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Abstract 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.

Multi-task learning (MTL) is a learning paradigm whose aim is to leverage information shared across related tasks to improve the generalization of models. Motivated by the success of proximal optimization algorithms and single-task learning regression models, sparse proximal multi-task learning (SPMTL) for genome-wide prediction (GWP) should be explored. This study investigates proximal gradient descent splitting algorithms with five non-smooth sparsity-inducing norm regularizers, including the novel $L_{2,\frac {1}{2}}$ norm for GWP. Additionally, two popular methods based on Markov chain Monte Carlo (MCMC) are examined. To improve the computational efficiency, parallel Bayesian optimization strategy is employed for efficient hyperparameter tuning. Evaluation is conducted on three different real-world genomic datasets from mice, pigs and wheat, each associated with two, five, and four traits, respectively. Performance is assessed using mean squared error (MSE) and correlation coefficient between predicted and observed trait values in test sets. Experimental results reveal that the $L_{2,\frac {1}{2}}$ regularizer consistently achieves the best out-of-sample prediction across all datasets, demonstrating the effectiveness of SPMTL in leveraging shared information for improved GWP accuracy. Furthermore, the influence of different regularizers on sparsity and other properties of the SPMTL model are also explored.

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.

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.

Abstract 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.

BackgroundDeveloping 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. ObjectiveThis 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. MethodsThis 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. ResultsNurses were highly willing to provide IHC services and preferred service distances of 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 ¥10,000 (B=1.335, P

Abstract 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/p75NTR pathway in GBM. We found that SorCS3 co-localized with p75NTR in GBM cells and regulated the p75NTR protein level by promoting trafficking of the endosomal to the lysosome. Immunofluorescence (IF) and Co-Immunoprecipitation (Co-IP) detection confirmed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR 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.

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.

Abstract 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.

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.

Abstract Introduction Only two studies investigated the associations between peak width of skeletonized mean diffusivity (PSMD) and age‐related cognitive alterations, whereas none of the studies investigated the association with vascular risk factors. Methods We evaluated 801 stroke‐ and dementia‐free elderlies with baseline and 3‐year follow‐up assessments. Regression analyses were used to assess the association between age‐related cognitive functions and PSMD. Simple mediation models were used to study the mediation effect of PSMD between vascular risk factors and age‐related cognitive outcomes. Results PSMD was negatively associated with processing speed at baseline and negatively associated with processing and memory scores at 3‐year follow‐up. The association between vascular risk factors and age‐related cognition was mediated by PSMD, as well as other diffusion tensor imaging markers. Discussion PSMD is preferred over other diffusion tensor imaging markers as it is sensitive to age‐related cognitive alterations and calculation is fully automated. PSMD is proposed as a research tool to monitor age‐related cognitive alterations.

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.

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.

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.

Internal carotid artery dissection (ICAD) results from a tear in the intima or rupture of the vasa vasorum with bleeding within the media resulting in separation of the vessel wall layers and a false lumen. It may cause arterial stenosis, occlusion, or dissecting pseudoaneurysm. Currently, the treatment of ICAD is controversial, including drug therapy and endovascular stent implantation. Simultaneous spontaneous dissection of bilateral carotid artery is rarely reported. We reported a 39-year-old-man with bilateral ICAD. Although the long-term durability of endovascular stent remains to be determined, for ICAD failed with active drug treatment and combined with hemodynamic impairment, early endovascular stent should be considered.

