Development and external validation of a nomogram for the early prediction of acute kidney injury in septic patients: a multicenter retrospective clinical study.

Background and purpose: Acute kidney injury (AKI) is a common serious complication in sepsis patients with a high mortality rate. This study aimed to develop and validate a predictive model for sepsis associated acute kidney injury (SA-AKI). Methods: In our study, we retrospectively constructed a development cohort comprising 733 septic patients admitted to eight Grade-A tertiary hospitals in Shanghai from January 2021 to October 2022. Additionally, we established an external validation cohort consisting of 336 septic patients admitted to our hospital from January 2017 to December 2019. Risk predictors were selected by LASSO regression, and a corresponding nomogram was constructed. We evaluated the model's discrimination, precision and clinical benefit through receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) and clinical impact curves (CIC) in both internal and external validation. Results: AKI incidence was 53.2% in the development cohort and 48.2% in the external validation cohort. The model included five independent indicators: chronic kidney disease stages 1 to 3, blood urea nitrogen, procalcitonin, D-dimer and creatine kinase isoenzyme. The AUC of the model in the development and validation cohorts was 0.914 (95% CI, 0.894-0.934) and 0.923 (95% CI, 0.895-0.952), respectively. The calibration plot, DCA, and CIC demonstrated the model's favorable clinical applicability. Conclusion: We developed and validated a robust nomogram model, which might identify patients at risk of SA-AKI and promising for clinical applications.

ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban.

BACKGROUND: Intracellular Ca2+ cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) is responsible for the sequestration of cytosolic Ca2+ into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear. METHODS: Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20flox mice with Myh6-Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca2+ content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes. CONCLUSIONS: These data point to ZBTB20 as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.

Septic macrophages induce T cells immunosuppression in a cell-cell contact manner with the involvement of CR3.

Background: In addition to excessive inflammation, immunosuppression has been recognized as a contributing factor to poor prognosis of sepsis. Although it has been reported that T cells can become functionally impaired during sepsis, the underlying mechanisms responsible for this phenomenon remain unclear. This study aims to elucidate the mechanisms by which macrophages induce immunosuppression in T cells. Methods: In an in vivo setting, C57BL-6J mice were subjected to cecal ligation and puncture (CLP) with or without depletion of macrophages, and the functions of T cells were assessed. In vitro experiments involved direct co-culture or separate culture of T cells and septic macrophages using a transwell system, followed by analysis of T cell immunity. Additionally, a siRNA targeting CD18 on macrophages was utilized to investigate the role of complement receptor 3 (CR3). Results: Both macrophages and T cells exhibited immunosuppression during sepsis. In the in vivo experiments, the absence of macrophages partially alleviated T cell immunosuppression, as evidenced by restored vitality, increased production of TNF-α and IFN-γ, elevated CD8+ T cell levels, and decreased CD25+ T cell levels. In the in vitro experiments, direct co-culture of T cells with septic macrophages resulted in diminished T cell immunity, which was improved when T cells and macrophages were separated by a chamber wall. The expression of CR3 (CD11b/CD18) was upregulated on septic macrophages, and silencing of CD18 led to decreased TNF-α production by T cells, reduced CD4+ T cell numbers, and increased CD25+ T cell numbers. Conclusion: In sepsis, macrophages induce immunosuppression in T cells through direct cell-cell contact, with the involvement of CR3.

Prognostic Accuracy of the Different Scoring Systems for Assessing Coagulopathy in Sepsis: A Retrospective Study.

There is no gold standard for the diagnosis of coagulation dysfunction in sepsis, and the use of the current scoring systems is still controversial. The purpose of this study was to assess the performance of sepsis-induced coagulopathy (SIC), the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC), and the International Society on Thrombosis and Haemostasis overt DIC (ISTH overt-DIC). The relationship between each scoring system and 28-day all-cause mortality was examined. Among 452 patients (mean age, 65 [48,76] years), 306 [66.7%] were men, the median SOFA score was 6 [4,9], and the median APACHE II score was 15 [11,22]. A total of 132 patients (29.2%) died within 28 days. Both the diagnosis of SIC (AUROC, 0.779 [95% CI, 0.728-0.830], P < 0.001) and ISTH overt-DIC (AUROC, 0.782 [95% CI, 0.732-0.833], P < 0.001) performed equally well in the discrimination of 28-day all-cause mortality (between-group difference: SIC versus ISTH overt-DIC, -0.003 [95% CI, -0.025-0.018], P = 0.766). However, the SIC demonstrated greater calibration for 28-day all-cause mortality than ISTH overt-DIC (the coincidence of the calibration curve of the former is higher than that of the latter). The diagnosis of JAAM DIC was not independently associated with 28-day all-cause mortality in sepsis (RR, 1.115, [95% CI 0.660-1.182], P = 0.684). The SIC scoring system demonstrated superior prognostic prediction ability in comparison with the others and is the most appropriate standard for diagnosing coagulopathy in sepsis.

