of IHC services., (©Jinghui Zhang, Sha Peng, Jianmei Hou, Guiyuan Ma, Yanhui Liu, Yuhua Fan, Lingxia Luo, Zhengkun Shi. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 04.08.2023.)

Various carcinogenic dyes in water bodies are difficult to degrade due to their stability to light and oxidants, causing extended pollution. In this study, MOF 1 ({[Co(tib) 2 ]·(H 2 O) 2 ·SO 4 } n ) and MOF 2 ({[Cu(tib) 2 ]·(H 2 O) 2 ·SO 4 } n ) (tib = 1,3,5-tirs(1-imidazolyl)benzene) were synthesized by the solvothermal method. MOFs 1 and 2 were successfully characterized by single-crystal X-ray diffraction (XRD) and powder X-ray diffraction (PXRD). Based on the structural characteristics of MOFs 1 and 2 , we designed two cationic MOF material skeletons, namely, MOFs I and II ([Co(tib) 2 2+ ] n and [Cu(tib) 2 2+ ] n ), which were obtained by calcination in combination with the thermogravimetric curve to remove the free components in the lattice. As expected, MOFs I and II showed an excellent adsorption effect on sulfonic anionic dyes. Notably, the adsorption capacity of MOF I can reach 2922.8 mg g -1 for Congo Red (CR) at room temperature (RT). The adsorption process fits the pseudo-second-order kinetic model and Freundlich isotherm model. Moreover, zeta potential tests and quantum chemical calculations indicate that electrostatic interactions and hydrogen bond between the hydroxyl group on the sulfonic acid group and the N atom on the imidazole ring mainly promote the adsorption of CR dyes on MOF I . MOFs I and II are revealed as a promising novel adsorption material to remove hazardous organic aromatic pollutants with high efficiency in future endeavors.

Background: Apathy has been considered a common neuropsychiatric symptom and an important contributor to cognitive impairment in cerebral small vessel disease (SVD). However, the mechanism leading to apathy in SVD and the process whereby apathy promotes cognitive impairments remain largely unknown. We aimed to explore the relationship between apathy, cognition, and structural changes of deep grey matter (DGM) in SVD patients., Methods: Participants were screened for SVD, completed assessments of apathy cognition, underwent magnetic resonance imaging (MRI) scanning, and then stratified into apathy and non-apathy groups. We used region of interest (ROI)-based, voxel-based volume, and vertex-based shape analyses to compare DGM structures between study groups. Using linear regression analysis, we examined the association between apathy, structural changes, and cognition, followed by a mediation analysis of these factors., Results: A total of sixty-four SVD participants were included, with thirty in the apathy group and thirty-four in the non-apathy group. Intergroup comparison showed significantly lower volumes in bilateral caudate, right putamen, and pallidum and smaller vertex-based shapes in the right caudate and pallidum in participants with apathy compared to those without apathy. Apathy was associated with the striatal atrophy (i.e., lower volumes and smaller shape) and independently contributed to cognitive impairments in SVD. However, the above structural differences did not mediate the association between apathy and cognitive impairments., Conclusion: These results highlight the important role of striatal atrophy in apathy in SVD and call for additional studies to explore the relationship between apathy, cognition, and DGM., Competing Interests: Conflict of interest The authors declare no potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Metal-organic frameworks (MOFs) have exhibited appreciable potential as catalytic agents in the field of material science. The research of new MOFs with dual functions in electrocatalysis and photocatalysis under ultraviolet (UV) irradiation is extremely pivotal for renewable energy applications. Hence, we synthesized a series of three-dimensional MOFs, namely, [Cd(bimb) 2 (HITA) 2 ] n ( Cd - MOF 1 ), {[Cd(bimb) 6 ](NO 3 ) 2 } n ( Cd - MOF 2 ), and [Cd(bimb) 4 (ONO 2 ) 2 ] n ( Cd - MOF 3 ) (bimb = 1,4-bis(imidazol-1-ylmethyl)benzene; H 2 ITA = 5-hydroxyisophthalic acid), with applicability in the oxygen evolution reaction process and Fenton-like photocatalysis. The obtained results show that Cd - MOF 1 exhibited the most remarkable catalytic performance, affording a current density of 10 mA cm -2 at a very low overpotential of 279 mV and the smallest Tafel slope of 85.13 mV dec -1 . Meanwhile, these MOFs can generate hydroxyl radicals (•OH) under UV light irradiation with the existence of H 2 O 2 , enabling the rapid degradation of organic pollutants. This study provides a valuable direction for producing multifunctional and environmentally friendly catalysts.

Long noncoding RNAs (lncRNAs) play a critical role in the regulation of atherosclerosis. Here, we investigated the role of the lncRNA growth arrest-specific 5 (lncR-GAS5) in atherogenesis. We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis, which presented as increased plaque size and reduced collagen content. Moreover, impaired autophagy was observed, as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells. By contrast, lncR-GAS5 knockdown promoted autophagy. Moreover, serine/arginine-rich splicing factor 10 (SRSF10) knockdown increased the LC3II/LC3I ratio and decreased the P62 level, thus enhancing the formation of autophagic vacuoles, autolysosomes, and autophagosomes. Mechanistically, lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium, which was reversed by the knockdown of SRSF10. Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene, SRSF10. Notably, miR-193-5p overexpression decreased plaque size and increased collagen content. Altogether, these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy. In conclusion, lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway. Thus, miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis., (© 2023. Higher Education Press.)

