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Background: The relationship between Insulin-like growth factor 2 (IGF2) methylation in the P3 promoter region and birth outcomes in a hypobaric-hypoxia environment has never been investigated. This study examined the association and compared birth outcomes and IGF2 methylation in this region by ethnicity and altitude. Methods: Four hundred and six (406) mother and newborn pairs in the Tibetan Plateau were enrolled in a birth cohort study. Data were collected through interviews using structural questionnaires or extracted from medical records. Pyrosequencing was performed for IGF2 methylation in the P3 promoter region in maternal peripheral and umbilical cord blood. Birth outcomes and IGF2 methylation were compared among three groups: Han in high altitude (HHA, n=164, 2000-3500m), Tibetan in high altitude (THA, n=42, 2000-3500m), and Tibetan in ultra-high altitude (TUHA, n=200, 3500m and higher). Results: TUHA seemed to have a higher prevalence of macrosomia (7.5%) than both THA (0.0.%) and HHA (2.4%) and a lower IGF2 methylation level in maternal blood than THA (P=0.008). No difference in the IGF2 methylation levels was found between THA and HHA. The IGF2 methylation levels in maternal peripheral blood were associated with a reduced risk of macrosomia (RR= 0.726, 95% CL [0.528,0.998], P=0.049) among all mother and newborn pairs. Conclusions: Increased altitude appears to be associated with decreased maternal IGF2 methylation levels in the P3 promoter region, and maternal IGF2 methylation levels in this region was associated with reduced risk of macrosomia in newborns in the hypobaric hypoxic Tibetan Plateau environment. Keywords Macrosomia; IGF2; DNA methylation; high altitude; Tibet Plateau

Multidrug resistance (MDR) is the major clinical obstacle in the management of cancer by chemotherapy. Overexpression of ATP-dependent efflux transporter P-glycoprotein (PGP) is a key factor contributing to multidrug resistance of cancer cells. The purpose of the present study was to use the endosomal pH-sensitive MSN (mesoporous silica nanoparticles; MSN-Hydrazone-Dox) for controlled release of doxorubicin (Dox) in an attempt to overcome the PGP-mediated MDR. In vitro cell culture studies indicate that uptake of MSN-Hydrazone-Dox by the human uterine sarcoma MES-SA/Dox-resistant tumor (MES-SA/Dx-5) cell occurs through endocytosis, thus bypassing the efflux pump resistance. This improves the efficacy of the drug and leads to significant cytotoxicity and DNA fragmentation evidenced by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and DNA laddering assays. In vivo studies show that the intratumor injection of MSN-Hydrazone-Dox induces significant apoptosis of MES-SA/Dox-resistant cancer cells. This is validated by active caspase-3 immunohistochemical analysis. However, MSN-Hydrazone, without doxorubicin conjugation, cannot induce apoptosis in vitro and in vivo. In conclusion, both in vitro and in vivo studies show that MSN could serve as an efficient nanocarrier entering cell avidly via endocytosis, thus bypassing the PGP efflux pump to compromise the PGP-mediated MDR. MSN-Hydrazone-Dox could further respond to endosomal acidic pH to release doxorubicin in a sustained manner. Besides the cell study, this is the first report that successfully shows the therapeutic efficacy of using MSN against MDR cancer in vivo. Mol Cancer Ther; 10(5); 761–9. ©2011 AACR.

Supplementary Figures 1-2 from Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

As a common air pollutant, formaldehyde is widely present in nature, industrial production and consumer products. Endogenous formaldehyde is mainly produced through the oxidative deamination of methylamine catalysed by semicarbazide‐sensitive amine oxidase (SSAO) and is ubiquitous in human body fluids, tissues and cells. Vascular endothelial cells and smooth muscle cells are rich in this formaldehyde‐producing enzyme and are easily damaged owing to consequent cytotoxicity. Consistent with this, increasing evidence suggests that the cardiovascular system and stages of heart development are also susceptible to the harmful effects of formaldehyde. Exposure to formaldehyde from different sources can induce heart disease such as arrhythmia, myocardial infarction (MI), heart failure (HF) and atherosclerosis (AS). In particular, long‐term exposure to high concentrations of formaldehyde in pregnant women is more likely to affect embryonic development and cause heart malformations than long‐term exposure to low concentrations of formaldehyde. Specifically, the ability of mouse embryos to effect formaldehyde clearance is far lower than that of the rat embryos, more readily allowing its accumulation. Formaldehyde may also exert toxic effects on heart development by inducing oxidative stress and cardiomyocyte apoptosis. This review focuses on the current progress in understanding the influence and underlying mechanisms of formaldehyde on cardiovascular disease and heart development.