Aim Cerebral venous sinus thrombosis (CVST) is a less common cerebrovascular disease that predominantly affects young patients. The incidence of CVST is 2–5/10 000 000/year, accounting for 0.5%–1% of all stroke. To reduce mortality and morbidity associated with CVST, Chinese Stroke Association commissioned the authors to write the current guideline on the management of CVST.Methods PubMed (MEDLINE), CNKI and Wanfang database were searched for studies related to CVST from 1 January 1990 to 31 July 2019. Data were synthesised by evidence tables. Each recommendation was fully discussed by the writing group members and reviewed by Chinese Stroke Association Stroke Fellow Committees. Levels of evidence grading algorithm of Chinese Stroke Association was used to grade each recommendation.Results This guideline mainly focuses on the diagnostic evaluation, therapeutic strategies and secondary prevention of CVST. CT/CTV and MRI/MRV are recommended in the initial imaging evaluation of patients with suspected CVST. Anticoagulation therapy with low-molecular weight heparin should be initiated in patients with CVST immediately. After the acute stage, warfarin is recommended for 3–6 months to prevent the recurrence of CVST and other venous thromboembolic events.Conclusions The guideline summarises the current evidence regarding the management of CVST, and provides references for diagnosis, treatment and secondary prevention of CVST in China.

Recently, multimodality molecular imaging has evolved into a fast-growing research field with goals of detecting and measuring biological processes in vivo non-invasively. Researchers have come to realize that the complementary abilities of different imaging modalities over single modality could provide more precisely information for the diagnosis of diseases. At present, nanoparticles-based multimodal imaging probes have received significant attention because of their ease of preparation and straightforward integration of each modality into one entity. More importantly, nanotechnology has an increasing impact on multimodality molecular imaging of cardiovascular diseases, such as atherosclerosis and vulnerable plaque, myocardial infarction, angiogenesis, apoptosis and so on. In this review, we briefly summarize that various nanoprobes are exploited for targeted molecular imaging of cardiovascular diseases, as well as associated multimodality imaging approaches and their applications in the diagnosis and treatment of cardiovascular diseases.

Background/Aims: Abdominal obesity is recognized as the main reason of metabolic syndrome, which is closely related to disordered skeletal and/or abdominal muscle metabolic functions. Metabolomics is a comprehensive assessment system in biological metabolites. The aim of our present study is to investigate the diet-induced metabolic risk factors by metabolic in the abdominal muscles and clarify the relationship between atheroprotective effects of Resveratrol (Rev) and abdominal muscles metabolic components during the development of atherosclerosis. Methods: The mice were randomly divided into three groups including normal group (N), high fat diet (HFD or H) group and high fat diet with Rev treated group (HR). GC-MS combined with pattern recognition approaches were employed to obtain comprehensive metabolic signatures and related differential metabolites after 24 week HFD feeding. Oil Red O staining and Electron microscopy technology (EMT) were employed to detect the size of fatty plaques and intracellular lipid accumulation, respectively. Results: The result indicated that 22 types of metabolites in the abdominal muscles were obviously altered by HFD feeding group. Moreover, Rev treatment obviously increased 11 different kinds of metabolites, most of which were involved in the carbohydrate, amino acid and lipid metabolisms. Importantly, these elevated different metabolites were involved in pathways mainly related to galactose metabolism, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism in abdominal muscles. Oil Red O staining and Electron microscopy showed less lipid accumulation in the lesions and decreased intracellular lipid deposition in the foam cells in HR group. Conclusions: We concluded that Rev produced a beneficial effect partially by modulating multiple metabolism pathways and metabolites in the abdominal muscles, which may provide a new protective mechanism of Rev on the progression of atherosclerosis. These notably changed metabolites might be potential biomarkers or therapeutic targets during development of metabolic syndrome and atherosclerosis.