Background: Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis., Methods: Apolipoprotein E deficiency (ApoE -/- ) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA-protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages., Results: The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed., Conclusion: These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages., (© 2023. The Author(s).)

Backgroud: Previous in vitro studies have indicated that pyrimidinergic receptor P2Y6 (P2RY6, P2Y6 receptor) may function as a cancer-promoting factor in lung adenocarcinoma (LUAD). However, the prognostic significance of P2RY6 expression in LUAD has not been investigated., Objective: This study aimed to assess the impact of P2RY6 expression on the survival of patients with LUAD., Methods: First, we assessed P2RY6 mRNA and protein expression in LUAD and non-cancerous lung tissues using the online bioinformatics analysis tool GEPIA, fresh LUAD tissues, and LUAD tissue microarrays (TMAs). Second, we investigated the correlation between P2RY6 expression and clinicopathological parameters of LUAD patients based on data from The Cancer Genome Atlas (TCGA) database and TMAs. Finally, we analyzed the prognostic significance of P2RY6 expression in LUAD using the online survival analysis tool Kaplan-Meier Plotter and data from TMAs., Results: We demonstrated that P2RY6 mRNA and protein expression levels in LUAD tissues were significantly higher than those in non-cancerous lung tissues. The expression of P2RY6 in LUAD was positively correlated with poor differentiation, more lymph node metastasis, and more advanced clinical stage. Higher P2RY6 expression level was correlated with shorter survival of the LUAD patients. Univariate and multivariate Cox regression analyses indicated that higher P2RY6 tumor expression was an independent unfavorable prognostic factor for LUAD patients., Conclusions: P2RY6 expression was elevated in LUAD and correlated with poor prognosis.

Background: Matrix metalloproteinases from macrophages are important intraplaque components that play pivotal roles in plaque progression and regression. This study sought to develop a novel multifunctional positron emission tomography (PET) and magnetic resonance imaging (MRI) contrast agents based on MMP-2 cleavable nanoparticles to noninvasive assessment of MMP-2 activity in mouse carotid atherosclerotic plaques., Results: Macrophage-rich vascular lesions were induced by carotid ligation plus high-fat diet and streptozotocin-induced diabetes in CL57/BL6 mice. To render iron oxide nanoparticles (IONP) specific for the extracellular MMP-2, the magnetic nanoparticle base material has been derivatized with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for the nuclear tracer 64 Cu labeling and the MMP-2-cleavable peptide modified with polyethylene glycol 2000, yielding a multi-modality reporter ( 64 Cu-NOTA-IONP@MMP2c-PEG2K, MMP2cNPs) for PET/MR imaging. Small animal PET imaging and biodistribution data revealed that MMP2cNPs exhibited remarkable plaque uptake (3.06 ± 0.87% ID/g and 1.83 ± 0.28% ID/g at 4 and 12 h, respectively). And MMP2cNPs were rapidly cleared from the contralateral normal carotid artery, resulting in excellent plaque-to-normal carotid artery contrasts. Furthermore, in vivo MRI showed a preferential accumulation of MMP2cNPs in atherosclerotic lesions compared with the non-cleavable reference compound, MMP2ncNPs. In addition, histological analyses revealed iron accumulations in the carotid atherosclerotic plaque, in colocalization with MMP-2 expression and macrophages., Conclusion: Using a combination of innovative imaging modalities, in this study, we demonstrate the feasibility of applying the novel smart MMP2cNPs as a PET/MR hybrid imaging contrast agent for detection of MMP-2 in atherosclerotic plaque in vivo., Competing Interests: The patent issued relevant to the work. Patent authors: Yingfeng Tu, Jiannan Dai, Huai Yu, Jinwei Tian, Lulu Li. Patent number: CN110302400A. Patent title: Structure and application of PET/MRI multimodal molecular imaging nanoprobes for early diagnosis of vulnerable atherosclerotic plaques. The authors report no other conflicts of interest in this work., (© 2022 Tu et al.)

Purpose: The present study aims to evaluate the current situation of knowledge, attitude and practice of clinical nurses in catheter-related thrombosis, analyze its influencing factors, enhance the attention of nursing managers and clinical nurses about catheter-related thrombosis, and provide a basis for formulating catheter-related thrombosis training plan., Patients and Methods: The research was conducted from January 1 to February 31, 2022, we recruited 549 nurses from two hospitals in Hunan province in this cross-sectional study using a two-stage random sampling method. We used a self-designed questionnaire with good reliability and validity to measure clinical nurses' knowledge, attitudes, and practice toward catheter-related thrombosis. We used χ 2 test, Welch t -test, and multiple linear regression analysis to analyze the data., Results: The knowledge of clinical nurses about catheter-related thrombosis was insufficient (55.00%), while the attitude was positive (88.49%) and the practice was inadequate (68.62%). Knowledge of clinical nurses was significantly associated with job title (β: 1.069, P <0.001), educational level (β: 0.094, P <0.05), and training times (β: 0.085, P <0.05), which were positive factors while whether they are specialized nurses in intravenous therapy (β: -0.126, P <0.05), and hospital level (β: -0.101, P <0.05) were negative factors. Training times (β: 0.166, P <0.001), job title (β: 0.099, P <0.019), and hospital level (β: 0.090, P <0.05) were associated factors of attitude. Moreover, training times (β: 0.255, P <0.001) was the only factor associated with the practice., Conclusion: Although clinical nurses hold a positive attitude towards catheter-related thrombosis, their knowledge level was unsatisfactory and their practice was affected by many factors, suggesting that nursing managers should strengthen the training and skill assessment of catheter-related thrombosis. At the same time, the hospital can formulate relevant rules, regulations, and guidelines to reduce the incidence of catheter-related thrombosis., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Peng et al.)

