CircMap4k2 reactivated by aneurysm plication alleviates residual cardiac remodeling after SVR by enhancing cardiomyocyte proliferation in post-MI mice.

INTRODUCTION: Surgical ventricular reconstruction (SVR) is an alternative therapeutic approach in patients with refractory heart failure (HF), but residual remodeling after SVR limits the improvement of HF. Recently, we reported that SVR may act as an environmental cue to reactivate endogenous proliferation of cardiomyocytes; however, it is unclear whether enhancing endogenous cardiomyocyte regeneration further improves HF after SVR. OBJECTIVES: We aimed to explore whether circular RNAs (circRNAs) would involved in SVR and their mechanisms. METHODS: Male C57BL/6 mice were subjected to myocardial infarction (MI) or sham surgery. Four weeks later, MI mice with a large ventricular aneurysm underwent SVR or a second open-chest operation only. Echocardiography and histological analysis were used to evaluate heart function, cardiac remodeling, and myocardial regeneration. Sequencing of circular RNAs, RNA immunoprecipitation, RNA pulldown, and luciferase reporter assay were used to explore the underlying mechanisms. RESULTS: SVR markedly attenuated cardiac remodeling and induced cardiomyocyte regeneration, as evidenced by positive staining of Ki-67, phospho-histone H3 (pH3), and Aurora B in the plication zone, but significant residual remodeling still existed in comparison with the sham group. Sequencing results showed that SVR altered the expression profile of cardiac circRNAs, and circMap4k2 was identified as the most upregulated one. After characterizing circMap4k2, we noted that overexpression of circMap4k2 significantly promoted proliferation of cardiomyocytes in cultured neonatal rat cardiomyocytes and silencing of circMap4k2 significantly inhibited it; similar results were obtained in SVR-treated MI mice but not in MI mice without SVR treatment. Residual cardiac remodeling after SVR was further attenuated by circMap4k2 overexpression. CircMap4k2 bound with miR-106a-3p and inhibited cardiomyocyte proliferation by targeting a downstream effector of the antizyme inhibitor 1 (Azin1) gene. CONCLUSIONS: CircMap4k2 acts as an environmental cue and targets the miR-106a-3p/Azin1 pathway to increase cardiac regeneration in the plication zone and attenuate residual remodeling after SVR.

A fully integrated, standalone stretchable device platform with in-sensor adaptive machine learning for rehabilitation.

Post-surgical treatments of the human throat often require continuous monitoring of diverse vital and muscle activities. However, wireless, continuous monitoring and analysis of these activities directly from the throat skin have not been developed. Here, we report the design and validation of a fully integrated standalone stretchable device platform that provides wireless measurements and machine learning-based analysis of diverse vibrations and muscle electrical activities from the throat. We demonstrate that the modified composite hydrogel with low contact impedance and reduced adhesion provides high-quality long-term monitoring of local muscle electrical signals. We show that the integrated triaxial broad-band accelerometer also measures large body movements and subtle physiological activities/vibrations. We find that the combined data processed by a 2D-like sequential feature extractor with fully connected neurons facilitates the classification of various motion/speech features at a high accuracy of over 90%, which adapts to the data with noise from motion artifacts or the data from new human subjects. The resulting standalone stretchable device with wireless monitoring and machine learning-based processing capabilities paves the way to design and apply wearable skin-interfaced systems for the remote monitoring and treatment evaluation of various diseases.

ZetaDesign: an end-to-end deep learning method for protein sequence design and side-chain packing.

Computational protein design has been demonstrated to be the most powerful tool in the last few years among protein designing and repacking tasks. In practice, these two tasks are strongly related but often treated separately. Besides, state-of-the-art deep-learning-based methods cannot provide interpretability from an energy perspective, affecting the accuracy of the design. Here we propose a new systematic approach, including both a posterior probability and a joint probability parts, to solve the two essential questions once for all. This approach takes the physicochemical property of amino acids into consideration and uses the joint probability model to ensure the convergence between structure and amino acid type. Our results demonstrated that this method could generate feasible, high-confidence sequences with low-energy side conformations. The designed sequences can fold into target structures with high confidence and maintain relatively stable biochemical properties. The side chain conformation has a significantly lower energy landscape without delegating to a rotamer library or performing the expensive conformational searches. Overall, we propose an end-to-end method that combines the advantages of both deep learning and energy-based methods. The design results of this model demonstrate high efficiency, and precision, as well as a low energy state and good interpretability.

