Interleukin-18 enhances vascular calcification and osteogenic differentiation of vascular smooth muscle cells through TRPM7 channel activation

Objective—Vascular calcification (VC) is an important predictor of cardiovascular morbidity and mortality. Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is a key mechanism of VC. Recent studies show that IL-18 (interleukin-18) favors VC while TRPM7 (transient receptor potential melastatin 7) channel upregulation inhibits VC. However, the relationship between IL-18 and TRPM7 is unclear. We questioned whether IL-18 enhances VC and osteogenic differentiation of VSMCs through TRPM7 channel activation. Approach and Results—Coronary artery calcification and serum IL-18 were measured in patients by computed tomographic scanning and enzyme-linked immunosorbent assay, respectively. Primary rat VSMCs calcification were induced by high inorganic phosphate and exposed to IL-18. VSMCs were also treated with TRPM7 antagonist 2-aminoethoxy-diphenylborate or TRPM7 small interfering RNA to block TRPM7 channel activity and expression. TRPM7 currents were recorded by patch-clamp. Human studies showed that serum IL-18 levels were positively associated with coronary artery calcium scores (r=0.91; P<0.001). In VSMCs, IL-18 significantly decreased expression of contractile markers α-smooth muscle actin, smooth muscle 22 α, and increased calcium deposition, alkaline phosphatase activity, and expression of osteogenic differentiation markers bone morphogenetic protein-2, Runx2, and osteocalcin (P<0.05). IL-18 increased TRPM7 expression through ERK1/2 signaling activation, and TRPM7 currents were augmented by IL-18 treatment. Inhibition of TRPM7 channel by 2-aminoethoxy-diphenylborate or TRPM7 small interfering RNA prevented IL-18–enhanced osteogenic differentiation and VSMCs calcification. Conclusions—These findings suggest that coronary artery calcification is associated with increased IL-18 levels. IL-18 enhances VSMCs osteogenic differentiation and subsequent VC induced by β-glycerophosphate via TRPM7 channel activation. Accordingly, IL-18 may contribute to VC in proinflammatory conditions

A survey on adaptive random testing

Random testing (RT) is a well-studied testing method that has been widely applied to the testing of many applications, including embedded software systems, SQL database systems, and Android applications. Adaptive random testing (ART) aims to enhance RT's failure-detection ability by more evenly spreading the test cases over the input domain. Since its introduction in 2001, there have been many contributions to the development of ART, including various approaches, implementations, assessment and evaluation methods, and applications. This paper provides a comprehensive survey on ART, classifying techniques, summarizing application areas, and analyzing experimental evaluations. This paper also addresses some misconceptions about ART, and identifies open research challenges to be further investigated in the future work

The expression profile analysis of NKX2-5 knock-out embryonic mice to explore the pathogenesis of congenital heart disease

AbstractBackgroundMutation of NKX2-5 could lead to the development of congenital heart disease (CHD) which is a common inherited disease. This study aimed to investigate the pathogenesis of CHD in NKX2-5 knock-out embryonic mice.MethodsThe expression profile in the NKX2-5 knock-out embryonic mice (GSE528) was downloaded from Gene Expression Omnibus. The heart tissues from the null/heterozygous embryonic day 12.5 mice were compared with wild-type mice to identify differentially expressed genes (DEGs), and then DEGs corresponding to the transcriptional factors were filtered out based on the information in the TRANSFAC database. In addition, a transcriptional regulatory network was constructed according to transcription factor binding site information from the University of California Santa Cruz database. A pathway interaction network was constructed by latent pathways identification analysis.ResultsThe 42 DEGs corresponding to transcriptional factors from the null and heterozygous embryos were identified. The transcriptional regulatory networks included five down-regulated DEGs (SP1, SRY, JUND, STAT6, and GATA6), and six up-regulated DEGs [POU2F1, NFY (NFYA/NFYB/NFYC), USF2 and MAX]. Latent pathways analysis demonstrated that ribosome, glycolysis/gluconeogenesis, and dilated cardiomyopathy pathways significantly interacted.ConclusionThe identified DEGs and latent pathways could provide new comprehensive view for understanding the pathogenesis of CHD

A Global Analysis of the Relationship Between Urbanization and Fatalities in Earthquake-Prone Areas

