A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution.

Bulk-tissue DNA methylomes represent an average over many different cell types, hampering our understanding of cell-type-specific contributions to disease development. As single-cell methylomics is not scalable to large cohorts of individuals, cost-effective computational solutions are needed, yet current methods are limited to tissues such as blood. Here we leverage the high-resolution nature of tissue-specific single-cell RNA-sequencing datasets to construct a DNA methylation atlas defined for 13 solid tissue types and 40 cell types. We comprehensively validate this atlas in independent bulk and single-nucleus DNA methylation datasets. We demonstrate that it correctly predicts the cell of origin of diverse cancer types and discovers new prognostic associations in olfactory neuroblastoma and stage 2 melanoma. In brain, the atlas predicts a neuronal origin for schizophrenia, with neuron-specific differential DNA methylation enriched for corresponding genome-wide association study risk loci. In summary, the DNA methylation atlas enables the decomposition of 13 different human tissue types at a high cellular resolution, paving the way for an improved interpretation of epigenetic data.

Real-World Practice Patterns Favor Minimally Invasive Methods over Ureteral Reconstruction in the Initial Treatment of Severe Blunt Ureteral Trauma: A National Trauma Data Bank Analysis.

PURPOSE: We utilized the National Trauma Data Bank® database to report practice patterns in managing blunt traumatic ureteral injuries and assess the consistency with current guidelines/literature. MATERIALS AND METHODS: Between 2007 and 2016 all National Trauma Data Bank database patients with blunt traumatic ureteral injuries were identified using ICD-9 and Abbreviated Injury Scale codes. Penetrating trauma and missing data were excluded. Patients were unstable if Injury Severity Score was above 15 or systolic blood pressure was 90 mmHg or less. Abbreviated Injury Scale severity score 2 or less was a low severity ureteral injury. Treatment options were minimally invasive methods or ureteral reconstruction. Patients who underwent laparotomy for associated injuries were identified. Chi-square, Fisher exact or 2-tailed t-test was utilized to evaluate differences. Univariable logistic regression identified independent variables that favored a specific treatment. RESULTS: A total of 147 blunt traumatic ureteral injuries were used for analysis. Of the patients 98 (66.7%) were unstable and 51 (34.7%) had a high severity ureteral injury. Patients with low and high severity ureteral injuries were treated more frequently with minimally invasive methods over ureteral reconstruction. Laparotomy for associated injuries resulted in a higher frequency of ureteral reconstruction (15 of 55, 27.3%) vs laparotomy for ureteral reconstruction alone (9 of 55, 16.4%; p=0.0012). On univariable analysis patients who underwent exploratory laparotomy or underwent an associated injury repair that facilitated retroperitoneal exploration had significantly higher odds of receiving ureteral reconstruction over minimally invasive methods. CONCLUSIONS: Contrary to guidelines, practice patterns favor treating severe blunt traumatic ureteral injuries with minimally invasive methods over ureteral reconstruction. Ureteral reconstruction is favored when patients undergo laparotomy for associated injuries.

The Impact of Preoperative Oral Health on Buccal Mucosa Graft Histology.

PURPOSE: Previous studies have elucidated the unique macroscopic and histological properties of buccal mucosa that make it a viable and durable graft for urethral augmentation. However, no prior literature has directly investigated the impact of preoperative oral health on these features. MATERIALS AND METHODS: We analyzed all consenting patients who underwent buccal mucosal graft (BMG) urethroplasty at our institution from 2018 to 2020. Validated oral health surveys, the Oral Health Impact Profile (OHIP-14) and the Kayser-Jones Brief Oral Health Status Examination (BOHSE) were completed preoperatively. A staff pathologist analyzed BMG histology and quantified oral mucositis using a modified Oral Mucosa Rating Scale. RESULTS: We analyzed 51 patients with a median age of 40 years (IQR 31-58). Mean BOHSE score was 1.1 and OHIP-14 score was 1.4. Median epithelial thickness was 530 µm and lamina propria thickness was 150 µm. On age-adjusted analysis, increasing BOHSE and OHIP-14 were associated with decreasing epithelial thickness (p values <0.05). Higher BOHSE scores also correlated with thinner lamina proprias (p=0.05) and increased graft stretch (p=0.03). The 2 patients with postoperative urine leaks and available graft histology had lamina propria thicknesses well below the cohort median, at 50 µm and 60 µm. CONCLUSIONS: This is the first study to demonstrate that oral health conditions impact graft histology and stretch. Although much remains to be learned, our findings shed light on the potential importance of optimizing oral health prior to BMG urethroplasty, and raise the question of if preoperative mucosal biopsy could help inform surgical decision making and discussions regarding surgical success.