Background/Objectives: The polyphenol resveratrol (Rev) has been found to exhibit various beneficial effects including prevention of pulmonary arterial hypertension (PAH). The present study was designed to investigate the action and potential mechanism of Rev on PAH, focusing on the role of SIRT1 (Silent Information Regulator 1) in apoptosis of pulmonary artery smooth muscle cells (PASMCs). Methods: PAH rats were established by exposure to hypoxia for 21 days. Rev and SRT1720 (a selective SIRT1 activator) were used to reverse PAH by gavaging rats. PASMCs were confronted with hypoxia for 24 h or 48 h and were then treated with Rev or SRT1720 in vitro. Western blot was performed to detect the protein expression of SIRT1. CCK-8 and scratch wound experiments were carried out to verify cell proliferation. In addition, the TUNEL positive assay and flow cytometry assay were used to measure PASMC apoptosis. Mitochondrial permeability transition (mPT) was identified by confocal microscopy. Right ventricular systolic pressure (RVSP) was determined with a Gould pressure transducer, and right ventricular hypertrophy (RVH) was determined by weighing the cardiac muscle. Results: We demonstrated that Rev could reverse the remodelling of the pulmonary vasculature, thus contributing to alleviating the severity of PAH. Down-regulation of SIRT1 was observed in PAH, but administration of Rev had no obvious effect on the protein expression of SIRT1. In addition, Rev could induce mitochondrial swelling and nuclear pyknosis, leading to small, dense, and dysmorphic mitochondria in rats exposed to hypoxia alone. Rev treatment inhibited PASMC proliferation in a dose-dependent manner in vitro. Incubation with SRT1720, a specific activator of SIRT1, significantly retarded PASMC proliferation and promoted PASMC apoptosis in vitro. The mechanism could be associated with inducing mPT damage in PASMCs. Rev and SRT1720 treatment mitigated RVSP and reduced RVH. Conclusion: Rev produced a beneficial effect partially by enhancing the activation of SIRT1, thus improving RVSP and reducing RVH. SIRT1 activation increased PASMC apoptosis by inducing mPT dysfunction, which might be a novel future strategy for the treatment of PAH.

Background The poor viability of transplanted mesenchymal stem cells (MSCs) hampers their therapeutic efficacy for ischemic heart disease. MicroRNAs are involved in regulation of MSC survival and function. The present study was designed to investigate the molecular effects of miR‐15a/15b on MSC survival, focusing on the role of vascular endothelial growth factor receptor 2. Methods and Results We first harvested donor luc(Luciferase)‐MSCs (5×105) isolated from the luciferase transgenic mice with FVB background. Luc‐MSCs were transfected with miR‐15a/15b mimics or inhibitors and cultured under oxygen glucose deprivation condition for 12 hours to mimics the harsh microenvironment in infarcted heart; they were subjected to MTT (3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide?Thiazolyl Blue Tetrazolium Bromide) assay, bioluminescence imaging, quantitative reverse transcription–polymerase chain reaction, transferase‐mediated deoxyuridine triphosphate–digoxigenin nick‐end labeling assay, and flow cytometry. Furthermore, the levels of vascular endothelial growth factor receptor 2, protein kinase B, p(Phosphorylate)‐protein kinase B, Bcl‐2, Bax, and caspase‐3 proteins were available by Western blotting assay. In vivo, acute myocardial infarction was induced in 24 mice by coronary ligation, with subsequent receipt of Luc‐MSCs, Luc‐MSCs+miR‐15a/15b inhibitors, or PBS treatment. The therapeutic procedure and treatment effects were tracked and assessed using bioluminescence imaging and echocardiographic measurement. Next, ex vivo imaging and immunohistochemistry were conducted to verify the distribution of MSCs. We demonstrated that miR‐15a/15b targeted vascular endothelial growth factor receptor 2 to modulate MSC survival, possibly via phosphatidylinositol 3‐kinase/protein kinase B signaling pathway, which was proved by bioluminescence imaging, immunohistochemistry analysis, and echocardiographic measurement. Conclusions Luc‐MSCs could be followed dynamically in vitro and in vivo by bioluminescence imaging, and the role of miR‐15a/b could be inferred from the loss of signals from luc‐MSCs. This finding may have practical clinical implications in miR‐15a/15b–modified MSC transplantation in treating myocardial infarction.