Photoactivation of Boronic Acid Prodrugs via a Phenyl Radical Mechanism: Iridium(III) Anticancer Complex as an Example.

Boronic acid (or ester) is a well-known temporary masking group for developing anticancer prodrugs responsive to tumoral reactive oxygen species (ROS), but their clinic application is largely hampered by the low activation efficiency. Herein, we report a robust photoactivation approach that can spatiotemporally convert boronic acid-caged iridium(III) complex IrBA into bioactive IrNH2 under hypoxic tumor microenvironments. Mechanistic studies show that the phenyl boronic acid moiety in IrBA is in equilibrium with phenyl boronate anion that can be photo-oxidized to generate phenyl radical, a highly reactive species that is capable of rapidly capturing O2 at extremely low concentrations (down to 0.02%). As a result, while IrBA could hardly be activated by intrinsic ROS in cancer cells, upon light irradiation, the prodrug is efficiently converted into IrNH2 even in limited O2 supply, along with direct damage to mitochondrial DNA and potent antitumor activities in hypoxic 2D monolayer cells, 3D tumor spheroids, and mice bearing tumor xenografts. Of note, the photoactivation approach could be extended to intermolecular photocatalytic activation by external photosensitizers with red absorption and to activate prodrugs of clinic compounds, thus offering a general approach for activation of anticancer organoboron prodrugs.

The Knowledge Profile, Competence and Pending Problems of Chinese Anesthesiologists in Dealing with Malignant Hyperthermia: A Cross-Sectional Survey.

Purpose: The National Remote Emergency System for Malignant Hyperthermia (MH-NRES) is an applet in China, designed to help anesthesiologists manage MH crisis. However, there is limited information about encountered difficulties in dealing with MH among Chinese anesthesiologists. The purpose of the study was to explore the current competency and encountered difficulties in the management of MH, as a key first step for assessing the potential user needs to develop the MH-NRES. Methods: The hospitals of different levels in different provinces across China were invited to participate in an online survey from November to December 2021. Anesthesiologists completed the online questionnaire containing four sections including demographic information, knowledge, competency, and continuing education about MH. Results: A total of 1357 valid questionnaires were completed from anesthesiologists, most respondents (66.7%, n = 905) correctly answered the MH trigger drugs included volatile anesthetics and succinylcholine. However, most respondents (77.0%, n = 1045) did not know that the recommended initial dose of domestic dantrolene. Up to 83.9% (n = 1138) stated that their hospitals did not store dantrolene for MH emergency. More than half of respondents thought that it would take more than one hour to obtain dantrolene in emergency. Less work experiences, lower levels of hospital and educations and professional titles were associated with lower competency scores in managing MH. Only 31.0% (n = 936) reported that their hospital had ever conducted MH continuing education curricula. Scenario simulation is the training method that most interests the participants (79.0%, n = 1072) but a whopping 46.9% (n = 637) never received simulation. Conclusion: The study indicated that difficulty in obtaining dantrolene, lack of competency in management of MH, difficulty in obtaining professional help, and poor teamwork were the main problems of most anesthesiologists in face of MH.

Circ-Ddx60 contributes to the antihypertrophic memory of exercise hypertrophic preconditioning.