Clinical Characteristics and Surgical Treatment of Infective Endocarditis With Bicuspid Aortic Valve.

This study aimed to evaluate the clinical characteristics and surgical treatment of bicuspid aortic valve (BAV) infective endocarditis (IE) compared with tricuspid aortic valve (TAV) IE in China.The relevant pre-, intra- and post-operative materials of all IE patients undergoing cardiac surgery in our center between January 2003 and December 2012 were investigated and analyzed retrospectively.From January 2003 to December 2012, 345 consecutive IE patients received surgery in our center. A total of 171 native aortic valve IE patients were enrolled in this study, accounting for 49.6% of the total population. Among these 171 IE patients, 29.8% (n = 51) were BAV, and the remaining (n = 120) were TAV. There was a strong male predominance (92.2% versus 70.8%, P = 0.002) and a higher frequency of aortic perivalvular abscess (45.1% versus 18.3%, P < 0.001) in the BAV IE group compared with the TAV IE group. In multivariate analysis, BAV was the only independent predictor associated with an increased risk of aortic perivalvular abscess (OR = 4.365, 95% CI 1.30-14.65, P = 0.017). Six patients died postoperatively and no significant difference was found about in-hospital mortality between the BAV IE group and TAV IE group (2.0% versus 4.2%, P = 0.793).BAV is common in patients with confirmed aortic valve IE. BAV IE patients have a significantly increased risk of perivalvular abscess. Prompt diagnosis and timely surgery for BAV IE patients might be needed to prevent the formation and extension of perivalvular abscess.

[Research on On-Line Calibration Based Photoacoustic Spectrometry System for Monitoring the Concentration of CO2 in Atmosphere].

Resonate frequency and cell constant of photoacoustic spectrum system are usually calibrated by using standard gas in laboratory, whereas the resonate frequency and cell constant will be changed in-situ, leading to measurement accuracy errors, caused by uncertainties of standard gas, differences between standard and measured gas components and changes in environmental condition, such as temperature and humidity. As to overcome the above problems, we have proposed an on-line atmospheric oxygen-based calibration technology for photoacoustic spectrum system and used in measurement of concentration of carbon dioxide in atmosphere. As the concentration of atmospheric oxygen is kept as constant as 20.96%, the on-line calibration for the photoacoustic spectrum system can be realized by detecting the swept-frequency and peak signal at 763.73 nm. The cell of the PAS has a cavity with length of 100 mm and an inner diameter of 6 mm, and worked in a first longitudinal resonant mode. The influence of environmental temperature and humidity, gas components on the photoacoustic cell's performance has been theoretically analyzed, and meanwhile the resonant frequencies and cell constants were calibrated and acquired respectively using standard gas, indoor air and outdoor air. Compared with calibrated gas analyzer, concentration of carbon dioxide is more accurate by using the resonant frequency and cell constant calculated by oxygen in tested air, of which the relative error is less than 1%, much smaller than that calculated by the standard gas in laboratory. The innovation of this paper is that using atmospheric oxygen as photoacoustic spectrum system's calibration gas effectively reduces the error caused by using standard gas and environmental condition changes, and thus improves the on-line measuring accuracy and reliability of the photoacoustic spectrum system.