Urbanization can be a challenge and an opportunity for earthquake risk mitigation. However, little is known about the changes in exposure (for example, population and urban land) to earthquakes in the context of global urbanization, and their impacts on fatalities in earthquake-prone areas. We present a global analysis of the changes in population size and urban land area in earthquake-prone areas from 1990 to 2015, and their impacts on earthquake-related fatalities. We found that more than two thirds of population growth (or 70% of total population in 2015) and nearly three quarters of earthquake-related deaths (or 307,918 deaths) in global earthquake-prone areas occurred in developing countries with an urbanization ratio (percentage of urban population to total population) between 20 and 60%. Holding other factors constant, population size was significantly and positively associated with earthquake fatalities, while the area of urban land was negatively related. The results suggest that fatalities increase for areas where the urbanization ratio is low, but after a ratio between 40 and 50% occurs, earthquake fatalities decline. This finding suggests that the resistance of building and infrastructure is greater in countries with higher urbanization ratios and highlights the need for further investigation. Our quantitative analysis is extended into the future using Shared Socioeconomic Pathways to reveal that by 2050, more than 50% of the population increase in global earthquake-prone areas will take place in a few developing countries (Pakistan, India, Afghanistan, and Bangladesh) that are particularly vulnerable to earthquakes. To reduce earthquake-induced fatalities, enhanced resilience of buildings and urban infrastructure generally in these few countries should be a priority

Abnormal Calcium Metabolism Mediated Increased Risk of Cardiovascular Events Estimated by High Ankle-Brachial Index in Patients on Peritoneal Dialysis

Cardiovascular disease (CVD) is the leading cause of death in peritoneal dialysis (PD) patients. But the relationship between regular PD and the risk of major adverse cardiovascular events (MACE) remains controversial. The possible risk factors are not fully elucidated. This study aims to investigate the possible factors affecting the risk of MACE estimated by high ankle-brachial index (ABI) in PD patients. A total of 243 patients were enrolled and divided into chronic kidney diseases (CKD) stage 1, non-dialyzed CKD stages 2–5, and PD groups. The prevalence of high ABI, indicating increased MACE, was elevated with CKD progression but not further increased in PD patients. Systolic blood pressure was closely correlated with high ABI in non-dialyzed CKD patients (β = 0.059, P = 0.001). But in PD patients, serum calcium had a crucial effect on high ABI (β = −9.853, P < 0.001). Additionally, PD patients with high ABI tended to dialyze inadequately (Kt/V <1.7) compared to those with normal ABI (29.0 vs. 13.3%, P = 0.031). Further mediation analysis revealed that ~86.2% of the relationship between Kt/V and high ABI was mediated by serum calcium in PD patients (mediation effect = 86.2%, ab = −0.220, 95% CI: −0.381 to −0.059, P = 0.008), especially in those starting PD before 55 years of age and with normal body mass index. This present study indicated that improvement of PD adequacy by maintaining calcium balance might be a promising method to reduce the risk of MACE estimated by high ABI for PD patients

CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation

Runx2, an essential transactivator for osteoblast differentiation, is tightly regulated at both the transcriptional and posttranslational levels. In this paper, we report that CHIP (C terminus of Hsc70-interacting protein)/STUB1 regulates Runx2 protein stability via a ubiquitination-degradation mechanism. CHIP interacts with Runx2 in vitro and in vivo. In the presence of increased Runx2 protein levels, CHIP expression decreases, whereas the expression of other E3 ligases involved in Runx2 degradation, such as Smurf1 or WWP1, remains constant or increases during osteoblast differentiation. Depletion of CHIP results in the stabilization of Runx2, enhances Runx2-mediated transcriptional activation, and promotes osteoblast differentiation in primary calvarial cells. In contrast, CHIP overexpression in preosteoblasts causes Runx2 degradation, inhibits osteoblast differentiation, and instead enhances adipogenesis. Our data suggest that negative regulation of the Runx2 protein by CHIP is critical in the commitment of precursor cells to differentiate into the osteoblast lineage

TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation

<p>Abstract</p> <p>Background</p> <p>The discovery of heat-sensitive Transient Receptor Potential Vanilloid (TRPV) ion channels provided a potential molecular explanation for the perception of innocuous and noxious heat stimuli. TRPV1 has a significant role in acute heat nociception and inflammatory heat hyperalgesia. Yet, substantial innocuous and noxious heat sensitivity remains in TRPV1 knockout animals. Here we investigated the role of two related channels, TRPV3 and TRPV4, in these capacities. We studied TRPV3 knockout animals on both C57BL6 and 129S6 backgrounds, as well as animals deficient in both TRPV3 and TRPV4 on a C57BL6 background. Additionally, we assessed the contributions of TRPV3 and TRPV4 to acute heat nociception and inflammatory heat hyperalgesia during inhibition of TRPV1.</p> <p>Results</p> <p>TRPV3 knockout mice on the C57BL6 background exhibited no obvious alterations in thermal preference behavior. On the 129S6 background, absence of TRPV3 resulted in a more restrictive range of occupancy centered around cooler floor temperatures. TRPV3 knockout mice showed no deficits in acute heat nociception on either background. Mice deficient in both TRPV3 and TRPV4 on a C57BL6 background showed thermal preference behavior similar to wild-type controls on the thermal gradient, and little or no change in acute heat nociception or inflammatory heat hyperalgesia. Masking of TRPV1 by the TRPV1 antagonist JNJ-17203212 did not reveal differences between C57BL6 animals deficient in TRPV3 and TRPV4, compared to their wild-type counterparts.</p> <p>Conclusions</p> <p>Our results support the notion that TRPV3 and TRPV4 likely make limited and strain-dependent contributions to innocuous warm temperature perception or noxious heat sensation, even when TRPV1 is masked. These findings imply the existence of other significant mechanisms for heat perception.</p

