The Chains of Ferroptosis Interact in the Whole Progression of Atherosclerosis.

Atherosclerosis (AS), a category of cardiovascular disease (CVD) that can cause other more severe disabilities, increasingly jeopardizes human health. Owing to its imperceptible and chronic symptoms, it is hard to determine the pathogenesis and precise therapeutics for AS. A novel type of programmed cell death called ferroptosis was discovered in recent years that is distinctively different from other traditional cell death pathways in morphological and biochemical aspects. Characterized by iron overload, redox disequilibrium, and accumulation of lipid hydroperoxides (L-OOH), ferroptosis influences endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages, as well as inflammation, partaking in the pathology of many cardiovascular diseases such as atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure. The mechanisms behind ferroptosis are so sophisticated and interwoven that many molecules involved in this procedure are unknown. This review systematically depicts the initiation and modulation of ferroptosis and summarizes the contribution of ferroptosis to AS, which may open a feasible approach for target treatment in the alleviation of AS progression.

The therapeutic efficacy and clinical translation of mesenchymal stem cell-derived exosomes in cardiovascular diseases.

Exosomes, mainly derived from mesenchymal stem cells, provide a good reference for cardiac function repair and clinical application in cardiac and vascular diseases by regulating cardiomyocyte viability, inflammatory levels, angiogenesis, and ventricular remodeling after a heart injury. This review presents the cardioprotective efficacy of mesenchymal stem cell-originated exosomes and explores the underlying molecular mechanisms. Furthermore, we expound on several efficient approaches to transporting exosomes into the heart in clinical application and comment on the advantages and disadvantages of each method.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Alleviate Diabetic Kidney Disease in Rats by Inhibiting Apoptosis and Inflammation.

BACKGROUND AND AIMS: Previous studies have confirmed the anti-inflammation effect of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exo). We aimed to investigate the therapeutic effect of BMSC-Exo on diabetic kidney disease (DKD), as well as the underlying mechanisms. METHODS: SD rats were induced by streptozotocin combined with a high-fat diet to establish a diabetes disease model. BMSCs-Exo were injected via tail veins at a weekly dose of 100 µg for 12 weeks. Pathological changes in the rat kidneys were evaluated using HE, Masson, and Periodic Acid-Schiff and immunohistochemical staining. TUNEL staining and western blot were used to evaluate the expression levels of apoptosis-related proteins in the rat kidney cells. The TNF-α level was detected by PCR and NF-κB (p65) by western blotting to examine the inflammatory responses in the renal tissue. RESULTS: BMSCs-Exo significantly alleviated the renal structural damage and the distribution of apoptotic cells in diabetic rats. Furthermore, BMSCs-Exo increased the expression of pro-apoptosis protein Bax and decreased the expression of apoptosis-executing protein Cleaved Caspase 9 and Cleaved caspase 3. In addition, the transcription level of TNF-α in kidney tissue and NF-κB (p65) expression was also decreased through BMSCs-Exo treatment. Besides, the levels of glucose (GLU), creatinine (Cr), and burea nitrogen (BUN) in diabetic rats were decreased by the BMSC-Exo treatment. CONCLUSIONS: BMSCs-Exo may alleviate diabetic kidney damage by inhibiting apoptosis and inflammation.

Improved Thermal Anisotropy of Multi-Layer Tungsten Telluride on Silicon Substrate.

WTe2, a low-symmetry transition metal dichalcogenide, has broad prospects in functional device applications due to its excellent physical properties. When WTe2 flake is integrated into practical device structures, its anisotropic thermal transport could be affected greatly by the substrate, which matters a lot to the energy efficiency and functional performance of the device. To investigate the effect of SiO2/Si substrate, we carried out a comparative Raman thermometry study on a 50 nm-thick supported WTe2 flake (with κzigzag = 62.17 W·m-1·K-1 and κarmchair = 32.93 W·m-1·K-1), and a suspended WTe2 flake of similar thickness (with κzigzag = 4.45 W·m-1·K-1, κarmchair = 4.10 W·m-1·K-1). The results show that the thermal anisotropy ratio of supported WTe2 flake (κzigzag/κarmchair ≈ 1.89) is about 1.7 times that of suspended WTe2 flake (κzigzag/κarmchair ≈ 1.09). Based on the low symmetry nature of the WTe2 structure, it is speculated that the factors contributing to thermal conductivity (mechanical properties and anisotropic low-frequency phonons) may have affected the thermal conductivity of WTe2 flake in an uneven manner when supported on a substrate. Our findings could contribute to the 2D anisotropy physics and thermal transport study of functional devices based on WTe2 and other low-symmetry materials, which helps solve the heat dissipation problem and optimize thermal/thermoelectric performance for practical electronic devices.