βII spectrin, the most common isoform of non-erythrocyte spectrin, is a cytoskeleton protein present in all nucleated cells. Interestingly, βII spectrin is essential for the development of various organs such as nerve, epithelium, inner ear, liver and heart. The functions of βII spectrin include not only establishing and maintaining the cell structure but also regulating a variety of cellular functions, such as cell apoptosis, cell adhesion, cell spreading and cell cycle regulation. Notably, βII spectrin dysfunction is associated with embryonic lethality and the DNA damage response. More recently, the detection of altered βII spectrin expression in tumors indicated that βII spectrin might be involved in the development and progression of cancer. Its mutations and disorders could result in developmental disabilities and various diseases. The versatile roles of βII spectrin in disease have been examined in an increasing number of studies; nonetheless, the exact mechanisms of βII spectrin are still poorly understood. Thus, we summarize the structural features and biological roles of βII spectrin and discuss its molecular mechanisms and functions in development, homeostasis, regeneration and differentiation. This review highlight the potential effects of βII spectrin dysfunction in cancer and other diseases, outstanding questions for the future investigation of therapeutic targets. The investigation of the regulatory mechanism of βII spectrin signal inactivation and recovery may bring hope for future therapy of related diseases.

Flooding imposes considerable property risk, and flood maps and flood insurance help prospective and existing property owners assess the potential risk. The US Federal Emergency Management Agency (FEMA) works with local and state officials to produce flood maps. Using these flood maps and demographic attributes, prior research has demonstrated correlations between the percent of a tract identified as disadvantaged and the percent of the tract covered by flood zones. Until recently, FEMA flood maps were the primary assessment tool for flood risk, but First Street Foundation (FSF) has developed its own flood risk tools. This paper compares these alternative flood risk measures as a percent of census tracts in the Southeastern US states and assesses models of the risk measures with demographic, housing, policy and control variables. The main results are first that the FEMA and FSF maps often reveal diverging levels of risk per tract. Second, the demographics correlating with tract-level risk differ markedly for the two risk measures. Third, the results vary considerably by state with more divergence in some states than others, and who is at risk of flooding across the states varies between the FEMA and FSF measures.

Hospitals play a critical role during disasters where they provide critical medical care to disaster victims and help the community to respond more effectively and recover quicker. However, hospitals face risks from the natural environment, such as floor risks. Amid the increasing flood risks due to climate change, it is essential to examine hospitals’ risk exposure. Motivated by this, this paper aims to answer four specific questions related to hospitals in Florida: 1) Are hospitals located in flood zones? 2) What is the relationship between hospital network size and flood risk? 3) To what extent does hospital flood risk vary by hospital attributes? 4) How do hospitals' flood risks differ from other public structures' flood risks? By leveraging two micro-level datasets, we found that approximately 12% of Florida hospitals are in flood zones, and that hospitals’ flood risk is not influenced by hospital network size or hospital attributes. We also find that hospitals are one of the most flood-prone public structures in our sample, raising questions about public infrastructure in flood management. We conclude by offering recommendations for improving hospital resilience to future disasters.

A voltage-driven cathode sheath model in an atmospheric-pressure argon arc discharge is developed in the framework of an implicit particle-in-cell Monte Carlo collision (PIC–MCC) method. Plasma transport processes are solved numerically in one dimension without any local-equilibrium hypotheses, in particular, without explicitly dividing sheath and a quasi-neutral plasma region. The right boundary of the computational domain located at the pre-sheath is determined first by observing the variation in typical parameters. A comparison of results is given with different positions of the right boundary to study the plasma transport processes in the cathode sheath. Number densities, spatially averaged energies, electric field and potential, collision frequency, heating rate of electrons, as well as the spatially averaged electron energy probability function inside the sheath, are predicted self-consistently based on this newly developed kinetic model. It is shown that both excitation collisions and ionization collisions occur inside the sheath, and collision frequency of the former is larger than the latter. The collision frequency of charge exchange is higher than that of elastic collision for ions. In addition, the effects of different electron emission processes are described. It is indicated that the thermionic emission on the hot cathode surface is not the only significant emission mechanism to sustain the arc discharges.