INTRODUCTION: We previously reported a phenomenon called exercise hypertrophic preconditioning (EHP), the underlying mechanisms of which need further clarification. OBJECTIVES: We aimed to investigate whether circular RNAs (circRNAs) are involved in EHP. METHODS: CircRNA sequencing of myocardial tissue was performed in male C57BL/6 mice with EHP and sedentary. Bioinformatics analysis and Sanger sequencing were used to screen hub circRNA expression and to detect full-length circRNAs, respectively. Loss-of-function analyses were conducted to assess the effects of circ-Ddx60 (c-Ddx) on EHP. After 21 days of swimming training or resting, mice underwent transverse aortic constriction (TAC) or sham surgery. Echocardiography, invasive hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. The presence of interaction between c-Ddx and proteins was investigated using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS). RESULTS: In this study, we identified a novel circRNA, named c-Ddx that was preferentially expressed in myocardial tissue and significantly up-regulated in EHP mice. Silencing of c-Ddx attenuated the antihypertrophic effect of EHP and worsened heart failure in mice that underwent TAC. ChIRP-MS and molecular docking analysis validated the combination of c-Ddx and eukaryotic elongation factor 2 (eEF2). Mechanistically, c-Ddx silencing inhibited the increase of phosphorylation of eEF2 and its upstream AMP-activated protein kinase (AMPK) induced by EHP. CONCLUSIONS: C-Ddx contributes to the antihypertrophic memory of EHP by binding and activating eEF2, which would provide opportunity to search new therapeutic targets for pathological hypertrophy of heart.

Advances in Next-Generation Coronavirus Vaccines in Response to Future Virus Evolution.

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread to more than 230 countries and territories worldwide since its outbreak in late 2019. In less than three years, infection by SARS-CoV-2 has resulted in over 600 million cases of COVID-19 and over 6.4 million deaths. Vaccines have been developed with unimaginable speed, and 11 have already been approved by the World Health Organization and given Emergency Use Listing. The administration of several first-generation SARS-CoV-2 vaccines has successfully decelerated the spread of COVID-19 but not stopped it completely. In the ongoing fight against viruses, genetic mutations frequently occur in the viral genome, resulting in a decrease in vaccine-induced antibody neutralization and widespread breakthrough infection. Facing the evolution and uncertainty of SARS-CoV-2 in the future, and the possibility of the spillover of other coronaviruses to humans, the need for vaccines with a broad spectrum of antiviral variants against multiple coronaviruses is recognized. It is imperative to develop a universal coronavirus or pan-coronavirus vaccine or drug to combat the ongoing COVID-19 pandemic as well as to prevent the next coronavirus pandemic. In this review, in addition to summarizing the protective effect of approved vaccines, we systematically summarize current work on the development of vaccines aimed at suppressing multiple SARS-CoV-2 variants of concern as well as multiple coronaviruses.

Metabolic Responses and Pathway Changes of Vero Cells under High-Vitamin B Medium.

The production efficiency of a cell substrate directly affects the yield of target products such as viruses, while its density is mainly regulated by the type of culture medium and culture conditions. In this study, Vero cells were used as model cells for systematic medium screening, and a high-efficiency medium for biological drug production was identified. Through the results of cell proliferation by a cell counting kit (CCK)-8 assay, 5-Ethynyl-2'-deoxyuridine(EdU) assay, real-time quantitative PCR (RT-qPCR) and Western blotting, we found that adding an appropriate amount of vitamin B to the conventional basic medium can significantly improve and maintain the high-density growth of Vero cells. In addition, the molecular mechanism of the high-density culture of Vero cells promoted by B vitamins is explained for the first time by using the systems multi-omics analysis methods. Here, we determined that B vitamins regulate cell proliferation through the synthesis and metabolism of unsaturated fatty acids, affecting the productivity of cell substrate in industrial production. This study provides an important tool for the screening of key components of cell-based high-efficiency medium.

Dapagliflozin attenuates residual cardiac remodeling after surgical ventricular reconstruction in mice with an enlarged heart after myocardial infarction.