Exploring the causal relationship between interleukin-6 or C reactive protein and malignant melanoma using a two-sample Mendelian randomization approach.

The goal was to explore the effect of interleukin-6 (IL6) and C reactive protein (CRP) on malignant melanoma (MM) using two-sample Mendelian randomization. Methods: Data for this study were obtained from the IEU Open GWAS project website for genome-wide association study data (GWAS) on interleukin-6, C reactive protein levels and malignant melanoma. Inverse variance weighted (IVW) method was mainly used and supplemented with MR-Egger regression and weighted median. Finally, horizontal multivariate validity and heterogeneity tests were performed to assess the stability and reliability of the results. Results: The results of univariate two-sample MR analyses showed no significant effect of CRP on MM: inverse variance weighting method (OR=0.999, 95% CI: 0.998-1.001, P=0.343), MR-Egger regression (OR= 1.000, 95% CI: 0.998-1.001, P= 0.180), and weighted median method (OR= 0.999, 95% CI: 0.997 to 1.000, P= 0.583), and weighted model (OR= 0.999, 95% CI: 0.998 to 1.001, P= 0.328). Also,IL-6 had no significant effect on MM: inverse variance weighting method (OR= 1.001, 95% CI: 0.999 to 1.002, P=0.461), MR-Egger regression (OR= 1.000, 95% CI: 0.997 to 1.004, P= 0.910), weighted median method (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.749), and weighted mode (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.820). Conclusion: There was no causal relationship between C-reactive protein and IL-6 on the risk of malignant melanoma.

Comparing the time efficiency of two lasers used in FLACS: real-world observational study.

PURPOSE: To evaluate time efficiencies in the laser room for 2 different femtosecond laser systems. SETTING: 1 private practice in Atlanta, Georgia, and 1 private practice in Los Angeles, California. DESIGN: Prospective, observational, single-masked study. METHODS: Patients scheduled to receive femtosecond laser-assisted cataract surgery (FLACS) included those who were not pregnant, had no previous eye surgeries, and were not scheduled to undergo additional surgical procedures at the time of treatment; patients who received a standard, monofocal lens without undergoing arcuate incisions were excluded. Patients taking Flomax or any tamsulosin were also excluded from the study. Each comparable step in the LenSx and CATALYS workflow was identified and clearly defined. Time for each step was evaluated and compared using t tests and regression analyses to control for patient and site-specific differences between the 2 groups. RESULTS: Time data were collected for 89 patients (89 eyes). The overall procedure was 2.86 minutes shorter for the LenSx system when compared with the CATALYS system ( P < .05). Per patient, the LenSx system had significantly shorter time for patient positioning (57.26 vs 122.00 seconds; P < .05), imaging (33.23 vs 42.17 seconds; P < .05), laser treatment (21.57 vs 39.67 seconds; P < .05), and undocking/transition (67.13 vs 185.30 seconds; P < .05) compared with the CATALYS system. Regression analyses yielded similar results, with the LenSx system being over 35% (3.21 minutes; P < .05) shorter overall than the CATALYS system controlling for location, age, sex, lens thickness, cataract grade, fragmentation pattern, and arcuate incisions. CONCLUSIONS: LenSx procedures were significantly shorter than the CATALYS procedures overall, which can enable ophthalmology practices to increase efficiency.

Impact of a Swept Source-Optical Coherence Tomography Device on Efficiency in Cataract Evaluation and Surgery: A Time-and-Motion Study.