When providing route guidance to pedestrians, one of the major safety considerations is to ensure that streets are crossed at places with pedestrian crossings. As a result, map service providers are keen to gather the location information about pedestrian crossings in the road network. Most, if not all, literature in this field focuses on detecting the pedestrian crossing immediately in front of the camera, while leaving the other pedestrian crossings in the same image undetected. This causes an under-utilization of the information in the video images, because not all pedestrian crossings captured by the camera are detected. In this research, we propose a coarse-to-fine framework to detect pedestrian crossings from probe vehicle videos, which can then be combined with the GPS traces of the corresponding vehicles to determine the exact locations of pedestrian crossings. At the coarse stage of our approach, we identify vanishing points and straight lines associated with the stripes of pedestrian crossings, and partition the edges to obtain rough candidate regions of interest (ROIs). At the fine stage, we determine whether these candidate ROIs are indeed pedestrian crossings by exploring their prior constraint information. Field experiments in Beijing and Shanghai cities show that the proposed approach can produce satisfactory results under a wide variety of situations.

Objective: Nonconvulsive status epilepticus (NCSE) is an uncommon clinical manifestation in patients with TBC1D24 mutations. In addition, NCSE has not been reported as a syndrome together with cerebellar ataxia and ophthalmoplegia.Methods: We herein report the clinical and genetic features of a four-year-old patient with NCSE, cerebellar ataxia, and ophthalmoplegia caused by hitherto unidentified TBC1D24 mutations. We performed 24-h video electroencephalogram (EEG), magnetic resonance imaging, and gene sequencing on the patient and her parents to determine the diagnosis.Results: We identified a novel c.1416_1437del (p.Ser473Argfs*43) mutation, as well as the previously identified c.1499C>T (p.Ala500Val) mutation in TBC1D24, by using targeted next-generation sequencing. The novel mutation (inherited from the mother) is the first reported deletion mutation longer than 20 bp in TBC1D24. The p.Ala500Val mutation inherited from father has been reported in a German patient with infantile myoclonic, for whom results from the EEG and neuroimaging were normal. These two mutations resulted in the severe phenotypes observed in our patientConclusions: The identification of the novel TBC1D24 mutation and consequent complicated clinical manifestations suggest that patients with NCSE and ataxia demand more attention. We further recommend that genetic test should be administered to these patients to avoid genetic inheritance of this mutation.

ObjectivePrimary amyloidosis is a disease with a poor prognosis and multi-organ involvement. Here, we report the clinical and pathological features of a patient with primary amyloidosis featuring autonomic neuropathy as the initial symptom and albuminocytologic dissociation in the cerebrospinal fluid (CSF).MethodsThe patient was a 60-year-old Chinese male with numbness, orthostatic hypotension, and gastrointestinal symptoms. For diagnosis, we performed an electromyogram (EMG), lumbar puncture, Bence Jones protein urine test, serum electrophoresis blood test, sural nerve and rectal membrane biopsies, transthyretin (TTR) gene sequencing, and bone marrow puncture.ResultsCongo red staining of sural nerve and rectal membrane biopsies showed amyloid deposition and apple-green birefringence was visualized under polarized light microscopy. TTR gene sequencing showed no causative mutation. Following lumbar puncture, normal CSF cell counts and elevated CSF protein concentration (1,680 mg/L) were detected. Bone marrow puncture showed that out of the total number of whole blood cells, 0.56% were abnormal plasma cells and that 87.4% of the total number of plasma cells were abnormal. EMG results showed mixed peripheral nerve damage predominately in the sensory nerve fibers.ConclusionObvious symptoms of neuropathy, particularly autonomic neuropathy, albuminocytologic dissociation, and organ function damage suggested a diagnosis of amyloidosis. In such patients, neurologists should use caution to differentiate between chronic inflammatory demyelinating polyneuropathy, primary amyloidosis, and familial amyloid neuropathy.