The cGAS-STING Pathway: A Ubiquitous Checkpoint Perturbing Myocardial Attributes.

As an innate immune route of defense against microbial infringement, cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)- stimulator of interferon genes (STING) signaling does not simply participate in amplifying inflammatory responses via releasing type-I interferon (IFN) or enhance the expression of pro-inflammatory genes, but also interplays with multifarious pathophysiological activities, such as autophagy, apoptosis, pyroptosis, ferroptosis, and senescence in a broad repertoire of cells like endothelial cells, macrophages and cardiomyocyte. Thus, the cGAS-STING pathway is closely linked with aberrant heart morphologically and functionally via these mechanisms. The past few decades have witnessed an increased interest in the exact relationship between the activation of the cGAS-STING pathway and the initiation or development of certain cardiovascular diseases (CVD). A group of scholars has gradually investigated the perturbation of myocardium affected by the overactivation or suppression of the cGAS-STING. This review focuses on how the cGAS-STING pathway interweaves with other pathways and creates a pattern of dysfunction associated with cardiac muscle. This sets treatments targeting the cGAS-STING pathway apart from traditional therapeutics for cardiomyopathy and achieves better clinical value.

GATR: A Road Network Traffic Violation Prediction Method Based on Graph Attention Network.

Prediction of traffic violations plays a key role in transportation safety. Combining with deep learning to predict traffic violations has become a new development trend. However, existing methods are based on regular spatial grids which leads to a fuzzy spatial expression and ignores the strong correlation between traffic violations and road network. A spatial topological graph can express the spatiotemporal correlation more accurately and then improve the accuracy of traffic violation prediction. Therefore, we propose a GATR (graph attention network based on road network) model to predict the spatiotemporal distribution of traffic violations, which adopts a graph attention network model combined with historical traffic violation features, external environmental features, and urban functional features. Experiments show that the GATR model can express the spatiotemporal distribution pattern of traffic violations more clearly and has higher prediction accuracy (RMSE = 1.7078) than Conv-LSTM (RMSE = 1.9180). The verification of the GATR model based on GNN Explainer shows the subgraph of the road network and the influence degree of features, which proves GATR is reasonable. GATR can provide an important reference for prevention and control of traffic violations and improve traffic safety.

Exploring the Coordination and Spatial-Temporal Characteristics of the Tourism-Economy-Environment Development in the Pearl River Delta Urban Agglomeration, China.

The rise of mass tourism has encouraged rapid economic growth; meanwhile, the eco-environmental system has come under increasing pressure. To achieve sustainable development, it is critical to deeply explore the relationship and evolution characteristics between three subsystems: tourism, the economy, and the eco-environment. This study aims to develop a more comprehensive indicator system for evaluating the coupling coordination degree (CCD) of the tourism-economy-environment (TEE) system using statistical data from nine cities in the Pearl River Delta (PRD) urban agglomeration from 2010 to 2019. We investigated the spatial-temporal evolution characteristics and driving forces of the TEE system in the PRD using the CCD model and the geo-detector model. The research results show the following: (1) The comprehensive benefits of the TEE system have increased steadily over the past 10 years, whereas the benefits of the eco-environment subsystem have fluctuated and been relatively unstable. (2) Spatially, in terms of tourism development, the eastern regions of the PRD are more developed than the western regions, and the regions with the greatest tourism benefits have gradually shifted to the northeastern regions of the PRD. Economic development presented an imbalanced but relatively stable spatial pattern. Guangzhou and Shenzhen have been the two most economically developed cities over the past 10 years. The eco-environment development has fluctuated over time, revealing a spatial pattern of cities with low environmental benefits in the center and cities with high eco-environmental benefits in the surrounding regions. (3) The PRD's TEE system has become more integrated, moving from moderate disorder to a model of high-quality coordinated development, demonstrating a spatial pattern in which the cities of high development coordination are located near the Pearl River Estuary, and the coordination decreases the further away they are from the estuary. (4) The major driving factors of heterogeneous TEE coordination development include eco-environment protection, opening-up policies, education investment, technological innovation level, and the regional economic development level. The results are expected to effectively promote economic, tourism, and environmental improvement in the PRD, as well as to provide policy recommendations for coordinated TEE development in other similar urban agglomerations.

cGAS-STING Pathway Performance in the Vulnerable Atherosclerotic Plaque.