Purpose: This study aims to assess the time impact of ARGOS® (image-guided swept-source optical coherence tomography biometer integrated with operating room (OR) technologies (SS-OCT w/ORT)) compared to LENSTAR LS 900 (optical low-coherence reflectometry (OLCR)), IOLMaster 500 (partial coherence interferometry (PCI)), and IOLMaster 700 (SS-OCT) on efficiency in the cataract evaluation and surgery. Patients and Methods: Data from 212 patients (two study sites) who underwent evaluation and/or cataract surgery were collected. The primary objective was to compare the performance of four biometers; statistical analyses were conducted to compare 1) biometer measurement times for all patients (ANOVA w/post-hoc Dunnett's test) and stratified by cataract density (ANOVA) and 2) rate of biometer acquisition failure (Chi-square test w/post-hoc Bonferroni correction). Real-world observational data collected were then used to develop a practice-based time-efficiency model to demonstrate the combined effect that adopting an SS-OCT w/ORT has on a practice's cataract workflow. Real-world data inputs included assessment of patient's eyes' cataract grade density, time taken for optical biometry, Manual A-scan (ultrasound biometer) when acquisition failed, and measurement times associated with other devices used in cataract evaluation and surgery. Results: For 208 patients (56% non-dense, 44% dense), the SS-OCT w/ORT biometer had a 0% acquisition failure (SS-OCT: 3% (p = 0.05); OLCR: 5% (p = 0.004); PCI: 15% (p < 0.0001)) and an average time savings of 30 seconds/patient compared to the other biometers in this study (p < 0.05). When acquisition failed, ultrasound biometry resulted in an additional 2.5 minutes/patient. For a cohort of 1000 patients, an SS-OCT w/ORT and an image-guidance system adopted at a practice using an SS-OCT, femtosecond laser, and intraoperative aberrometer offer up to 58% efficiency gain across the cataract workflow. Conclusion: Results from this study demonstrate an SS-OCT w/ORT's efficiencies in cataract evaluation and surgery driven by faster measurement times, reducing the need for ultrasound biometry, and its integration benefits with other devices.

Trehalose promotes functional recovery of keratinocytes under oxidative stress and wound healing via ATG5/ATG7.

Wounds are in a stressed state, which precludes healing. Trehalose is a stress metabolite that protects cells under stress. Here, we explored whether trehalose reduces stress-induced wound tissue damage. A stress model was prepared by exposing human keratinocytes to hydrogen peroxide (H2O2), followed by trehalose treatment. Trehalose effects on expression of the autophagy-related proteins ATG5 and ATG7 and cell proliferation and migration were evaluated. For in vivo verification, a wound model was established in Sprague-Dawley rats, to measure the effects of trehalose wound-healing rate and reactive oxygen species (ROS) content. Histological changes during wound healing and trehalose's effects on ATG5 and ATG7 expression, necrosis, and apoptosis were examined·H2O2 stress increased ATG5 and ATG7 expression in vitro, but this was insufficient to prevent stress-induced damage. Trehalose further increased ATG5/ATG7 levels, which restored proliferation and increased migration by depolymerizing the cytoskeleton. However, trehalose did not exert these effects after ATG5 and ATG7 knockout. In vivo, the ROS content was higher in the wound tissue than in normal skin. Trehalose increased ATG5/ATG7 expression in wound tissue keratinocytes, reduced necrosis, depolymerized the cytoskeleton, and promoted cell migration, thereby promoting wound healing.

Minimally Invasive Biochimney Technique for Postrepair Mitral Stenosis.

Postrepair mitral stenosis is an important complication but associated with less-than-optimal surgical management. Reoperative mitral valve replacement is challenging due to the narrowness of the mitral annulus. We here present a minimally invasive biochimney technique performed in an elderly patient with postrepair mitral stenosis, in whom a composite of bioprosthetic valve and vascular graft was sutured on the extremely narrow mitral annulus.

A Hard Day at Work: An Analysis of Occupational Genitourinary Injuries in the United States Workforce.