Commiphora opobalsamum is a Traditional Chinese Medicine used to treat traumatic injury, mainly by relaxing blood vessels. In this study, two diterpenes, dehydroabietic acid (DA) and sandaracopimaric acid (SA) were obtained from it by a bioassay-guided approach using isolated rat pulmonary artery rings. The structures of the two compounds were elucidated by spectroscopic methods (IR, 1H- and 13C-NMR, HR-ESI-MS). Both DA and SA reduced the contraction of phenylephrine-induced pulmonary arteries in a concentration-dependent manner, and endothelium contributed greatly to the vasodilatory effect of DA. This effect of DA was attenuated by NG-Nitro-L-arginine methyl ester (L-NAME, an eNOS inhibitor). Meanwhile, DA increased nitric oxide (NO) production, along with the increase of phosphorylation level of eNOS and Akt in endothelial cells. LY294002 (a PI3K inhibitor) could reverse this effect, which suggested the endothelial PI3K/Akt pathway involved in the mechanism underlying DA-induced relaxation of pulmonary artery. This work provided evidence of vasorelaxant substances in Commiphora opobalsamum and validated that PI3K/Akt-eNOS pathway was associated with DA-induced pulmonary artery vasodilation.

Background/Aims: Arsenic trioxide (As2O3) is a highly effective agent for treatment of acute promyelocytic leukemia (APL). However, consecutively administered As2O3 induces serious adverse cardiac effects, including long QT syndrome (LQTs) and even sudden cardiac death. Previous studies have shown that genistein (Gen) exerts anti-oxidant, anti-inflammatory, and anti-apoptotic effects. The present study aimed to explore the potential protective effects of Gen on As2O3-induced adverse cardiac effects, and to elucidate the underlying molecular mechanisms. Methods: A rat model of As2O3-induced QT prolongation was generated by intravenous injection with As2O3. Surface electrocardiogram (ECG) and hemodynamics were employed to assess the LQTs and cardiac function. Intracellular calcium concentration ([Ca2+]i) and mitochondrial membrane potential (Δψm) were measured by confocal microscopy, and cardiomyocytes apoptosis were assessed by TUNEL assay. Western blot was applied to determine protein levels. Results: We found for the first time that treatment with Gen significantly reversed LQTs and dose-dependently improved As2O3-induced impairment of cardiac function. As2O3 elevated [Ca2+]i and Gen mitigated this effect. Meanwhile, Gen significantly reversed As2O3-mediated cardiomyocytes apoptosis. Furthermore, Gen dose-dependently inhibited the phosphorylated JNK and p38-MAPK (pp38-MAPK), and blocked Δψm collapse, and further decreased cleaved caspase-3. Conclusion: Gen protects against the adverse cardiac effects of As2O3 partly by mitigating cardiomyocytes apoptosis induced by As2O3 through attenuating intracellular calcium overload and downregulating protein expression of p-JNK and pp38-MAPK to ameliorate the damage of Δψm leading to suppression of caspase-3 activation. Gen might be used as an adjunction therapy in APL patients receiving As2O3 treatment to avoid, at least to minimize, the adverse cardiac effects of As2O3.

BackgroundThe polyphenol resveratrol (Rev) has been reported to exhibit cardioprotective effects, such as inhibition of TAC (transverse aortic constriction) or isoprenaline (ISO)‐induced hypertrophy. MicroRNA‐155 (miR‐155) was found to be decreased in hypertrophic myocardium, which could be further reduced by pretreatment of Rev. The study was designed to investigate the molecular effects of miR‐155 on cardiac hypertrophy, focusing on the role of breast cancer type 1 susceptibility protein (BRCA1). Methods and ResultsWe demonstrated that Rev alleviated severity of hypertrophic myocardium in a mice model of cardiac hypertrophy by TAC treatment. Down‐regulation of miR‐155 was observed in pressure overload– or ISO‐induced hypertrophic cardiomyoctyes. Interestingly, administration of Rev substantially attenuated miR‐155 level in cardiomyocytes. In agreement with its miR‐155 reducing effect, Rev relieved cardiac hypertrophy and restored cardiac function by activation of BRCA1 in cardiomyoctyes. Our results further revealed that forkhead box O3a (FoxO3a) was a miR‐155 target in the heart. And miR‐155 directly repressed FoxO3a, whose expression was mitigated in miR‐155 agomir and mimic treatment in vivo and in vitro. ConclusionsWe conclude that BRCA1 inactivation can increase expression of miR‐155, contributing to cardiac hypertrophy. And Rev produces their beneficial effects partially by down‐regulating miR‐155 expression, which might be a novel strategy for treatment of cardiac hypertrophy.