Effects of combined use of intermittent theta burst stimulation and cognitive training on post-stroke cognitive impairment : a single-blind randomized controlled trial.

OBJECTIVE: Post-stroke cognitive impairment (PSCI) substantially affects patients' quality of life. This study explored the therapeutic efficacy of intermittent theta burst stimulation (iTBS) combined with cognitive training for PSCI. DESIGN: The experimental group received iTBS and cognitive training, whereas the control group only received cognitive training, both for six weeks. The outcome measures were the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA), Modified Barthel Index (MBI), Transcranial Doppler Ultrasonography (TCD), and Functional Near-infrared Spectroscopy (fNIRS). RESULTS: After therapy, between-group comparisons revealed a substantial difference in the LOTCA scores (P = 0.024). Improvements in visuomotor organization and thinking operations were more noticeable in the experimental group than in the other groups (P = 0.017 and P = 0.044, respectively). After treatment, the resistance index of the experimental group differed from that of the control group; channels 29, 37, and 41 were activated(P < 0.05). The active locations were the left dorsolateral prefrontal cortex (DLPFC), prefrontal polar cortex, and left Broca's region. CONCLUSION: iTBS combined with cognitive training had a superior effect on improving cognitive function and everyday activities compared with cognitive training alone, notably in visuomotor organization and thinking operations. iTBS may enhance cognitive performance by improving network connectivity.

Woody plant functional traits and phylogenetic signals correlate with urbanization in remnant forest patches.

Exploring the alterations in functional traits of urban remnant vegetation offers a more comprehensive perspective on plant assembly within the context of urbanization. While plant functional traits are influenced by both environmental gradients and the evolutionary history of plant species, the specific mechanisms by which urbanization mediates the combination of functional traits and the evolutionary history of remnant vegetation remain unclear. To examine the relationship between functional traits and phylogenies of remnant vegetation and urbanization, we classified the woody plant species surveyed in 72 sample plots in nine remnant forest patches in Guiyang, China, into four groups (urban, rural, middle and general groups) according to their location under different levels of urbanization and measured nine functional traits of these species. The phylogenetic signals of each functional trait of the four species groups were then quantified based on Blomberg's K. Furthermore, we analysed the correlations between functional traits and species abundance using phylogenetic generalized least squares. The results showed that significant phylogenetic signals were detected in more functional traits of the urban group than other groups. Thirteen and three significant relationships between functional traits and species abundance were detected for tree and shrub species after removing phylogenies. Tall tree species were more abundant in the urban group, while the general group favoured the species with adaptable traits (low height and high leaf area and C/N). Overall, we demonstrate that urbanization drove shifts in plant functional traits in remnant forests after combining the phylogenetic patterns.

NTA-Cholesterol Analogue for the Nongenetic Liquid-Ordered Phase-Specific Functionalization of Lipid Membranes with Proteins.

The nongenetic modification of cell membranes with proteins is a straightforward way of cellular engineering. In these processes, it is important to specifically address the proteins to liquid-ordered (Lo) or liquid-disordered (Ld) domains as this can largely affect their biological functions. Herein, we report a cholesterol analogue (CHIM) with a nitrilotriacetic acid (NTA) headgroup, named CHIM-NTA. CHIM-NTA integrates into lipid membranes similar to the widely used phospholipid-derived DGS-NTA and, when loaded with Ni2+, allows for specific membrane immobilization of any polyhistidine-tagged proteins of choice. Yet, unlike DGS-NTA, it localizes to the Lo phase in phase-separated giant unilamellar vesicles (GUVs) and allows addressing His-tagged proteins to Lo domains. Furthermore, CHIM-NTA readily integrates into the membranes of live cells and thus enables the nongenetic modification of the cell surface with proteins. Overall, CHIM-NTA provides a facile and flexible way to modify biological membranes, in particular Lo domains, with His-tagged proteins and can serve as a broadly applicable molecular tool for cell surface engineering.