OBJECTIVE: To use national data to identify risk factors for occupational genitourinary (GU) injuries and to expose potential workplace safety issues requiring national regulation. MATERIALS AND METHODS: The National Trauma Data Bank was queried to identify all adults who suffered a work-related GU injury from 2007 to 2016. Injury was stratified by individual organ and by organ type: intra-abdominopelvic (IAP) vs external genitalia (EG). Distinct multivariable logistic regression models were used to examine associations between prespecified risk factors and GU injury (organ and type) and to identify predictors of intensive care unit and operating room (OR) transfer. RESULTS: Two thousand one hundred thirty-nine patients (total of 2681 GU injuries), were included. A mean of 1.3 GU organ injuries and 7.6 total injuries were suffered per patient. 72% suffered an IAP GU injury, 23% an EG injury, and 5% suffered both. Patients working in agriculture/forestry/fishing, (OR 2.3, P = .003), manufacturing (OR 1.9, P = .05), and natural resources/mining (OR 2.3, P = .012) were at significantly increased risk of EG injury. The penis and urethra were particularly at-risk in agriculture/forestry/fishing (OR 4.0, P = .005; OR 3.0, P = .002) and the urethra in natural resources/mining (OR 3.4, P = .004). IAP GU injury was a significant predictor of intensive care unit transfer (OR 1.8, P <.001), whereas EG injury was a significant predictor of OR transfer (OR 2.5, P <.001). CONCLUSION: Occupational GU injuries remain a major issue for blue-collar workers. External genitalia are particularly at-risk, and injuries often require emergent surgery. National occupational health agencies need to continue to enhance on-the-job safety for those at-risk.

Advances in research on the effects of platelet activation in acute lung injury (Review).

Acute lung injury (ALI) is an acute hypoxic respiratory insufficiency or failure caused by various factors inside and outside the lungs. ALI is associated with high morbidity and a poor prognosis in hospitalized patients. The lungs serve as a reservoir for platelet precursor megakaryocytes and are closely associated with platelets. Platelets not only play a central role in hemostasis, coagulation and wound healing, but can also act as inflammatory cells capable of stimulating non-hemostatic immune functions under inflammatory conditions, participating in the progression of various inflammatory diseases, and can result in tissue damage. Therefore, it was speculated that platelets may play an important role in the pathogenesis of ALI. In this review, the latest research progress on secretion of bioactive mediators from platelets, platelet activation-related signaling pathways, and the direct contact reactions between platelets and neutrophils with endothelial cells that result in ALI are described, providing evidence to support the importance of the consideration of platelets in the search for ALI interventional targets.

Mini-Invasive Bentall Procedure Performed via a Right Anterior Thoracotomy Approach With a Costochondral Cartilage Sparing.

Objectives: A right minithoracotomy approach with a sternal sparing technique is a minimally invasive option for surgeons performing aortic root surgery. This report presents our initial clinical results of the right minithoracotomy Bentall procedure. Methods: Clinical data of 15 patients were retrospectively analyzed who underwent the minimally invasive Bentall procedure through the right anterior thoracotomy via the second intercostal incision without any costochondral cartilage invasion at our institution between October, 2019 and June, 2021. The operative time, length of intensive care unit stay and postoperative hospital stay, perioperative outcomes, and follow-up results were analyzed. Results: The median aortic cross-clamping time was 95.0 (85.5-98.8) min. Three (21.4%) patients received blood transfusion. The median drainage volume in the first 24 h was 200.0 ml, with no redo for bleeding. The median duration of mechanical ventilation was 12.5 (11.0-25.0) h, and median length of intensive care unit stay was 1.5 (1.0-3.0) day. All patients discharged 5.8 ± 1.2 days following surgery, with no dead patients found. At 6 months following surgery, all patients survived with an improved New York Heart Association (NYHA) functional class. Conclusion: The right minithoracotomy Bentall procedure may be performed safely with low morbidity and mortality. This approach should be considered as an option in carefully selected patients requiring aortic root replacement.

Tissue residues and withdrawal time of moxidectin treatment of swine by topical pour-on application.