BACKGROUND: Severe heart failure refractory to conventional therapy requires alternative treatment modalities. Surgical ventricular reconstruction (SVR) has been used to reverse cardiac remodeling in post-myocardial infarction (MI) patients with large left ventricular (LV) aneurysm, however, residual LV remodeling and dysfunction remain postoperatively. It is unclear whether SVR recovers response to drug treatment and whether the sodium-glucose co-transporter 2 inhibitor dapagliflozin (DAPA) reverses residual LV remodeling after SVR. METHODS: Adult male C57 mice were subjected to MI or sham surgery. Four-week later, MI mice with LV aneurysm underwent modified SVR or second open-chest sham operation and were randomized to DAPA or vehicle for four-week. Cardiac remodeling, LV function, and the underlying mechanisms were evaluated by echocardiography, invasive LV hemodynamic measurements, mRNA sequencing, and bioinformatics analysis. RESULTS: SVR significantly decreased LV volume; increased myocardial strain, LV pressure change rates and end-systolic elastance; and decreased heart-to-body weight ratio and myocardial fibrosis. However, significant residual cardiac remodeling remained. DAPA significantly attenuated residual cardiac remodeling and improved LV function in SVR mice but did not have curative effects in non-SVR mice. Of the 1532 genes differentially expressed in SVR and MI mice, 1037 were associated with cardiac metabolism; Src, Crebbp, Fn1, Grb2, and Mapk14 were the top 5 hub genes. Unlike sham surgery, MI upregulated those 5 genes, and treatment with SVR + DAPA normalized their expression. CONCLUSIONS: SVR restores therapeutic response in the post-MI heart with large LV aneurysm, and DAPA attenuates residual cardiac remodeling after SVR by normalizing some cardiac metabolism-related hub genes.

Clinical Survey of Current Perioperative Body Temperature Management: What Major Factors Influence Effective Hypothermia Prevention Practice?

Purpose: Inadvertent intraoperative hypothermia (IIH) is generally associated with several postoperative complications. Inspite of the existing guidelines, the global incidence of IIH remains unacceptably high. Understanding the conditions that influence temperature management is critical for developing future interventions to improve the postoperative patient outcomes. This study aimed to identify the major factors that hinder the implementation of IIH prevention practices. Methods: Through a literature research, pilot small-sample investigation, and expert suggestions, 11 factors that may hinder the implementation of IIH prevention practices were identified. A questionnaire was developed, and each question was used to assess each factor. After approval by the Research Ethics Board, the questionnaires were sent to the staff anaesthesiologists at two academic hospitals via WeChat. Each answer was coded according to the degree to which the factor was affected, as anticipated. Finally, the answers were analysed based on the 80/20 rule to identify the major barriers to effective temperature management. Results: We included 195 participants. Knowledge, memory, attention and decision processes, beliefs about consequences, and environmental context and resources were the major factors, with cumulative composition ratios of 24%, 43.4%, 57.7%, and 70.7%, respectively. Meanwhile, behavioural regulation and social influence were the secondary factors, with cumulative composition ratios of 80.4% and 87.5%, respectively. Reinforcement, confidence in capacity, duty realisation, skills, and intention were the general factors with cumulative composition ratios of 94.3%, 99.8%, 100%, 100%, and 100%, respectively. Conclusion: Four factors-knowledge, memory, attention and decision process, beliefs about consequences, and environmental context and resources-were the major factors that influence the effective hypothermia prevention practice. Relevance to Clinical Practice: These major factors will be used in further studies as a basis to develop the corresponding solutions and improve the patient outcomes in clinical practice.

Efficacy of a new day surgery management mode based on WeChat: a study protocol for randomised controlled trials.

INTRODUCTION: There is an enormous imbalance between the rapid development of day surgery and the current conventional medical services. Hence, an effective day surgery management mode should be developed that can be used to constantly follow up on patients both preoperatively and postoperatively. In this study, WeChat was chosen as the platform. This study aimed to investigate the feasibility and effectiveness of a new day surgery management mode. METHODS AND ANALYSIS: This randomised controlled study investigated the efficacy of a new day surgery management mode based on WeChat. The target number of participants was 1000 per group. The application (app) will send personalised information based on the medical history of the patient and the type of surgery at different time points preoperatively and postoperatively. The healthcare worker can follow up the patient and acquire clinical data by simply signing into the app. The patient and the healthcare worker can also engage in video or voice chats using the app when necessary. Multiple departments, including anaesthesiology, internal medicine, surgery, nursing and psychology, will participate in this new mode. ETHICS AND DISSEMINATION: Ethical approval was obtained from the West China Hospital of Sichuan University Biomedical Research Ethics Committee. Results of this study will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2100050793.

circRNAome profiling reveals circFgfr2 regulates myogenesis and muscle regeneration via a feedback loop.