Evidence on the relationship between periodic limb movements during sleep (PLMS) and cerebral small vessel disease is lacking. This study aimed to assess the association between the PLMS index and the neuroimaging features of cerebral small vessel disease on magnetic resonance imaging. Consecutive patients diagnosed with cerebral small vessel disease were enrolled. Data on the clinical characteristics, polysomnography, and brain magnetic resonance imaging were collected. The Accubrain software was used to calculate automatically the volume of white matter hyperintensities, the number of lacunar infarctions, and cerebral microbleeds. The severity of white matter hyperintensities, enlarged basal ganglia perivascular spaces, and the total cerebral small vessel disease scores were also rated visually using semiquantitative scales. The severity of PLMS was measured using the PLMS index, and the patients were divided into two groups using an established cut-off value of ≥15 per hour. Logistic regression was used to examine the association between PLMS and the neuroimaging features of cerebral small vessel disease. In total, 37 patients were included in the final analyses. The mean age was 66.49 ± 11.31 years, and 73.0% were males. The mean PLMS index was 19.30 ± 10.18. In univariate analyses, it was found that patients with cerebral small vessel disease with a PLMS index ≥15 had increased enlarged basal ganglia perivascular spaces (OR 6.136, 95%CI 1.101-34.214) and increased total cerebral small vessel disease scores (OR 6.0, 95%CI 1.253-28.742). Only the association between the PLMS index and the total cerebral small vessel disease burden score remained statistically significant after adjusting for age, sex, and the presence of moderate to severe obstructive sleep apnea syndrome. In conclusion, an elevated PLMS index is likely to be associated with a greater cerebral small vessel disease burden. PLMS might be a novel potential marker of cerebral small vessel disease., (© 2022 European Sleep Research Society.)

Cerebral small-vessel disease (CSVD) has been found to have a strong association with vascular cognitive impairment (VCI) and functional loss in elderly patients. At present, the diagnosis of CSVD mainly relies on brain neuroimaging markers, but they cannot fully reflect the overall picture of the disease. Currently, some biomarkers were found to be related to CSVD, but the underlying mechanisms remain unclear. We aimed to systematically review and summarize studies on the progress of biomarkers related to the pathogenesis of CSVD, which is mainly the relationship between these indicators and neuroimaging markers of CSVD. Concerning the pathophysiological mechanism of CSVD, the biomarkers of CSVD have been described as several categories related to sporadic and genetic factors. Monitoring of biomarkers might contribute to the early diagnosis and progression prediction of CSVD, thus providing ideas for better diagnosis and treatment of CSVD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Sun, Yang and Fan.)

Purpose: The present study aimed to investigate nurses' willingness and demand for Internet +home care services in different levels of hospitals in China and analyze the influencing factors., Participants and Methods: From October 1 to December 31, 2021, 5714 nurses from 15 hospitals in five regions of China were recruited in this cross-sectional study using a two-stage random sampling method. A self-designed questionnaire with good reliability and validity was used to measure nurses' willingness and demand for Internet +home care services. χ 2 test, Welch t -test, and multiple linear regression analyses were used to analyze the data., Results: Nurses were highly willing to provide Internet +home care services. Statistical differences were found in the willingness to provide Internet +home care services and the preference for service distance, service platform, and single service fee between nurses in different levels of hospitals (both P<0.05). The willingness to provide "catheter maintenance service" and "rehabilitation nursing service" of nurses in different levels of hospitals were statistically significant (both P<0.05). Nurses' demand for Internet +home care services increased with the level of their hospital. Multiple linear regression showed that professional title, educational level, monthly family income, and mortgage or car loan influence nurses' demand for Internet +home care services., Conclusion: Nurses' willingness and demand for Internet +home care services vary with the level of their hospitals. It is recommended that government and hospitals regulate the service items, the service distance, single service fee, and other contents according to nurses' willingness and demand and establish relevant laws and regulations to ensure the steady and orderly development of the Internet +home care services., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Ma et al.)