Design, synthesis and bioactivity evaluation of a series of quinazolinone derivatives as potent PI3Kγ antagonist.

Targeting PI3Kγ would be a useful strategy for treating inflammatory and cancer diseases. However, the development of selective inhibitors of PI3Kγ is very challenging due to the high structural and sequence homology with other PI3K isoforms. A series of quinazolinone derivatives were designed, synthesized and biologically evaluated as PI3Kγ-selective inhibitors. Among all the 28 compounds, compound 9b was found to be the most potent selective inhibitor with IC50 values of 13.11 nM against PI3Kγ kinase. Additionally, compound 9b could generate toxicity on leukemia cells in a panel of 12 different of cancer cell lines with the IC50 value of 2.41 ± 0.11 µM on Jurkat cell. Preliminary mechanism studies indicated that compound 9b through inhibit the activity of PI3K-AKT in human and murine leukemia cells, and activated phosphorylated p38 and phosphorylated ERK presented potent antiproliferative activity, which provided a potent small molecule for further cancer therapy.

Transparent, intrinsically stretchable cellulose nanofiber-mediated conductive hydrogel for strain and humidity sensing.

Conductive hydrogels (CHs) have attracted considerable attentions in the fields of wearable electronics, disease diagnosis, and artificial intelligence. However, it is still a great challenge to prepare a single CH system with integrated characteristics of high stretchability, good transparency, and multisensory function through a simple fabrication process. Herein, carboxylic cellulose nanofibers (CCNF) were used to assist the homogeneous distribution of opaque conductive poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (PEDOT: PSS) into the crosslinked polyacrylamide network for the fabrication of stretchable and transparent interpenetrating network CH, aiming for a high-performance multisensory system. As expected, the ready formation of hydrogen bonds between the water molecules and a great deal of hydrophilic groups in the hydrogel endow the obtained CH with excellent humidity response behavior in a wide range (0-85%), and the introduction of CCNF and PEDOT: PSS is proved to be an effective strategy to enhance the humidity sensitivity, exhibiting great potential for the noncontact sensing of human respiration and finger movement. Meanwhile, it also displays excellent strain sensing behavior with favorable sensitivity in a broad range (0-837 %), fast response and reliable stability and reproducibility. Importantly, our prepared CH can also detect and discriminate complicated human activities and physiological signals. All these demonstrate the superiority of our prepared CH for the new generation of flexible wearable electronics.

Effects of the Targeted Regulation of CCRK by miR-335-5p on the Proliferation and Tumorigenicity of Human Renal Carcinoma Cells.

Cell cycle-related kinase (CCRK) is most closely related to cyclin-dependent protein kinase, which may activate cyclin-dependent kinase 2 and is associated with the growth of human cancer cells. However, the expression and function of CCRK in the pathogenesis of clear cell renal cell cancer (ccRCC) are unclear. Herein, this research aimed to explore the potential mechanism of the targeted regulation of CCRK by miR-335-5p on the proliferation and tumorigenicity of human ccRCC cells. The results showed that CCRK was significantly overexpressed in ccRCC tissues and cells, and knockdown of the CCRK expression by shRNA inhibited cell proliferation in vitro and in vivo and enhanced cell apoptosis in vitro, which indicated that CCRK could be a potential target for antitumour drugs in the treatment of ccRCC. Moreover, miR-335-5p was found to bind directly to the 3' untranslated region of CCRK, was expressed at markedly low levels in ccRCC cells, and was closely associated with the tumour stage. The overexpression of CCRK partially reversed the inhibitory effects of miR-335-5p on the cell growth of ccRCC, which implied that miR-335-5p could serve as a promising tumour inhibitor for ccRCC. In summary, CCRK could serve as an alternative antitumour drug target, and miR-335-5p could be a promising therapeutic tumour inhibitor for ccRCC treatment.

Proteomics and bioinformatics analysis of follicular fluid from patients with polycystic ovary syndrome.