BACKGROUND: Circular RNAs (circRNAs) represent a novel class of non-coding RNAs formed by a covalently closed loop and play crucial roles in many biological processes. Several circRNAs associated with myogenesis have been reported. However, the dynamic expression, function, and mechanism of circRNAs during myogenesis and skeletal muscle development are largely unknown. METHODS: Strand-specific RNA-sequencing (RNA-seq) and microarray datasets were used to profile the dynamic circRNAome landscape during skeletal muscle development and myogenic differentiation. Bioinformatics analyses were used to characterize the circRNAome and identify candidate circRNAs associated with myogenesis. Bulk and single-cell RNA-seq were performed to identify the downstream genes and pathways of circFgfr2. The primary myoblast cells, C2C12 cells, and animal model were used to assess the function and mechanism of circFgfr2 in myogenesis and muscle regeneration in vitro or in vivo by RT-qPCR, western blotting, dual-luciferase activity assay, RNA immunoprecipitation, RNA fluorescence in situ hybridization, and chromatin immunoprecipitation. RESULTS: We profiled the dynamic circRNAome in pig skeletal muscle across 27 developmental stages and detected 52 918 high-confidence circRNAs. A total of 2916 of these circRNAs are conserved across human, mouse, and pig, including four circRNAs (circFgfr2, circQrich1, circMettl9, and circCamta1) that were differentially expressed (|log2 fold change| > 1 and adjusted P value < 0.05) in various myogenesis systems. We further focused on a conserved circRNA produced from the fibroblast growth factor receptor 2 (Fgfr2) gene, termed circFgfr2, which was found to inhibit myoblast proliferation and promote differentiation and skeletal muscle regeneration. Mechanistically, circFgfr2 acted as a sponge for miR-133 to regulate the mitogen-activated protein kinase kinase kinase 20 (Map3k20) gene and JNK/MAPK pathway. Importantly, transcription factor Kruppel like factor 4 (Klf4), the downstream target of the JNK/MAPK pathway, directly bound to the promoter of circFgfr2 and affected its expression via an miR-133/Map3k20/JNK/Klf4 auto-regulatory feedback loop. RNA binding protein G3BP stress granule assembly factor 1 (G3bp1) inhibited the biogenesis of circFgfr2. CONCLUSIONS: The present study provides a comprehensive circRNA resource for skeletal muscle study. The functional and mechanistic analysis of circFgfr2 uncovered a circRNA-mediated auto-regulatory feedback loop regulating myogenesis and muscle regeneration, which provides new insight to further understand the regulatory mechanism of circRNAs.

A Bibliometric and Visualized Analysis of Cardiac Regeneration Over a 20-Year Period.

Background: Recent research has suggested that cardiac regeneration may have the widely applicable potential of treating heart failure (HF). A comprehensive understanding of the development status of this field is conducive to its development. However, no bibliometric analysis has summarized this field properly. We aimed to analyze cardiac regeneration-related literature over 20 years and provide valuable insights. Methods: Publications were collected from the Web of Science Core Collection (WoSCC). Microsoft Excel, VOSviewer, CiteSpace, and alluvial generator were used to analyze and present the data. Results: The collected 11,700 publications showed an annually increasing trend. The United States and Harvard University were the leading force among all the countries and institutions. The majority of articles were published in Circulation Research, and Circulation was the most co-cited journal. According to co-citation analysis, burst detection and alluvial flow map, cardiomyocyte proliferation, stem cells, such as first-and second-generation, extracellular vesicles especially exosomes, direct cardiac reprogramming, macrophages, microRNAs, and inflammation have become more and more popular recently. Conclusions: Cardiac regeneration remains a research hotspot and develops rapidly. How to modify cardiac regeneration endogenously and exogenously may still be the hotspot in the future and should be discussed more deeply.

The genome variation and developmental transcriptome maps reveal genetic differentiation of skeletal muscle in pigs.