Silencing of rhomboid domain containing 1 to inhibit the metastasis of human breast cancer cells in vitro

Objective(s): A growing body of evidence indicates that rhomboid domain containing 1 (RHBDD1) plays an important role in a variety of physiological and pathological processes, including tumorigenesis. We aimed to determine the function of RHBDD1 in breast cancer cells. Materials and Methods: In this study, we used the Oncomine™ database to determine the expression patterns of RHBDD1 in normal and breast cancer tissues. We performed lentiviral transfection of RHBDD1-specific small interfering RNA into the breast cancer cell lines ZR-75-30 and MDA-MB-231 in order to investigate the effects of RHBDD1 deficiency on breast cancer metastasis. Results: We found that knockdown of RHBDD1 inhibited breast cancer cell migration and invasion in vitro. Moreover, knockdown of RHBDD1 promoted epithelial–mesenchymal transition (EMT) by suppressing the expression of MPP2, MPP9, fibronectin 1, vimentin, SRY-box 2, zinc finger E-box binding homeobox 1, and snail family transcriptional repressor 1, and promoting the expression of cadherin 1. Additionally, knockdown of RHBDD1 inhibited the protein expression and phosphorylation of Akt.Conclusion: Our data indicate that RHBDD1 overexpression may promote breast cancer metastasis via the regulation of EMT, suggesting that RHBDD1 may be an important regulator of breast cancer metastasis

Assessment of the reliability and quality of breast cancer related videos on TikTok and Bilibili: cross-sectional study in China

BackgroundAs the most common malignant tumor in the world, breast cancer also brings a huge disease burden to China. Ordinary people are increasingly inclined to use the Internet, especially video social platforms, as a source of health information. Educating the public to obtain correct information is important to reduce the incidence of breast cancer and improve the prognosis. However, the quality and reliability of breast cancer-related video content have not been fully studied.ObjectiveThis study aims to evaluate the quality of the information of breast cancer-related videos on TikTok and Bilibili video sharing platforms and factors related to video quality.MethodsWe collected the top 100 videos about breast cancer on TikTok and Bilibili, respectively. Categorize videos according to video source and video content. Video quality and reliability were assessed using Global Quality Score (GQS) and modified DISCERN (mDISCERN) tools. We also analyzed the correlation between video quality and video likes, comments, saves, and shares.ResultsAlthough the quality and reliability of Bilibili’s breast cancer videos were higher than TikTok (p = 0.002 and p = 0.001, respectively), the video quality of both video sharing platforms was not satisfactory, with a median GQS scores of 2.00 and 3.00 and mDISCERN scores of 1.00 and 2.00, respectively. In general, the quality and reliability of videos released by medical practitioners were higher than those of non-medical practitioners, and the quality and reliability of videos covering disease-related knowledge were higher than those of news reports (all p &lt; 0.001). Among medical practitioners, the quality of videos uploaded by doctors in breast disease was significantly lower than that of doctors in other areas (p &lt; 0.05). There was a significant positive correlation between video quality and duration (r = 0.240, p &lt; 0.001), a weak negative correlation between video quality and likes (r = 0.191, p &lt; 0.01), video quality and comments (r = 0.256, p &lt; 0.001), video reliability and likes (r = 0.198, p &lt; 0.001), video reliability and comments (r = 0.243, p &lt; 0.01).ConclusionOur study shows that the quality and reliability of breast cancer-related videos on TikTok and Bilibili are poor, and the overall quality is unsatisfactory. But videos uploaded by medical practitioners covering disease knowledge, prevention and treatment are of higher quality. Medical practitioners are encouraged to publish more high-quality videos, while video social platforms should formulate relevant policies to censor and supervise health education videos, so as to enable the public to obtain reliable health information