The important role of Ca2+ in pathogenic store-operated calcium entry (SOCE) is well-established. Among the proteins involved in the calcium signaling pathway, Stromal interacting molecule 1 (STIM1) is a critical endoplasmic reticulum transmembrane protein. STIM1 is activated by the depletion of calcium stores and then binds to another calcium protein, Orai1, to form a channel through which the extracellular Ca2+ can enter the cytoplasm to replenish the calcium store. Multiple studies have shown that increased STIM1 facilitates the aberrant proliferation and apoptosis of vascular smooth cells (VSMC) and macrophages which can promote the formation of rupture-prone plaque. Together with regulating the cytosolic Ca2+ concentration, STIM1 also activates STING through altered intracellular Ca2+ concentration, a critical pro-inflammatory molecule. The cGAS-STING pathway is linked with cellular proliferation and phenotypic conversion of VSMC and enhances the progression of atherosclerosis plaque. In summary, we conclude that STIM1/cGAS-STING is involved in the progression of AS and plaque vulnerability.

Exploring the Association between Neighborhood Blue Space and Self-Rated Health among Elderly Adults: Evidence from Guangzhou, China.

Blue spaces is associated with self-rated health (SRH), but little is known about the pathways underlying this association among Chinese urban elderly individuals. Based on neighborhood effect theory, this study examined the relationship between neighborhood blue spaces and SRH among elderly individuals using data from a questionnaire survey conducted in Guangzhou, remote sensing images, street views, and environmental information in the context of a Chinese megacity. In addition, multilevel linear model and mediating effect model empirical analyses were performed. Results showed that first, the SRH of the elderly was associated with individual- and neighborhood-level factors. Second, the multilevel mediation model revealed that multiple biopsychosocial pathways existed between neighborhood blue spaces and the SRH of the elderly, specifically, the blue space characteristics related to the SRH of the elderly via the mediating effect of stress. Third, owing to demographic characteristics and socioeconomic status, the stratified analyses also indicated a strong association between neighborhood blue spaces and SRH outcomes in the older and low-income groups. The mediating effect of stress in the age and income groups was also observed, and the mediation pathways and group differences were confirmed in the context of Chinese cities. This research enriches the empirical literature on blue spaces and elderly health from a multidisciplinary perspective and suggests the need for "healthy neighborhood" and "health-aging" planning in Chinese settings.

Associations between Community Cohesion and Subjective Wellbeing of the Elderly in Guangzhou, China-A Cross-Sectional Study Based on the Structural Equation Model.

Population aging has become one of the most prominent population trends in China and worldwide. Given the retirement and physical limitation of the elderly, the neighborhood has gradually become the center of their daily lives and communication. Community cohesion plays an essential role in improving the elderly's subjective wellbeing. However, most present studies on the concept and relationship between different dimensions of community cohesion are mainly in western countries. Meanwhile, most of the studies on the relationship between community cohesion and subjective wellbeing only focused on one aspect of community cohesion such as community interaction. To address this research gap, this study sampled 20 communities in Guangzhou, conducted a questionnaire survey on 969 elderly people, and explored the relationship between four aspects of community cohesion (community interaction, environmental satisfaction, belonging, and participation) and their associations with subjective wellbeing using the Structural Equation Model (SEM). In addition, we performed multi-group analysis to study the association differences among older individuals in communities with different socioeconomic types. We found that: (1) The conceptual relationship between different aspects of community cohesion among older adults is significant; (2) Community environmental satisfaction, interaction, and belonging associate with the elderly's subjective wellbeing, whereas there is no significant association between community participation and subjective wellbeing; (3) Mental health is an important mediating factor connecting community cohesion and subjective wellbeing, whereas physical health is not. (4) The association pattern of older adults in communities with different socio-economic status are identical, whereas the association strengths are different. In high Socio-Economic Status Index (SESI) communities (communities where older adults with relatively high socioeconomic attributes gather, such as high income and education level), community belonging and participation are significantly associated with community environmental satisfaction and interaction, respectively. In low SESI communities (communities in which older adults with relatively low socioeconomic attributes gather, such as low income and education level), community interaction, belonging, and participation considerably link to community environmental satisfaction, interaction, and belonging, respectively. Regarding the association between community cohesion and subjective wellbeing, community interaction has stronger linkage with the elderly's subjective wellbeing of in high-SESI aging community than low-SESI aging community. While community environmental satisfaction has stronger association with the elderly's subjective wellbeing of the elderly in low-SESI aging community than high-SESI aging community. Therefore, it is sensible for community planning to focus on community environment improvement and vibrant community activities organization.