Objectives: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder with heterogeneous manifestations and complex etiology. We used quantitative proteomics analysis based on mass spectrometry to identify the differences in proteomics profiles for follicular fluid obtained from patients with or without PCOS and explore possible mechanisms underlying PCOS. Methods: Follicular fluid samples were collected from infertile patients with (n = 9) or without (n = 9) PCOS. Total protein was extracted, quantitatively labeled with a tandem mass tag (TMT), and analyzed using liquid chromatography-mass spectrometry (LC-MS). TMT-based proteomics and bioinformatics analysis were used to determine the differentially expressed proteins (DEPs) and understand the protein networks. The analysis included protein annotation, unsupervised hierarchical clustering, functional classification, functional enrichment and clustering, and protein-protein interaction analysis. Selected DEPs were confirmed by ELISA, and correlation analysis was performed between these DEPs and the clinical characteristics. Results: In this study, we have identified 1,216 proteins, including 70 DEPs (32 upregulated proteins, 38 downregulated proteins). Bioinformatics analysis revealed that the inflammatory response, complement and coagulation cascades, activation of the immune response, lipid transport, and regulation of protein metabolic processes were co-enriched in patients with PCOS. Based on ELISA results, insulin-like growth factor binding protein 1 (IGFBP1) and apolipoprotein C2 (APOC2) were differentially expressed between patients with and without PCOS. Follicular IGFBP1 showed a positive correlation with the serum levels of high-density lipoprotein cholesterol (HDL-C) (r = 0.3046, p = 0.0419), but negatively correlated with the serum levels of anti-Müllerian hormone (AMH) (r = -0.2924, p = 0.0354) and triglycerides (r = -0.3177, p = 0.0246). Follicular APOC2 was negatively correlated with the serum apolipoprotein A1 (APOA1) levels (r = 0.4509, p = 0.0002). Conclusion: Our study identified DEPs in the follicular fluid of patients with PCOS. Inflammatory response, complement and coagulation cascades, activation of the immune response, lipid transport, and regulation of protein metabolic process were deregulated in PCOS, which may play essential roles in the pathogenesis of PCOS.

Breaching Bacterial Biofilm Barriers: Efficient Combinatorial Theranostics for Multidrug-Resistant Bacterial Biofilms with a Novel Penetration-Enhanced AIEgen Probe.

The formation of microbial biofilms is acknowledged as a major virulence factor in a range of persistent local infections. Failures to remove biofilms with antibiotics foster the emergence of antibiotic-resistant bacteria and result in chronic infections. As a result, the construction of effective biofilm-inhibiting and biofilm-eradicating chemicals is urgently required. Herein, we designed a water-soluble probe APDIS for membrane-active fluorescence and broad-spectrum antimicrobial actions, particularly against methicillin-resistant Staphylococcus aureus (MRSA), which shows multidrug resistance. In vitro and in vivo experiments demonstrate its high antibacterial effects comparable to vancomycin. Furthermore, it inhibits biofilm formation by effectively killing planktonic bacteria at low inhibitory concentrations, without toxicity to mammalian cells. More importantly, this probe can efficiently penetrate through biofilm barriers and exterminate bacteria that are enclosed within biofilms and startle existing biofilms. In the mouse model of implant-related biofilm infections, this probe exhibits strong antibiofilm activity against MRSA biofilms, thus providing a novel theranostic strategy to disrupt biofilms in vivo effectively. Our results indicate that this probe has the potential to be used for the development of a combinatorial theranostic platform with synergistic enhanced effects for the treatment of multidrug-resistant bacterial infections and antibiofilm medications.

The complete chloroplast genome of Strobilanthes crispus (Acanthaceae).

We reported and characterized the complete chloroplast genome sequence of Strobilanthes crispus Blume 1826. Strobilanthes crispus belongs to the Acanthaceae family and has a number of local names including Batuzin, Bayam Karang, Kotz Bellin, and Pekka Batu, which is native to Malaysian with diverse beneficial uses. Green leaves were determined using next-generation sequencing. We found that the entire chloroplast genome of S. crispus was 144,987 bp in length, included four segments, named a large single-copy (LSC) region (92,556 bp), a small single-copy (SSC) region (17,783 bp), and a pair inverted repeat regions (IRs) (17,324 bp in each), respectively. The chloroplast genome of S. crispus contained a total of 129 functional genes, including 84 protein-coding genes, 37 transfer RNAs (tRNAs), and eight ribosomal RNA (rRNA) genes. The phylogenetic tree reconstructed by nine chloroplast genomes reveals that S. crispus is most closely related to Strobilanthes bantonensis and Strobilanthes cusia.