Natural and artificial directional selections have resulted in significantly genetic and phenotypic differences across breeds in domestic animals. However, the molecular regulation of skeletal muscle diversity remains largely unknown. Here, we conducted transcriptome profiling of skeletal muscle across 27 time points, and performed whole-genome re-sequencing in Landrace (lean-type) and Tongcheng (obese-type) pigs. The transcription activity decreased with development, and the high-resolution transcriptome precisely captured the characterizations of skeletal muscle with distinct biological events in four developmental phases: Embryonic, Fetal, Neonatal, and Adult. A divergence in the developmental timing and asynchronous development between the two breeds was observed; Landrace showed a developmental lag and stronger abilities of myoblast proliferation and cell migration, whereas Tongcheng had higher ATP synthase activity in postnatal periods. The miR-24-3p driven network targeting insulin signaling pathway regulated glucose metabolism. Notably, integrated analysis suggested SATB2 and XLOC_036765 contributed to skeletal muscle diversity via regulating the myoblast migration and proliferation, respectively. Overall, our results provide insights into the molecular regulation of skeletal muscle development and diversity in mammals.

Landscape of tissue-specific RNA Editome provides insight into co-regulated and altered gene expression in pigs (Sus-scrofa).

RNA editing generates genetic diversity in mammals by altering amino acid sequences, miRNA targeting site sequences, influencing the stability of targeted RNAs, and causing changes in gene expression. However, the extent to which RNA editing affect gene expression via modifying miRNA binding site remains unexplored. Here, we first profiled the dynamic A-to-I RNA editome across tissues of Duroc and Luchuan pigs. The RNA editing events at the miRNA binding sites were generated. The biological function of the differentially edited gene in skeletal muscle was further characterized in pig muscle-derived satellite cells. RNA editome analysis revealed a total of 171,909 A-to-I RNA editing sites (RESs), and examination of its features showed that these A-to-I editing sites were mainly located in SINE retrotransposons PRE-1/Pre0_SS element. Analysis of differentially edited sites (DESs) revealed a total of 4,552 DESs across tissues between Duroc and Luchuan pigs, and functional category enrichment analysis of differentially edited gene (DEG) sets highlighted a significant association and enrichment of tissue-developmental pathways including TGF-beta, PI3K-Akt, AMPK, and Wnt signaling pathways. Moreover, we found that RNA editing events at the miRNA binding sites in the 3'-UTR of HSPA12B mRNA could prevent the miRNA-mediated mRNA downregulation of HSPA12B in the muscle-derived satellite (MDS) cell, consistent with the results obtained from the Luchuan skeletal muscle. This study represents the most systematic attempt to characterize the significance of RNA editing in regulating gene expression, particularly in skeletal muscle, constituting a new layer of regulation to understand the genetic mechanisms behind phenotype variance in animals.Abbreviations: A-to-I: Adenosine-to-inosine; ADAR: Adenosine deaminase acting on RNA; RES: RNA editing site; DEG: Differentially edited gene; DES: Differentially edited site; FDR: False discovery rate; GO: Gene Ontology; KEGG: Kyoto Encyclopaedia of Genes and Genomes; MDS cell: musclederived satellite cell; RPKM: Reads per kilobase of exon model in a gene per million mapped reads; UTR: Untranslated coding regions.

Sp1-Mediated circRNA circHipk2 Regulates Myogenesis by Targeting Ribosomal Protein Rpl7.

Circular RNAs (circRNAs) represent a class of covalently closed single-stranded RNA molecules that are emerging as essential regulators of various biological processes. The circRNA circHipk2 originates from exon 2 of the Hipk2 gene in mice and was reported to be involved in acute promyelocytic leukemia and myocardial injury. However, the functions and mechanisms of circHipk2 in myogenesis are largely unknown. Here, to deepen our knowledge about the role of circHipk2, we studied the expression and function of circHipk2 during skeletal myogenesis. We found that circHipk2 was mostly distributed in the cytoplasm, and dynamically and differentially expressed in various myogenesis systems in vitro and in vivo. Functionally, overexpression of circHipk2 inhibited myoblast proliferation and promoted myotube formation in C2C12 cells, whereas the opposite effects were observed after circHipk2 knockdown. Mechanistically, circHipk2 could directly bind to ribosomal protein Rpl7, an essential 60S preribosomal assembly factor, to inhibit ribosome translation. In addition, we verified that transcription factor Sp1 directly bound to the promoter of circHipk2 and affected the expression of Hipk2 and circHipk2 in C2C12 myoblasts. Collectively, these findings identify circHipk2 as a candidate circRNA regulating ribosome biogenesis and myogenesis proliferation and differentiation.

A comprehensive epigenome atlas reveals DNA methylation regulating skeletal muscle development.