Oxidative stress is thought to contribute to cancer development. Epstein-Barr virus (EBV) and its encoded oncoprotein, latent membrane protein 1 (LMP1), are closely associated with the transformation of nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma (BL). In this study, we used LMP1-transformed NP cells and EBV-related malignant cell lines to assess the effects of LMP1 on reactive oxygen species (ROS) accumulation and glycolytic activity. Using NPC tissue samples and a tissue array to address clinical implications, we report that LMP1 activates NAD(P)H oxidases to generate excessive amount of ROS in EBV-related malignant diseases. By evaluating NAD(P)H oxidase (NOX) subunit expression, we found that the expression of the NAD(P)H oxidase regulatory subunit p22phox was significantly upregulated upon LMP1-induced transformation. Furthermore, this upregulation was mediated by the c-Jun N-terminal kinase (JNK) pathway. In addition, LMP1 markedly stimulated anaerobic glycolytic activity through the PI3K/Akt pathway. Additionally, in both NPC cells and tissue samples, p22phox expression correlated with LMP1 expression. The NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI) also exerted a marked cytotoxic effect in LMP1-transformed and malignant cells, providing a novel strategy for anticancer therapy.

Cardiotoxicity is an aggravating side effect of many clinical antineoplastic agents such as arsenic trioxide (As2O3), which is the first-line treatment for acute promyelocytic leukemia (APL). Clinically, drug combination strategies are widely applied for complex disease management. Here, an optimized, cardiac-friendly therapeutic strategy for APL was investigated using a combination of As2O3 and genistein or resveratrol. Potential combinations were explored with respect to their effects on mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity, autophagy, and apoptosis in both NB4 cells and neonatal rat left ventricular myocytes. All experiments consistently suggested that 5 µM resveratrol remarkably alleviates As2O3-induced cardiotoxicity. To achieve an equivalent effect, a 10-fold dosage of genistein was required, thus highlighting the dose advantage of resveratrol, as poor bioavailability is a common concern for its clinical application. Co-administration of resveratrol substantially amplified the anticancer effect of As2O3 in NB4 cells. Furthermore, resveratrol exacerbated oxidative stress, mitochondrial damage, and apoptosis, thereby reflecting its full range of synergism with As2O3. Addition of 5 µM resveratrol to the single drug formula of As2O3 also further increased the expression of LC3, a marker of cellular autophagy activity, indicating an involvement of autophagy-mediated tumor cell death in the synergistic action. Our results suggest a possible application of an As2O3 and resveratrol combination to treat APL in order to achieve superior therapeutics effects and prevent cardiotoxicity.

BACKGROUND: Ischemic postconditioning (IPost) protects the reperfused heart from infarction which has drawn much attention recently. However, studies to date have rarely investigated the role of microRNAs (miRNAs) in IPost. The aims of this study were to investigate whether miR-21 is involved in the protective effect of IPost against myocardial ischemia-reperfusion (I/R) injury and disclose the potential molecular mechanisms involved. METHODS AND RESULTS: We found that miR-21 was remarkably up-regulated in mouse hearts after IPost. To determine the protective role of IPost-induced miR-21 up-regulation, the mice were divided into the following four groups: I/R group; I/R+IPost group (I/R mice treated with IPost); Antagomir-21+IPost+I/R group (I/R mice treated with anagomir-21 and IPost); Scramble+IPost+I/R group (I/R mice treated with scramble and IPost). The results showed IPost could reduce I/R injury-induced infarct size of the left ventricle, improve cardiac function, and prevent myocardial apoptosis, while knockdown of miR-21 with antagomir-21 could reverse these protective effects of IPost against mouse I/R injury. Furthermore, we confirmed that miR-21 plays a protective role in myocardial apoptosis through PTEN/Akt signaling pathway, which was abrogated by the PI3K inhibitor LY294002. The protective effect of miR-21 on myocardial apoptosis was further revealed in mouse hearts after IPost treatment in vivo. CONCLUSIONS: Our data clearly demonstrate that miR-21 is involved in IPost-mediated cardiac protection against I/R injury and dysfunction through the PTEN/Akt signaling pathway in vivo. Identifying the beneficial roles of IPost-regulated miRNAs in cardiac protection, which may be a rational target selection for ischemic cardioprotection.