Increased risk of abortion after frozen-thawed embryo transfer in women with polycystic ovary syndrome phenotypes A and D.

Polycystic ovary syndrome (PCOS) is associated with adverse pregnancy outcomes, including an increased risk of abortion, premature delivery, and even neonatal outcomes. After removing the effect of COH on patients, studying the pregnancy outcomes of patients with different PCOS phenotypes after FET may better reflect the impact of different PCOS phenotypes on ART outcomes. Data of 8903 patients who underwent FET between January 2017 and October 2019 were retrospectively collected and evaluated. All patients were divided into a control group and four phenotype groups based on Rotterdam criteria. The main outcomes were pregnancy outcomes after FET. We found significantly higher abortion (P = 0.010) and lower ongoing pregnancy (P = 0.023) rates for women with PCOS phenotypes A and D compared to those in the control group. After adjusting for potential confounders, PCOS phenotypes A and D were associated with an elevated risk of abortion (adjusted OR, 1.476, P = 0.016; adjusted OR, 1.348, P = 0.008, respectively). The results of this study suggest that when performing FET, clinicians should individually manage women with PCOS phenotypes A and D to reduce the rate of abortion and increase the rate of LB, and achieve better pregnancy outcomes.

Mucin 1 Inhibits Ferroptosis and Sensitizes Vitamin E to Alleviate Sepsis-Induced Acute Lung Injury through GSK3ß/Keap1-Nrf2-GPX4 Pathway.

Background: Ferroptosis is a nonapoptotic form of programmed cell death, which may be related to the occurrence and development of sepsis-induced acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). Mucin 1 (MUC1) is a kind of macromolecule transmembrane glycoprotein. Previous studies have shown that MUC1 could relieve ALI in sepsis and predict whether sepsis patients would develop into ARDS. However, the role of MUC1 in the ferroptosis of sepsis-induced ALI/ARDS remains unclear. Materials and Methods: Sera samples from 50 patients with sepsis/septic shock were used to detect iron metabolism-related markers. Western blot and qRT-PCR were conducted to detect the expression levels of ferroptosis-related genes. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate inflammatory factors. Transmission electron microscopy (TEM) was used to assess morphological changes of cells. Results: The results showed that the iron metabolism-related indicators in sepsis-induced ARDS patients changed significantly, suggesting the iron metabolism disorder. The expression levels of ferroptosis-related genes in lung tissues of sepsis had marked changes, and the lipid peroxidation levels increased, while Ferrostatin-1 (Fer-1) could reverse the above results, which confirmed the occurrence of ferroptosis. In terms of mechanism studies, inhibition of MUC1 dimerization could increase the expression level of Keap1, reduce the phosphorylation level of GSK3ß, inhibit the entry of Nrf2 into the nucleus, further inhibit the expression level of GPX4, enhance the lipid peroxidation level of lung tissues, trigger ferroptosis, and aggravate lung injury. Besides, inhibiting MUC1 reversed the alleviating effect of vitamin E on ALI caused by sepsis, increased the aggregation of inflammatory cells in lung tissues, and aggravated alveolar injury and edema. Conclusions: Our study was the first to explore the changes of iron metabolism indicators in ALI/ARDS of sepsis, clarify the important role of ferroptosis in ALI/ARDS induced by sepsis, and reveal the effects and specific mechanisms of MUC1 in regulating ferroptosis, as well as the sensitization on vitamin E.

Establishment of a novel risk score for in-hospital mortality in adult sepsis patients.