Moxidectin (MXD), an antiparasitic drug, is effective for a variety of external and internal parasites in companion and farm animals. This study aimed to calculate the withdrawal period by investigating the residue depletion of MXD in swine edible tissues after pouring at the dosage of 2.5 mg/kg B.W. The concentrations of MXD in swine edible tissues were determined by a modified preparation procedure based on HPLC-FLD. The method was validated giving LOD and LOQ of 0.5 µg/kg and 1 µg/kg respectively with measured recoveries ranging from 62.9%-89.2% at three different concentrations and a precision (RSD) of less or equal to 15.7%. The muscle, liver, kidney and fat tissues were collected at 0.5, 5, 10, 20, 25 d after administration. The results showed that fat was the target tissue with the highest concentration for MXD. The withdrawal period was 26 days for the MRL of 500 µg/kg in fat. The results provide fundamental information to ensure food safety and establishment of a rational medication regimen.

[Analysis of the risk factors of postoperative renal failure of type A aortic dissection].

OBJECTIVE: To evaluate the risk factors of postoperative renal failure (RF) in the patients with type A dissection of aorta operated on with cerebral perfusion and deep hypothermia circulatory arrest (DHCA). METHODS: From January 2004 to October 2007, 157 patients with type A dissection of aorta underwent surgical procedures with cerebral perfusion and DHCA. There were 115 male patients and 42 female patients with the age from 17 to 76 years old. Antegrade selective cerebral perfusion through axillary artery was performed for 129 patients and retrograde cerebral perfusion from superior cava vein was performed for 28 patients. All the factors underwent univariate and multivariate analysis. RESULTS: Mean cardiopulmonary bypass duration was (188.0 +/- 10.8) min and mean cerebral perfusion time was (36.0 +/- 3.1) min. Fifteen patients died in hospital and the hospital mortality was 9.6%. Permanent neurological dysfunction (PND) occurred in 8 patients (5.1%). Postoperative RF was observed in 20 patients (12.8%). Multivariate analysis showed the preoperative renal dysfunction (P = 0.042, OR = 4.41) and over seventy-year-old patients (P = 0.049, OR = 4.94) were found to be the risk factors of postoperative RF. There was a higher incidence of death (45%, P = 0.001) and PND (25%, P = 0.009) in the patients of postoperative RF when compared with the other patients. CONCLUSION: The preoperative renal dysfunction and elderly patients were found to be the risk factors of postoperative RF after type A dissection of aorta surgery.

Long-term Mortality in Pediatric Firearm Assault Survivors: A Multicenter, Retrospective, Comparative Cohort Study.

OBJECTIVES: The objective was to determine whether children surviving to hospital discharge after firearm assault (FA) and nonfirearm assault (NFA) are at increased risk of mortality relative to survivors of unintentional trauma (UT). Secondarily, the objective was to elucidate the factors associated with long-term mortality after pediatric trauma. METHODS: This was a multicenter, retrospective cohort study of pediatric patients aged 0 to 16 years who presented to the three trauma centers in San Francisco and Alameda counties, California, between January 2000 and December 2009 after 1) FA, 2) NFA, and 3) UT. The Social Security Death Master File and the California Department of Public Health Vital Statistics (2000-2014) were queried through December 31, 2014, to identify those who died after surviving their initial hospitalization and to delineate cause of death. Multivariate Cox proportional hazards regression was performed to determine associations between exposure to assault and long-term mortality. RESULTS: We analyzed 413 FA, 405 NFA, and 7,062 UT patients who survived their index hospital visit. A total of 75 deaths occurred, including 3.9, 3.2, and 0.7% of each cohort, respectively. Two-thirds of all long-term deaths were due to homicide. After multivariate adjustment, adolescent age, male sex, black race/ethnicity, and public insurance were independent risk factors for long-term mortality. FA (adjusted hazard ratio [AHR] = 1.8, 95% confidence interval [CI] = 0.82-4.0) and NFA (AHR = 1.9, 95% CI = 0.93-3.9) did not convey a statistically significant difference in risk of long-term mortality compared to UT. Being assaulted by any means (with or without a firearm), however, was an independent risk factor for long-term mortality in the full study population (AHR = 1.9, 95% CI = 1.01-3.4) and among adolescents (AHR = 1.9, 95% CI = 1.01-3.6). CONCLUSION: Children and adolescents who survive assault, including by firearm, have increased long-term mortality compared to those who survive unintentional, nonviolent trauma.