In the title salt, C6H9N2+·NO3−, the 2-amino-5-methylpyridinium cation and the nitrate anion are cyclically linked through pyridinium and amine N—H...O hydrogen bonds [graph set R43(12)]. These units are extended into a zigzag chain structure lying parallel to the a axis, through a second cyclic R22(8) association involving amine N—H...O and aromatic C—H...O hydrogen bonds to nitrate O-atom acceptors.

In the title complex, [Cu(C16H15NO3)(C10H8N2)]·3H2O, the CuII atom is five coordinated by O,N,O′-donor atoms of the Schiff base ligand and by two N atoms of the 2,2′-bipyridine ligand in a distorted square-pyramidal geometry. In the crystal, molecules are linked into a two-dimensional network parallel to (011) by O—H...O hydrogen bonds.

The M(3) subtype of muscarinic acetylcholine receptors (M(3)-mAChR) plays a protective role in myocardial ischemia and microRNAs (miRNAs) participate in many cardiac pathophysiological processes, including ischemia-induced cardiac injury. However, the role of miRNAs in M(3)-mAChR mediated cardioprotection remains unexplored. The present study was designed to identify miRNAs that are involved in cardioprotective effects of M(3)-mAChR against myocardial ischemia and elucidate the underlying mechanisms. We established rat model of myocardial ischemia and performed miRNA microarray analysis to identify miRNAs involved in the cardioprotection of M(3)-mAChR. In H9c2 cells, the viability, intracellular free Ca(2+) concentration ([Ca(2+)]i), intracellular reactive oxygen species (ROS), miR-376b-5p expression level, brain derived neurophic factor (BDNF) and nuclear factor kappa-B (NF-κB) levels were measured. Our results demonstrated that M(3)-mAChR protected myocardial ischemia injury. Microarray analysis and qRT-PCR revealed that miR-376b-5p was significantly up-regulated in ischemic heart tissue and the M(3)-mAChRs agonist choline reversed its up-regulation. In vitro, miR-376b-5p promoted H(2)O(2)-induced H9c2 cell injuries measured by cells viability, [Ca(2+)]i and ROS. Western blot and luciferase assay identified BDNF as a direct target of miR-376b-5p. M(3)-mAChR activated NF-κB and thereby inhibited miR-376b-5p expression. Our data show that a novel M(3)-mAChR/NF-κB/miR-376b-5p/BDNF axis plays an important role in modulating cardioprotection. MiR-376b-5p promotes myocardial ischemia injury possibly by inhibiting BDNF expression and M(3)-mAChR provides cardioprotection at least partially mediated by the downregulation of miR-376b-5p through NF-κB. These findings provide new insight into the potential mechanism by which M(3)-mAChR provides cardioprotection against myocardial ischemia injury.

This practice guideline focuses on the cognitive assessment for mild cognitive impairment in the Guangdong‐Hong Kong‐Macao Greater Bay Area. To achieve the standardization and normalization of its clinical practice and generate individualized intervention, the National Core Cognitive Center of the Second Affiliated Hospital of Guangzhou Medical University, the Cognitive Disorders Branch of Chinese Geriatic Society, the Dementia Group of Neurology Branch of Guangdong Medical Association and specialists from Hong Kong and Macao developed guidelines based on China's actual conditions and efficiency, economic cost and accuracy. The article addresses the significance, background, and the process of the assessment and follow‐up to realize the promotion and dissemination of cognitive assessment. [ABSTRACT FROM AUTHOR]

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 ß-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. [ABSTRACT FROM AUTHOR]