Background: With the aging of China's population, the incidence rate of chronic diseases is rising. At the same time, residents' health awareness is also increasing. Implementing Internet +home care is an inevitable trend in adapting social development. Currently, Internet +home care is in the pilot stage in China, relevant institutional measures are neither standardized nor perfect, and there is no set of quality supervision indicators (QSIs)., Purpose: The construction of Internet +home care QSIs in China will provide a theoretical basis for Internet +home care quality supervision., Materials and Methods: The Service-Quality model was used as the theoretical framework, and a literature review, semi-structured interviews, focus group discussions, and Delphi consultations determined the contents of the QSIs and the weight of each indicator., Results: Internet +home care QSIs were constructed and included 5 first-level indicators, 17 secondary indicators, and 69 tertiary indicators. The effective recovery rates of the two rounds of Delphi expert consultation were 100% and 85%, the expert authority coefficients were 0.810 and 0.833, and the Kendall harmony coefficients were 0.189 and 0.125 (P<0.01). The final set of Internet +home care QSIs was as follows: tangibility (4 secondary and 16 tertiary indicators), reliability (4 secondary and 19 tertiary indicators), guarantee (5 secondary and 20 tertiary indicators), responsiveness (2 secondary and 8 tertiary indicators), and empathy (2 secondary and 6 tertiary indicators)., Conclusion: The construction of Internet +home care QSIs based on the SERVQUAL model is scientifically valid, and the indicators are reliable. They provide guidance and reference values for the continuous improvement and promotion of Internet +home care. This work also provides a theoretical basis for researching and developing an Internet +home care quality supervision platform., Competing Interests: The authors declare that there are no conflicts of interest regarding this work., (© 2022 Ma et al.)

Background and Purpose: In China, stroke center certification was launched in 2015, but little is known about its impact on intravenous thrombolysis. This study aimed to evaluate the effects of stroke center certification on the use of intravenous thrombolysis during a five-year period in South China., Methods: We retrospectively collected data regarding the use of recombinant tissue plasminogen activator (rt-PA) in 21 cities of Guangdong from 2015 to 2020. The annual thrombolysis rate was defined as the number of patients who underwent intravenous rt-PA therapy divided by the number of those who had acute ischemic stroke within the same year. The density of stroke centers was calculated as the number of stroke centers divided by the corresponding residents. Spearman's correlation analysis was used to determine the correlations between the annual thrombolysis rates and the number/density of stroke centers. Paired t -test was used to compare differences in growth in annual thrombolysis rates before and after having stroke centers., Results: From 2015 to 2020, the annual rt-PA thrombolysis rates of Guangdong increased from 1.4% to 7.2%, which was accompanied by an increase in the number of stroke centers from 0 to 82 and density of stroke centers from 0.00 to 0.71 per million population. The average annual rt-PA use in stroke centers was higher than that in non-stroke centers from 2016 to 2020 (all P  < 0.05). There was a positive correlation of annual thrombolysis rates with the number of stroke centers ( r  = 1.00, P  = 0.0028) and with the density of stroke centers in the 21 cities from 2018 to 2020 (all P  < 0.05). The growth in annual thrombolysis rates significantly accelerated at the city-level after having stroke centers (1.55%/y vs. 0.77%/y, P  < 0.001)., Conclusions: Stroke center certification may partially drive the increased use of rt-PA thrombolysis. Stroke center certification should be continually promoted to facilitate access to intravenous thrombolysis for patients with acute ischemic stroke.

Glioblastoma (GBM) is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. Previous reports showed that Sortilin related VPS10 domain containing receptor 3 (SorCS3) has the ability to regulate internalization. However, the impacts of SorCS3 on the biological processes involved in GBM have not yet been reported. In this study, we investigated the bio-function of SorCS3 in GBM. We found that SorCS3 was significantly downregulated in GBM. In addition, low expression level of SorCS3 predicted poor prognoses in patients with GBM. Here, we proved that SorCS3 suppressed cell invasion and proliferation mainly via NGF/p75 NTR pathway in GBM. We found that SorCS3 co-localized with p75 NTR in GBM cells and regulated the p75 NTR protein level by promoting trafficking of the endosomal to the lysosome. Immunofluorescence (IF) and Co-Immunoprecipitation (Co-IP) detection confirmed that SorCS3 bound to p75 NTR , which subsequently increased the internalization of p75 NTR , and then transported p75 NTR to the lysosome for degradation, ultimately contributing to inhibit of glioma progression. Taken together, our work suggests that SorCS3 is a marker of promising prognosis in GBM patients and suggests that SorCS3 regulates internalization, which plays a pivotal role in inhibiting glioma progression., (© 2022. The Author(s).)