Purpose To investigate whether co-administration of antiarrhythmic dronedarone and anticoagulant rivaroxaban would increase the risks of hemorrhage after atrial fibrillation (AF) ablation. Methods A total of 100 patients with AF who underwent radiofrequency catheter ablation (CA) in the Department of Cardiology, the Affiliated Hospital of Qingdao University from 2019–12 to 2020–11 were included. Patients were divided into an oral dronedarone and rivaroxaban group (D-R group, N = 50) and an oral amiodarone and rivaroxaban group (A-R group, N = 50) according to the postoperative antiarrhythmic and anticoagulation strategies. Patients in 2 groups were given propensity score matching (PSM) to obtain a sample with balanced inter-group covariates. A retrospective observational study was conducted. After 3 months of follow-up, the incidence of clinically relevant non-major bleeding (CRNMB), major hemorrhages, and early AF recurrence was observed. Results After PSM, 41 patients were included in each group. With similarly distributed baseline characteristics and ablation characteristics after PSM, the CRNMB rate after AF ablation was significantly higher in the D-R group than in the A-R group (26.8% versus 7.3%, P = 0.02), and no major hemorrhages were detected in both groups. No significant difference was observed in the sinus rhythm maintenance rate between the D-R group and the A-R group (26.8% vs. 22.0%, P = 0.43). Conclusions Compared to co-administration of amiodarone and rivaroxaban, co-administration of dronedarone and rivaroxaban increases the risk of CRNMB but it does not increase the risk of major hemorrhages in blanking period after AF ablation.

In order to explore the changes of exhaust particulate matter (PM) with the addition of Ce-based catalyst in diesel, naphthenic acid cerium solution was selected as a fuel borne catalyst (FBC). Acc...

Circular RNAs (circRNAs) are a novel type of long non-coding RNAs that can regulate gene expression in heart development and heart disease. However, the expression pattern of circRNAs in congenital heart disease (CHD) induced by formaldehyde exposure is still unknown. We detected circRNAs expression profiles in heart tissue taken from six neonatal rat pups with formaldehyde exposure group and normal group using RNA-sequencing. Results revealed that a total of 54 circRNAs were dysregulated in the formaldehyde exposure group compared to the normal group. Among them, 31 were upregulated and 23 were downregulated (fold change = 2.0, p 0.0 5). The qRT-qPCR results showed that expressions of 12:628708|632694, 18:77477060|77520779, 5:167486001|167526275 were significantly upregulated, while that of 7:41167312|4116775 and 20:50659751|5068786 were notably downregulated; the expression pattern was consistent with the RNA sequencing data. Bioinformatics analysis shows that the pathogenesis of formaldehyde exposure-induced CHD may involve Hippo-YAP pathway、Notch signaling pathway and other pathways. A key miRNA (rno-miR-665) was identified by constructing a circRNA-miRNA-mRNA co-expression network. In summary, the study illustrated that circRNAs differentially expressed in fetal heart tissues during formaldehyde exposure has potential biological functions and may be a biomarker or therapeutic target for CHD.

A rapid, sensitive, and reliable liquid chromatography-tandem mass spectrometric method was developed to quantify ipatasertib in dog plasma. The dog plasma sample was deproteinated by using acetonitrile with ulixertinib as an internal standard followed by separation on a Spursil C18 -EP column with a gradient mobile phase comprising 2 mM ammonium acetate containing 0.1% formic acid and acetonitrile. Positive ion electrospray was used, and multiple reaction monitoring transitions were m/z 458.2 > 387.2 for ipatasertib and m/z 433.1 > 262.1 for the internal standard. The developed method was validated with a linear range of 0.3-1500 ng/mL, and with correlation coefficient greater than 0.9989. The lower limit of quantification was 0.3 ng/mL. The intra- and inter-day precision ranged from 3.58 to 14.32%, whereas the intra- and inter-day accuracy was in the range of -2.50-13.25%. No carry-over and matrix effects were observed under the current conditions. The extraction recovery was demonstrated to be greater than 85.43%. Ipatasertib was stable during the storage, processing, and determination. The validated assay was further successfully applied to a pharmacokinetic study of ipatasertib in dogs after oral and intravenous administrations. The bioavailability of ipatasertib was determined to be 19.3%.

This study was designed to conduct a retrospective and systematic occupational health risk assessment (OHRA) of enterprises that used benzene, toluene, and xylene (BTX) in Shanghai, China.All data for the study were obtained from 1,705 occupational health examination and evaluation reports from 2013 to 2017, and a semiquantitative model following Chinese OHRA guidelines (GBZ/T 298-2017) was applied for the assessment.The selected enterprises using BTX were mainly involved in manufacturing of products. Using the exposure level method, health risk levels associated with exposure to BTX were classified as medium, negligible, or low. However, the risk levels associated with benzene and toluene were significantly different according to job types, with gluers and inkers exhibiting greater health risks. For the same job type, the health risk levels assessed using the comprehensive index method were higher than those using the exposure level method.Our OHRA reveals that workers who are exposed to BTX still face excessive health risk. Additionally, the risk level varied depending on job categories and exposure to specific chemicals. Therefore, additional control measures recommended by OHRA guidelines are essential to reduce worker exposure levels.