Association Pathways Between Neighborhood Greenspaces and the Physical and Mental Health of Older Adults-A Cross-Sectional Study in Guangzhou, China.

According to the United Nations, the proportion of the older population is increasing at a faster rate than all other age groups. Hence, the well-being of older adults is a mounting concern worldwide in the current century. Using a single greenery metric, previous studies linked greenness to residents' well-being. This study aims to extend this field by focusing on the mental and physical well-being of older adults by using remote sensing and streetscape metrics in evaluating neighborhood greenness. We selected 20 residential neighborhoods in Guangzhou City, China as the cross-sectional case study areas. We investigated neighborhood normalized difference vegetation index (NDVI) collected using remote sensing images, streetscape greenery, and PM2.5 via field surveys. We assessed the health condition of 972 senior residents selected by multi-stage stratified probability proportionate to population size sampling technique (PPS) using a questionnaire survey. We adopted the structural equation model (SEM) in analyzing the pathways that link neighborhood greenness and the mental and physical health of older adults. We found that neighborhood greenness has a positive association with the physical activity by older adults that is positively linked to their physical health. Moreover, neighborhood greenness is positively related to regular social interactions among older adults that is positively linked to their mental health. These findings are consistent with those of previous studies. However, we obtained new results that were unique to China. We found that neighborhood greenness has no significant direct relationship with the physical and mental health of older adults and that social interactions of low-income senior groups are more substantially related to neighborhood greenness than the other groups. Therefore, community planning should emphasize the development of neighborhood greenness, such as parks and street trees, to provide natural spaces for social interactions and places for physical activities among older residents.

Computational Approaches in Preclinical Studies on Drug Discovery and Development.

Because undesirable pharmacokinetics and toxicity are significant reasons for the failure of drug development in the costly late stage, it has been widely recognized that drug ADMET properties should be considered as early as possible to reduce failure rates in the clinical phase of drug discovery. Concurrently, drug recalls have become increasingly common in recent years, prompting pharmaceutical companies to increase attention toward the safety evaluation of preclinical drugs. In vitro and in vivo drug evaluation techniques are currently more mature in preclinical applications, but these technologies are costly. In recent years, with the rapid development of computer science, in silico technology has been widely used to evaluate the relevant properties of drugs in the preclinical stage and has produced many software programs and in silico models, further promoting the study of ADMET in vitro. In this review, we first introduce the two ADMET prediction categories (molecular modeling and data modeling). Then, we perform a systematic classification and description of the databases and software commonly used for ADMET prediction. We focus on some widely studied ADMT properties as well as PBPK simulation, and we list some applications that are related to the prediction categories and web tools. Finally, we discuss challenges and limitations in the preclinical area and propose some suggestions and prospects for the future.

Pelvic plexus block to provide better anesthesia in transperineal template-guided prostate biopsy: a randomised controlled trial.