Background: Differences in culprit lesion characteristics remain unclear between premenopausal and postmenopausal women with acute coronary syndrome (ACS). Optical coherence tomography (OCT) enables high-resolution in vivo identification of plaques. We investigated potential differences in culprit lesions between premenopausal and postmenopausal women with ACS by means of OCT., Methods: We included 191 ACS patients who had undergone preinterventional OCT and stratified them into 2 groups according to their menopausal status: premenopausal (n = 97) and postmenopausal (n = 94). The characteristics of culprit lesions were compared between the 2 groups., Results: Multivessel lesions were more commonly noted on angiography in the postmenopausal group than in the premenopausal group (40.21% vs 72.34%; P < 0.0001). On OCT, the most common type of culprit plaque was the fibrous plaque in the premenopausal group and the lipid plaque in the postmenopausal group. Compared with the premenopausal group, plaque rupture was more common in the postmenopausal group (39.18% vs 55.32%; P = 0.0254); culprit lesions had more vulnerable features, including macrophage accumulation (58.76% vs 87.23%; P < 0.0001), microchannel (38.14% vs 84.04%; P < 0.0001), cholesterol crystals (30.93% vs 62.77%; P < 0.0001), lipid-rich plaque (32.99% vs 58.51%; P < 0.0001), thin-cap fibroatheroma (3.09% vs 21.28%; P = 0.0001), and calcium (20.62% vs 44.68%; P = 0.0004); maximum lipid arc was larger (121.06 ± 110.99° vs 220.12 ± 115.47°, P < 0.0001); and lipid length was longer (5.78 ± 5.29 mm vs 12.90 ± 8.97 mm; P < 0.0001)., Conclusions: Compared with premenopausal women with ACS, postmenopausal women with ACS had more vulnerable culprit lesions. These finding suggest potential optimised lipid-lowering therapy for postmenopausal women with ACS., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Silent brain infarction (SBI) had a higher prevalence in ischemic stroke patients than healthy population. Intracranial artery calcification, as the important component of atherosclerosis, is a known risk factor of ischemic stroke. Whether it is also the risk factor of SBI is uncertain. We aimed to assess the association between SBI and carotid siphon calcification (CSC) in ischemic stroke patients., Methods: We retrospectively collected consecutive data of acute ischemic stroke patients with and without SBI by Magnetic Resonance Imaging (MRI) and calcification using non-contrast Computerized Tomography (NCCT). We used a histopathologically validated method to score the circularity, thickness, and morphology of calcification. Clinical characteristics, prevalence and pattern (intimal and medial) of CSC were compared between patients with and without SBI. The association of CSC and SBI was investigated by logistic regression analysis., Results: Totally, 303 acute ischemic stroke patients were enrolled, of whom 260 (85.8%) had CSC. Patients with SBI were older (64.5 ± 10.4 years vs. 61.3 ± 12.1 years, P = 0.032), had a higher proportion of hypertension (77.5% vs. 65.7%, P = 0.035). Of the 260 CSC patients, there's no significant difference except for hyperlipidemia between patients with SBI and without SBI. The prevalence of intimal pattern of CSC was higher in those with SBI (adjusted odds ratio 2.42, 95% CI 1.219-4.794)., Conclusions: Patients with SBI at acute phase of ischemic stroke have more risk factors than mentioned previously. SBI associated with the intimal pattern of CSC which relate to the atherosclerosis process in symptomatic ischemic stroke patients., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Approximately two-thirds of ischemic stroke patients suffer from different levels of post-stroke cognitive impairment (PSCI), but the underlying mechanisms of PSCI remain unclear. Cerebral amyloid-β (Aβ) deposition, a pathological hallmark of Alzheimer's disease, has been discovered in the brains of stroke patients in some autopsy studies. However, less is known about the role of Aβ pathology in the development of PSCI. It is hypothesized that cerebral ischemic injury may lead to neurotoxic Aβ accumulation in the brain, which further induces secondary neurodegeneration and progressive cognitive decline after stroke onset. In this review, we summarized available evidence from pre-clinical and clinical studies relevant to the aforementioned hypothesis. We found inconsistency in the results obtained from studies in rodents, nonhuman primates, and stroke patients. Moreover, the causal relationship between post-stroke cerebral Aβ deposition and PSCI has been uncertain and controversial. Taken together, evidence supporting the hypothesis that brain ischemia induces cerebral Aβ deposition has been insufficient so far. And, there is still no consensus regarding the contribution of cerebral amyloid pathology to PSCI. Other non-amyloid neurodegenerative mechanisms might be involved and remain to be fully elucidated., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cholesterol biosynthetic intermediates, such as lanosterol and desmosterol, are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here, we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ 24 -reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single-cell transcriptomics in isolated CD45 + CD11b + cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial reactive oxygen species production and NLR family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage cholesterol metabolism and inflammatory activation and protecting from disease progression., Competing Interests: The authors declare no competing interest.

Background/Aims: Atherosclerosis (AS) is one of the major leading causes of death globally, which is highly correlated with metabolic abnormalities. Resveratrol (REV) exerts beneficial effects on atherosclerosis. Our aim is to clarify the involvement of liver metabolic reprogramming and the atheroprotective effects of REV. Methods: ApoE-deficient mice were administered with normal diet (N), high-fat diet (H), or HFD with REV (HR). Twenty-four weeks after treatment, Oil Red O staining was used to assess the severity of AS. Non-targeted metabolomics was employed to obtain metabolic signatures of the liver from different groups. Results: High-fat diet-induced AS was alleviated by REV, with less lipid accumulation in the lesions. The metabolic profiles of liver tissues from N, H, and HR groups were analyzed. A total of 1,146 and 765 differentially expressed features were identified between N and H groups, and H and HR groups, respectively. KEGG enrichment analysis uncovered several metabolism-related pathways, which are potential pathogenesis mechanisms and therapeutic targets including "primary bile acid biosynthesis," "phenylalanine metabolism," and "glycerophospholipid metabolism." We further conducted trend analysis using 555 metabolites with one-way ANOVA, where p < 0.05 and PLS-DA VIP >1. We found that REV could reverse the detrimental effect of high-fat diet-induced atherosclerosis. These metabolites were enriched in pathways including "biosynthesis of unsaturated fatty acids" and "intestinal immune network for IgA production." The metabolites involved in these pathways could be the potential biomarkers for AS-related liver metabolic reprogramming and the mechanism of REV treatment. Conclusions: REV exerted atheroprotective effects partially by modulating the liver metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ma, Li, Liu, Liu, Xu, Zhong, Zhi, Jia, Jiang and Fan.)