[Effects of rosuvastatin in homocysteine induced mouse vascular smooth muscle cell dedifferentiation and endoplasmic reticulum stress and its mechanisms].

OBJECTIVE: To investigate the effect of rosuvastatin on homocysteine (Hcy) induced mousevascular smooth muscle cells(VSMCs) dedifferentiation and endoplasmic reticulum stress(ERS). METHODS: VSMCs were co-cultured with Hcy and different concentration of rosuvastatin (0.1, 1.0 and 10 µmol/L). Cytoskeleton remodeling, VSMCs phenotype markers (smooth muscle actin-α, calponin and osteopontin) and ERS marker mRNAs (Herpud1, XBP1s and GRP78) were detected at predicted time. Tunicamycin was used to induce, respectively 4-phenylbutyrate(4-PBA) inhibition, ERS in VSMCs and cellular migration, proliferation and expression of phenotype proteins were analyzed. Mammalian target of rapamycin(mTOR)-P70S6 kinase (P70S6K) signaling agonist phosphatidic acid and inhibitor rapamycin were used in Rsv treated VSMCs. And then mTOR signaling and ERS associated mRNAs were detected. RESULTS: Compared with Hcy group, Hcy+ Rsv group (1.0 and 10 µmol/L) showed enhanced α-SMA and calponin expression (P<0.01), suppressed ERS mRNA levels (P<0.01) and promoted polarity of cytoskeleton. Compared with Hcy group, Hcy+Rsv group and Hcy+4-PBA group showed suppressed proliferation, migration and enhanced contractile protein expression (P<0.01); while tunicamycin could reverse the effect of Rsv on Hcy treated cells. Furthermore, alleviated mTOR-P70S6K phosphorylation and ERS (P<0.01)were observed in Hcy+Rsv group and Hcy+rapamycin group, compared with Hcy group; while phosphatidic acid inhibited the effect of Rsv on mTOR signaling activation and ERS mRNA levels (P<0.01). CONCLUSIONS: Rosuvastatin could inhibit Hcy induced VSMCs dedifferentiation via suppressing ERS, which might be regulated by mTOR-P70S6K signaling.

DNA methylome analysis reveals distinct epigenetic patterns of ascending aortic dissection and bicuspid aortic valve.

AIMS: Epigenetics may mediate the effects of environmental risk factors on disease, including heart disease. Thus, measuring the DNA methylome offers the opportunity to identify novel disease biomarkers and novel insights into disease mechanisms. The DNA methylation landscape of ascending aortic dissection (AD) and bicuspid aortic valve (BAV) with aortic aneurysmal dilatation remain uncharacterized. The present study aimed to explore the genome-wide DNA methylation landscape underpinning these two diseases. METHODS AND RESULTS: We used Illumina 450k DNA methylation beadarrays to analyse 21 ascending aorta samples, including 10 cases with AD, 5 with BAV and 6 healthy controls. We adjusted for intra-sample cellular heterogeneity, providing the first unbiased genome-wide exploration of the DNA methylation landscape underpinning these two diseases. We discover that both diseases are characterized by loss of DNA methylation at non-CpG sites. We validate this non-CpG hypomethylation signature with pyrosequencing. In contrast to non-CpGs, AD and BAV exhibit distinct DNA methylation landscapes at CpG sites, with BAV characterized mainly by hypermethylation of EZH2 targets. In the case of AD, integrative DNA methylation gene expression analysis reveals that AD is characterized by a dedifferentiated smooth muscle cell phenotype. Our integrative analysis further reveals hypomethylation associated overexpression of RARA in AD, a pattern which is also seen in cells exposed to smoke toxins. CONCLUSION: Our data supports a model in which increased cellular proliferation in AD and BAV underpins loss of methylation at non-CpG sites. Our data further supports a model, in which AD is associated with an inflammatory vascular remodeling process, possibly mediated by the epigenome and linked to environmental risk factors such as smoking.