DNA methylation is important for the epigenetic regulation of gene expression and plays a critical role in mammalian development. However, the dynamic regulation of genome-wide DNA methylation in skeletal muscle development remains largely unknown. Here, we generated the first single-base resolution DNA methylome and transcriptome maps of porcine skeletal muscle across 27 developmental stages. The overall methylation level decreased from the embryo to the adult, which was highly correlated with the downregulated expression of DNMT1 and an increase in partially methylated domains. Notably, we identified over 40 000 developmentally differentially methylated CpGs (dDMCs) that reconstitute the developmental trajectory of skeletal muscle and associate with muscle developmental genes and transcription factors (TFs). The dDMCs were significantly under-represented in promoter regulatory regions but strongly enriched as enhancer histone markers and in chromatin-accessible regions. Integrative analysis revealed the negative regulation of both promoter and gene body methylation in genes associated with muscle contraction and insulin signaling during skeletal muscle development. Mechanistically, DNA methylation affected the expression of muscle-related genes by modulating the accessibly of upstream myogenesis TF binding, indicating the involvement of the DNA methylation/SP1/IGF2BP3 axis in skeletal myogenesis. Our results highlight the function and regulation of dynamic DNA methylation in skeletal muscle development.

A Modified Surgical Ventricular Reconstruction in Post-infarction Mice Persistently Alleviates Heart Failure and Improves Cardiac Regeneration.

Objectives: Large ventricular aneurysm secondary to myocardial infarction (MI) results in severe heart failure (HF) and limits the effectiveness of regeneration therapy, which can be improved by surgical ventricular reconstruction (SVR). However, the conventional SVR procedures do not yield optimal long-term outcome in post-MI rodents. We hypothesized that a modified SVR procedure without aggressive purse string suture would persistently alleviate HF and improve cardiac regeneration in post-MI mice. Methods: Adult male C57 mice were subjected to MI or sham surgery. Four weeks later, mice with MI underwent SVR or 2nd open-chest operation alone. SVR was performed by plicating the aneurysm with a single diagonal linear suture from the upper left ventricle (LV) to the right side of the apex. Cardiac remodeling, heart function and myocardial regeneration were evaluated. Results: Three weeks after SVR, the scar area, LV volume, and heart weight/body weight ratio were significantly smaller, while LV ejection fraction, the maximum rising and descending rates of LV pressure, LV contractility and global myocardial strain were significantly higher in SVR group than in SVR-control group. The inhibitory effects of SVR on LV remodeling and HF persisted for at least eight-week. SVR group exhibited improved cardiac regeneration, as reflected by more Ki67-, Aurora B- and PH3-positive cardiomyocytes and a higher vessel density around the plication area of the infarcted LV. Conclusions: SVR with a single linear suture results in a significant and sustained reduction in LV volume and improvement in both LV systolic and diastolic function as well as cardiac regeneration.

Deep Learning Methods for Lung Cancer Segmentation in Whole-Slide Histopathology Images-The ACDC@LungHP Challenge 2019.

Accurate segmentation of lung cancer in pathology slides is a critical step in improving patient care. We proposed the ACDC@LungHP (Automatic Cancer Detection and Classification in Whole-slide Lung Histopathology) challenge for evaluating different computer-aided diagnosis (CADs) methods on the automatic diagnosis of lung cancer. The ACDC@LungHP 2019 focused on segmentation (pixel-wise detection) of cancer tissue in whole slide imaging (WSI), using an annotated dataset of 150 training images and 50 test images from 200 patients. This paper reviews this challenge and summarizes the top 10 submitted methods for lung cancer segmentation. All methods were evaluated using metrics using the precision, accuracy, sensitivity, specificity, and DICE coefficient (DC). The DC ranged from 0.7354 ±0.1149 to 0.8372 ±0.0858. The DC of the best method was close to the inter-observer agreement (0.8398 ±0.0890). All methods were based on deep learning and categorized into two groups: multi-model method and single model method. In general, multi-model methods were significantly better (p 0.01) than single model methods, with mean DC of 0.7966 and 0.7544, respectively. Deep learning based methods could potentially help pathologists find suspicious regions for further analysis of lung cancer in WSI.