Background: Head and neck squamous cell carcinoma (HNSCC) is characterised by a dismal prognosis; nonetheless, limited studies have unveiled the mechanisms underlying HNSCC relapse., Methods: Next-generation sequencing was performed to identify the somatic mutations in 188 matched samples, including primary tumours, tumour-adjacent tissues (TATs), pre- and post-operative plasma, saliva and peripheral blood lymphocytes (PBLs) from 27 patients. The evolutionary relationship between TATs and tumours were analysed. The dynamic changes of tumour- and TAT-specific mutations in liquid biopsies were monitored together with survival analysis., Results: Alterations were detected in 27 out of 27 and 19 out of 26 tumours and TATs, respectively. TP53 was the most prevalently mutated gene in TATs. Some TATs shared mutations with primary tumours, while some other TATs were evolutionarily unrelated to tumours. Notably, TP53 mutations in TATs are stringently associated with premalignant transformation and are indicative of worse survival (hazard ratio = 14.01). TAT-specific mutations were also detected in pre- and/or post-operative liquid biopsies and were indicative of disease relapse., Conclusions: TATs might undergo the processes of premalignant transformation, tumorigenesis and eventually relapse by either inheriting tumorigenic mutations from ancestral clones where the tumour originated or gaining private mutations independent of primary tumours. Detection of tumour- and/or TAT-specific genetic alterations in post-operative biopsies shows profound potential in prognostic use., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives/hypothesis: Tracheal stenosis is an obstructive disease of the upper airway that commonly develops as a result of abnormal wound healing. We evaluated the anti-inflammatory and antifibrotic properties of nintedanib on tracheal stenosis both in vitro and in vivo., Study Design: Prospective controlled animal study and in vitro comparative study of human cells., Methods: An animal model of tracheal stenosis was induced via tracheal trauma. Postsurgical rats were orally administered with nintedanib (10 or 20 mg/kg/d) or saline (negative control) for 2 weeks, and tracheal specimens were harvested after 3 weeks. Degree of stenosis, collagen deposition, fibrotic surrogate markers expression, and T-lymphocytic infiltration were evaluated. Human fetal lung fibroblast-1 (HFL-1) cells were cultured to determine the effects of nintedanib on changes of cellular biological function induced by transforming growth factor-β1 (TGF-β1)., Results: Rat tracheal stenotic tissues exhibited thickened lamina propria with irregular epithelium, characterized by significantly increased collagen deposition and elevated TGF-β1, collagen I, α-SMA and fibronectin expressions. Nintedanib markedly attenuated the tracheal stenotic lesions, reduced the collagen deposition and the expression of fibrotic marker proteins, and mitigated CD4+ T-lymphocyte infiltration. Additionally, cellular proliferation and migration were decreased dose-dependently in TGF-β1-stimulated HFL-1 cells when treated with nintedanib. Furthermore, nintedanib inhibited TGF-β1-induced HFL-1 differentiation and reduced the mRNA levels of the profibrotic genes. TGF-β1-activated phosphorylation of the TGF-β/Smad2/3 and ERK1/2 pathways were also blocked by nintedanib., Conclusion: Nintedanib effectively prevented tracheal stenosis in rats by inhibiting fibrosis and inflammation. The antifibrotic effect of nintedanib may be achieved by inhibiting fibroblasts' proliferation, migration and differentiation and suppressing the TGF-β1/Smad2/3 and ERK1/2 signaling pathways., Level of Evidence: NA Laryngoscope, 131:E2496-E2505, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc..)