Glutamate-induced excitotoxicity is a contributer to many neurological diseases. Astrocytes may represent a new target for treating glutamate-induced excitotoxicity. However, the in vitro culture system that mimics the in vivo microenvironment is lacking. This study aimed to establish a new in vitro co-culture system including neurons, astrocytes, and endothelial cells (NAE), and to investigate the effect of glutamate-induced excitotoxicity on DNA methylation in astrocytes. A NAE co-culture method was created using a Transwell chamber, in which neurons were seeded on the bottom of the lower chamber, endothelial cells were plated on the top membrane, and astrocytes were plated on the bottom membrane of the insert. Glutamate-induced toxicity was induced using glutamate and glycine, and examined using immunofluorescence and lactate dehydrogenase release assay. Global methylation in astrocytes was analyzed, and the expression of DNMT1 and DNMT3a was examined using Western blot analysis. Glutamate treatment induced less neuronal damage in the NAE system compared with the control group in which neurons and astrocytes were cultured alone. Global DNA methylation was increased and the expression of DNMT1 and DNMT3a in astrocytes was increased after glutamate treatment, which was blocked by application of the NMDAR inhibitor MK-801 and the DNMT inhibitor 5-azaC from the endothelial cells. The in vitro ANE culture system is effective for studying glutamate-induced excitotoxicity, and may be used for testing the passage of drugs across the blood–brain barrier. Inhibition of DNA methylation in astrocytes may be a new therapeutic strategy for treating glutamate-induced excitotoxicity.

The near-cathode region plays a crucial role in exploring the transport characteristics of the transition from arc column to the hot cathode in atmospheric-pressure arc discharges because of the existing non-equilibrium phenomena. A one-dimensional unified model, including the near-cathode region and the cathode body, is developed for an argon arc discharge with the tungsten cathode at atmospheric pressure in this paper. The electrostatic model coupled with an external circuit in the near-cathode region is solved based on the implicit particle-in-cell coupled Monte Carlo collision method without any assumptions of thermal or ionization equilibrium or quasi-neutrality. A detailed description of the arc plasma–cathode and cathode–gas interactions is obtained by calculating the nonlinear heat conduction equation in the cathode. It is shown that the space-charge sheath strongly affects particle transport in the near-cathode region and energy transport from arc plasma to the thermionic cathode. The total current density has significant effects on the kinetic characteristics of arc plasma by feedback-like mechanisms. The Joule heating by the external circuit and charged particles deposited into the cathode are dominating mechanisms of energy transfer from the near-cathode region to the cathode, while energy loss by radiation is more significant compared with natural convection.

Global DNA hypomethylation is commonly observed in benzene-exposed workers, but the underlying mechanisms remain unclear. We sought to discover the relationships among reduced white blood cell (WBC) counts, micronuclear (MN) frequency, and global DNA methylation to determine whether there were associations with mutations in DNMT3A/3B. Therefore, we recruited 410 shoe factory workers and 102 controls from Wenzhou in Zhenjiang Province. A Methylated DNA Quantification Kit was used to quantify global DNA methylation, and single nucleotide polymorphisms (SNPs) in DNMT3A (rs36012910, rs1550117, and R882) and DNMT3B (rs1569686, rs2424909, and rs2424913) were identified using the restriction fragment length polymorphism method. A multilinear regression analysis demonstrated that the benzene-exposed workers experienced significant global DNA hypomethylation compared with the controls (β = -0.51, 95% CI: -0.69 to -0.32, P < 0.001). The DNMT3A R882 mutant allele (R882H and R882C) (β = -0.25, 95% CI: -0.54 to 0.04, P = 0.094) and the DNMT3B rs2424909 GG allele (β = -0.37, 95% CI: -0.70 to -0.03, P = 0.031) were significantly associated with global DNA hypomethylation compared with the wild-type genotype after adjusting for confounding factors. Furthermore, the MN frequency in the R882 mutant allele (R882H and R882C) (FR = 1.18, 95% CI: 0.99 to 1.40, P = 0.054) was higher than that of the wild-type. The results imply that hypomethylation occurs due to benzene exposure and that mutations in DNMTs are significantly associated with global DNA methylation, which might have influenced the induction of MN following exposure to benzene. Environ. Mol. Mutagen. 58:678-687, 2017. © 2017 Wiley Periodicals, Inc.

We investigated the association between respiratory health and particulate matter (PM) air pollution in elderly type 2 diabetes mellitus (T2DM) pre-, during, and post-the Chinese Lunar New Year (CLNY) holiday in Shanghai, China.We conducted repeated measurements of lung function and inflammation biomarker in a cohort consisted of 60 participants with T2DM.Decreased PM2.5 exposure had an effect on respiratory health by increasing in forced expiratory flow in 1 second (FEV1) and forced vital capacity (FVC). Positive associations between PM exposure and exhaled nitric oxide (eNO) were observed.Our observations indicated that PM air pollution exposure would exert adverse effect on respiratory health in elderly T2DM population.