BACKGROUND: To evaluate the efficacy of pelvic plexus block (PPB) in relief pain during transperineal template-guided prostate biopsy (TTPB), compared with conventional periprostatic nerve block (PNB). METHODS: From July 2016 to August 2017, 245 patients who were performed TTPB in Clinical Medical College of Yangzhou University were recruited. The patients were randomized into three groups using a random number table. Group-1 received prostate capsule local anesthesia with 22 ml of 1% lidocaine. Group-2 additionally received PNB on the basis of Group-1. To perform PNB, 5 ml 1% lidocaine was injected into the region of prostatic neurovascular bundle situated in the angle of prostate-bladder-seminal vesicle. Group-3 received prostate capsule local anesthesia plus PPB (5 ml of 1% lidocaine injection into the pelvic plexus which located on lateral to the bilateral seminal vesicle apex). The patients' pain and satisfaction were evaluated by visual analogue scale and visual numerical scale, respectively. RESULTS: The age, total prostate volume, PSA and the number of cores were comparable among the three groups. The visual analog scale scores of group-3 were significantly lower than group-2 during biopsy (P = 0.003). Conversely, the visual numeric scale scores were higher in group-3 (P = 0.039). Both the group-2 and group-3 outperformed the group-1 in alleviating pain and had a higher quantification of satisfaction. There were no significant differences in the pain scores or the satisfaction scores at 30 min after the procedure among the three groups. CONCLUSIONS: The analgesic efficacy of PPB guided by Doppler ultrasound in TTPB was better than that of PNB and both were superior to no nerve block. TRIAL REGISTRATION: ChiCTR-IOR-17013533 , 01/06/2016.

Permanent 125 I prostate brachytherapy for castration-resistant prostate cancer.

OBJECTIVE: To evaluate the clinical significance of permanent 125 I prostate brachytherapy in patients with castration-resistant prostate cancer. METHODS: A retrospective study of 45 patients with castration-resistant prostate cancer from the Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China was carried out. Patients were divided into two groups according to different treatments: 21 patients received endocrine therapy alone (control group), and 24 patients underwent brachytherapy combined with endocrine therapy (treatment group). Prostate-specific antigen progression-free survival, cancer-specific survival, overall survival and quality of life of the two groups were compared. RESULTS: The median prostate-specific antigen progression-free survival and cancer-specific survival of the treatment group were 29 months (interquartile range 25-37 months) and 37 months (interquartile range 30-50 months), respectively. These were significantly longer than those of the control group (both P < 0.05). Prostate-specific antigen (before androgen deprivation therapy and before brachytherapy), prostate volume, Gleason score, clinical stage and brachytherapy were associated with prostate-specific antigen progression-free survival and cancer-specific survival on univariate analysis. For the quality of life after treatment, urinary symptoms/problems at 1 month after brachytherapy compared with the control group had a statistically significant difference and clinically relevant deterioration, but after 6 months there were no statistically significant differences and clinically relevant deterioration. Compared with the control group, the physical functioning, social functioning, global health and general physical discomfort of the treatment group were significantly improved. CONCLUSIONS: Brachytherapy with 125 I seed implantation can effectively prolong survival of patients with castration-resistant prostate cancer and, to a certain extent, improve patients' quality of life.

Reverse Screening Methods to Search for the Protein Targets of Chemopreventive Compounds.

This article is a systematic review of reverse screening methods used to search for the protein targets of chemopreventive compounds or drugs. Typical chemopreventive compounds include components of traditional Chinese medicine, natural compounds and Food and Drug Administration (FDA)-approved drugs. Such compounds are somewhat selective but are predisposed to bind multiple protein targets distributed throughout diverse signaling pathways in human cells. In contrast to conventional virtual screening, which identifies the ligands of a targeted protein from a compound database, reverse screening is used to identify the potential targets or unintended targets of a given compound from a large number of receptors by examining their known ligands or crystal structures. This method, also known as in silico or computational target fishing, is highly valuable for discovering the target receptors of query molecules from terrestrial or marine natural products, exploring the molecular mechanisms of chemopreventive compounds, finding alternative indications of existing drugs by drug repositioning, and detecting adverse drug reactions and drug toxicity. Reverse screening can be divided into three major groups: shape screening, pharmacophore screening and reverse docking. Several large software packages, such as Schrödinger and Discovery Studio; typical software/network services such as ChemMapper, PharmMapper, idTarget, and INVDOCK; and practical databases of known target ligands and receptor crystal structures, such as ChEMBL, BindingDB, and the Protein Data Bank (PDB), are available for use in these computational methods. Different programs, online services and databases have different applications and constraints. Here, we conducted a systematic analysis and multilevel classification of the computational programs, online services and compound libraries available for shape screening, pharmacophore screening and reverse docking to enable non-specialist users to quickly learn and grasp the types of calculations used in protein target fishing. In addition, we review the main features of these methods, programs and databases and provide a variety of examples illustrating the application of one or a combination of reverse screening methods for accurate target prediction.