Gastric cancer is one of the most common and deadly cancers among men and women and is the third leading cause of cancer mortality worldwide. Thus, discovering and developing novel therapeutics for gastric cancer has become a global priority. In this study, we synthesized two novel anthraquinone-based aspirin derivatives, Asp-X 3 and Asp-X 3 -CH 3 , with therapeutic potential for gastric cancer. The structures of the two compounds were determined by 1D, 2D-NMR, and High-Resolution Mass (HRSM). Asp-X 3 and Asp-X 3 -CH 3 could inhibit the growth of gastric cancer cells (SGC7901), yielding IC 50 values 10-fold lower than that of Aspirin. Asp-X 3 and Asp-X 3 -CH 3 were less toxic to gastric mucosal cells, yielding IC 50 values that were about 2-fold higher than the corresponding IC 50 values determined with SGC7901 cells. Asp-X 3 -CH 3 and Asp-X 3 also induced SGC7901 cells to undergo apoptosis, yielding apoptotic rates that were about twice the rate induced by Aspirin. Asp-X 3 -CH 3 did not cause significant loss of COX-1 expression in gastric mucosal cells, whereas Asp-X 3 and Aspirin both caused significant loss of COX-1 expression as demonstrated by Western blot, consistent with their effects on the content of PGE 2 in these cells as determined by ELISA assay. However, both Asp-X 3 -CH 3 and Asp-X 3 exerted a similar effect on the level of COX-2 in gastric cancer cells, causing as much as 90% and 95% reduction in COX-2 expression, respectively. Taken together, the results suggested that Asp-X 3 -CH 3 and Asp-X 3 were potentially better agents than Aspirin for the inhibition of gastric cancer cell growth, but Asp-X 3 -CH 3 was more effective., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Retinal vessels are known to be associated with various cardiovascular and cerebrovascular disease outcomes. Recent research has shown significant correlations between retinal characteristics and the presence of cerebral small vessel disease as measured by white matter hyperintensities from cerebral magnetic resonance imaging. Early detection of age-related white matter changes using retinal images is potentially helpful for population screening and allow early behavioural and lifestyle intervention. This study investigates the ability of the machine-learning method for the localization of brain white matter hyperintensities. All subjects were age 65 or above without any history of stroke and dementia and recruited from local community centres and community networks. Subjects with known retinal disease or disease influencing vessel structure in colour retina images were excluded. All subjects received MRI on the brain, and age-related white matter changes grading was determined from MRI as the primary endpoint. The presence of age-related white matter changes on each of the six brain regions was also studied. Retinal images were captured using a fundus camera, and the analysis was done based on a machine-learning approach. A total of 240 subjects are included in the study. The analysis of various brain regions included the left and right sides of frontal lobes, parietal-occipital lobes and basal ganglia. Our results suggested that data from both eyes are essential for detecting age-related white matter changes in the brain regions, but the retinal parameters useful for estimation of the probability of age-related white matter changes in each of the brain regions may differ for different locations. Using a classification and regression tree approach, we also found that at least three significant heterogeneous subgroups of subjects were identified to be essential for the localization of age-related white matter changes. Namely those with age-related white matter changes in the right frontal lobe, those without age-related white matter changes in the right frontal lobe but with age-related white matter changes in the left parietal-occipital lobe, and the rest of the subjects. Outcomes such as risks of severe grading of age-related white matter changes and the proportion of hypertension were significantly related to these subgroups. Our study showed that automatic retinal image analysis is a convenient and non-invasive screening tool for detecting age-related white matter changes and cerebral small vessel disease with good overall performance. The localization analysis for various brain regions shows that the classification models on each of the six brain regions can be done, and it opens up potential future clinical application., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Two novel 3D fluorescent metal-organic frameworks (MOFs), [Cd(L)(bbibp)] n ( 1 ) and [Cd(L)(bbibp) 0.5 ] n ( 2 ), where H 2 L = 4,4'-(4,4'-bipyridine-2,6-diyl)dibenzoic acid and bbibp = 4,4'-bis(benzoimidaz-1-yl)biphenyl, were acquired through a conventional method and characterized via IR spectra, single-crystal X-ray diffraction, elemental analysis, thermogravimetric analysis, powder X-ray diffraction (PXRD), scanning electron microscopy, N 2 adsorption-desorption isotherms, and X-ray photoelectron spectroscopy (XPS). The crystal framework of Cd-MOF 1 remained stable in the range of pH = 1.0-12.0. Interestingly, the emission peak of 1 showed a red shift and exhibited a fluorescence turn-on effect in an acidic environment. X-ray diffraction measurement revealed that the crystal structure of 1 remained unchanged after immersion in a pH = 1.0 solution. In addition, Cd-MOFs 1 and 2 displayed fluorescent quenching to l-glutamic acid with high sensitivity and selectivity. Meanwhile, 1 showed high selectivity in recognizing Fe 3+ under acidic conditions, which made 1 capable of detecting Fe 3+ in acidic industrial wastewater. Finally, the fluorescent sensing mechanism was carefully studied by PXRD, transient fluorescence lifetime, XPS, and UV spectroscopy.

Two biologically inspired tetranuclear nickel complexes [Ni 4 (L-H) 4 (CH 3 COO) 3 ]·Cl (1) and [Ni 4 (L-H) 4 (CH 3 COO) 4 ]·2CH 3 OH (2) (L = di(pyridin-2-yl)methanediol) have been synthesized and investigated by a combination of X-ray crystallography, PXRD, electrochemistry, in-situ UV-Vis spectroelectrochemistry and DLS. Both of the two complexes feature a core composed of four Ni(II) ions with the same peripheral ligation provided by the anionic di(pyridin-2-yl)methanediol and MeCOO - ligands. Whereas, complex 1 possesses one distorted cubane-like [Ni 4 (µ 3 -O) 4 ] core, while 2 has one extended butterfly-like [Ni 4 (µ 3 -O) 2 ] core. The homogeneous electrocatalytic reactivity of the two water-soluble complexes for water oxidation have been thoroughly studied, which demonstrates that both of them can efficiently electrocatalyze water oxidation with high stability under alkaline conditions, at relatively low over-potentials (η) of 420-790 mV for 1 and 390-780 mV for 2, both in the pH range of 7.67-12.32, with the high TOF of about 139 s -1 (1) and 69 s -1 (2) at pH = 12.32, respectively. By a series of comparative experiments for complexes 1 and 2, we proposed that their crystal geometries play an important role in their electrocatalytic reactivity for water oxidation. We verified that biomimetic cubane geometry could promote OER catalysis with two very similar compounds for the first time. Compared with 2, the biomimetic cubane topology of 1 could promote OER catalysis by facilitating efficient charge delocalization and electron-transfer.

Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most common malignant tumors in otolaryngology head and neck surgery and is one of the worst prognostic malignant tumors. Endogenous circular RNA (circRNA) is more stable than mRNA, microRNA (miRNA), and long non-coding RNA (LncRNA) in exosomes, plasma, and urine, and participates in gene expression regulation to perform different functions. Therefore, circRNA is expected to become a biomarker and therapy target for many tumors. However, the expression and function of circRNA regulated by N6-methyladenosine (m6A) are still unclear in HNSCC. In this study, we demonstrated that a specific circRNA, circCUX1, was upregulated in HPSCC patients who are resistant to radiotherapy and predicts poor survival outcome. We further found that methyltransferase like 3 (METTL3) mediated the m6A methylation of circCUX1 and stabilizes its expression. Knockdown circCUX1 promotes the sensitivity of hypopharyngeal cancer cells to radiotherapy. In addition, circCUX1 binds to Caspase1 and inhibits its expression, resulting in a decrease in the release of inflammatory factors, thereby developing tolerance to radiotherapy. Our findings indicate that circCUX1 is a potential therapeutic target for radiotherapy tolerance in HPSCC patients.

Pulmonary arterial hypertension (PAH) is a type of high morbidity and mortality disease. Currently, the intrinsic metabolic alteration and potential mechanism of PAH are still not fully uncovered. Previously, we have found that polyphenol resveratrol (Rev) reversed the remodeling of the pulmonary vasculature and decreased the number of mitochondria in pulmonary arterial smooth muscle cells (PASMCs) (Lei Yu et al. (2017)). However, potential effects of Rev on the changed metabolic molecules derived from lung tissue and serum have no fully elucidated. Thus, we conducted a systematic elaboration through the metabonomics method. Various of metabolites in different pathways including amino acid metabolism, tricarboxylic acid cycle (TCA), acetylcholine metabolism, fatty acid metabolism and biosynthesis in male Wistar rats' sera and lung tissues were explored in three groups (normal group, PAH group, PAH and Rev treatment group). We found that leucine and isoleucine degradation, valine, leucine and isoleucine biosynthesis, tryptophan metabolism and aminoacyl-tRNA biosynthesis were involved in the development of PAH. Hydroxyphenyllactic, isopalmitic acid and cytosine might be significant key metabolites. Further work in this area may inform personalized treatment approaches in clinical practice of PAH through elucidating pathophysiology mechanisms of experimental verification., (Copyright © 2020. Published by Elsevier Masson SAS.)

Laryngeal squamous cell carcinoma (LSCC) arises from the squamous epithelium of the larynx and is associated with a high incidence of cervical lymph node metastasis. MicroRNAs (miRNAs) play a crucial role in the epigenetic regulation of cellular biological processes, including cancer metastasis. However, the molecular mechanisms of specific miRNAs responsible for LSCC metastasis and their clinical significance have yet to be fully elucidated. In this study, LSCC cohort datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were downloaded and examined by comprehensive bioinformatics analysis, which revealed that upregulation of mRNA SERPINE1 and downregulation of miR-181c-5p were associated with unfavorable overall survival. Our analysis showed that SERPINE1 expression negatively correlated with the expression level of miR-181c-5p in our LSCC patient samples. Silencing of miR-181c-5p expression promoted cell migration and invasion in cell lines, whereas the overexpression of miR-181c-5p suppressed cell migration and epithelial-to-mesenchymal transition (EMT) through the downregulation of SERPINE1 . Further analysis showed that the enhancement effect on EMT and metastasis induced by silencing miR-181c-5p could be rescued through knockdown of SERPINE1 expression in vitro . Collectively, our findings indicated that miR-181c-5p acted as an EMT suppressor miRNA by downregulation of SERPINE1 in LSCC and offers novel strategies for the prevention of metastasis in LSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Li, Wu, Tang, Fan, Liu, Fang, Wang and Zhao.)

Background and Purpose: Understanding the mechanisms underlying progression/regression of symptomatic intracranial atherosclerotic stenosis (sICAS) will inform secondary prevention of the patients. Focal wall shear stress (WSS) may play an important role, which, however, had seldom been investigated., Methods: Patients with acute ischemic stroke or transient ischemic attack (TIA) attributed to 50% to 99% intracranial atherosclerotic stenosis were recruited. All patients underwent cerebral computed tomography angiography at baseline, and a computational fluid dynamics model was built based on computed tomography angiography to simulate blood flow and quantify WSS in the vicinity of the sICAS lesion. All patients received optimal medical treatment and a second computed tomography angiography at 1 year. The change in the luminal stenosis from baseline to 1 year in sICAS was defined as progression (increased >10%), quiescence (±10%), or regression (decreased >10%). Associations between baseline WSS metrics and sICAS regression were analyzed., Results: Among 39 patients (median age 62 years; 27 males), sICAS luminal stenosis progressed, remained quiescent and regressed in 6 (15.4%), 15 (38.5%), and 18 (46.2%) cases, respectively. A higher maximum WSS and larger high-WSS area, throughout the sICAS lesion or obtained separately in the proximal and distal parts of the lesion, were independently associated with regression of luminal stenosis in sICAS over 1 year., Conclusions: A majority of sICAS lesions regress or stay quiescent in the luminal stenosis over 1 year after stroke under optimal medical treatment, when higher focal WSS may facilitate stenosis regression. Further studies of the effects of hemodynamics including WSS in altering plaque vulnerability and stroke risks are needed.