Background: Existing scoring systems have limitations in predicting the in-hospital mortality of adult sepsis patients. We aimed to develop and validate a novel risk score for predicting the in-hospital mortality of adult sepsis patients. Methods: The clinical data of 1,335 adult sepsis inpatients were retrospectively analyzed. Enrolled patients were randomly divided into a modeling group and a validation group at a 3:2 ratio. The modeling group (n=801) was used to develop the risk score by univariate and multivariate logistic regression analyses. The score's performance was validated in the validation group (n=534). We classified patients into four risk levels according to the novel risk score. Results: Age, central vein catheterization, mechanical ventilation, vasopressin, Charlson comorbidity index (CCI), respiratory rate (RR), heart rate (HR), Glasgow coma scale (GCS) score, platelet (PLT), hematocrit (HCT), aspartate aminotransferase (AST), and activated partial thrombin time (APTT) were independent risk factors for in-hospital death in adult sepsis patients. Continuous variables were converted into classified variables to develop the risk score, with a total score of 39 points. Adult sepsis patients with low, lower medium, higher medium, and high risk levels had in-hospital mortality rates of 9.8%, 24.7%, 55.8%, and 83.5%, respectively. Conclusions: Compared with the Acute Physiology and Chronic Health Evaluation II scoring system (APACHE II) and the Modified Early Warning Score (MEWS), the novel risk score showed good predictive performance for in-hospital mortality in adult sepsis patients.

Corrigendum: Analysis of time series gene expression and DNA methylation reveals the molecular features of myocardial infarction progression.

[This corrects the article DOI: 10.3389/fcvm.2022.912454.].

DICER1-associated sarcoma of the aortic arch - a case report and literature review.

Primary sarcoma of the aorta is extremely rare. We herein report a case of DICER1-associated sarcoma originating from the aortic arch. A 45-year-old male was admitted to the hospital with a cold left hand and a weakened radial artery pulse on the left side. Computed tomography of the chest showed multiple penetrating ulcers with tumor-like ectasia at the aortic arch, diagnosed as a pseudoaneurysm. Histopathological analysis of the mass revealed a biphasic neoplasm composed of epithelial and mesenchymal components and a transition zone between the epithelial and mesenchymal cells, which supports the diagnosis of a biphasic sarcoma rather than carcinosarcoma. The differentiated cells of soft tissue showed strong and diffuse positivity for TLE-1, Bcl-2, and CD99; the nested epithelial cells were focally positive for CK-pan but negative for EMA, membranous localization of ß-catenin. This case showed a unique pattern of SS18-break-apart probe, with loss of the green signal (approximately 33%) by fluorescence in situ hybridization (FISH). Fusion gene profiling using whole transcriptome RNA sequencing (RNA-seq) indicated that this case was negative for common fusion genes including SS18. Next-generation sequencing (NGS) revealed somatic mutations in DICER1. Taken together, this case was diagnosed as a DICER-associated biphasic sarcoma of the aortic arch. The patient died four months after aorta replacement therapy without radiotherapy and chemotherapy.

Analysis of Time Series Gene Expression and DNA Methylation Reveals the Molecular Features of Myocardial Infarction Progression.

Myocardial infarction (MI) is one of the deadliest diseases in the world, and the changes at the molecular level after MI and the DNA methylation features are not clear. Understanding the molecular characteristics of the early stages of MI is of significance for the treatment of the disease. In this study, RNA-seq and MeDIP-seq were performed on heart tissue from mouse models at multiple time points (0 h, 10 min, 1, 6, 24, and 72 h) to explore genetic and epigenetic features that influence MI progression. Analysis based on a single point in time, the number of differentially expressed genes (DEGs) and differentially methylated regions (DMRs) increased with the time of myocardial infarction, using 0 h as a control group. Moreover, within 10 min of MI onset, the cells are mainly in immune response, and as the duration of MI increases, apoptosis begins to occur. Analysis based on time series data, the expression of 1012 genes was specifically downregulated, and these genes were associated with energy metabolism. The expression of 5806 genes was specifically upregulated, and these genes were associated with immune regulation, inflammation and apoptosis. Fourteen transcription factors were identified in the genes involved in apoptosis and inflammation, which may be potential drug targets. Analysis based on MeDIP-seq combined with RNA-seq methodology, focused on methylation at the promoter region. GO revealed that the downregulated genes with hypermethylation at 72 h were enriched in biological processes such as cardiac muscle contraction. In addition, the upregulated genes with hypomethylation at 72 h were enriched in biological processes, such as cell-cell adhesion, regulation of the apoptotic signaling pathway and regulation of angiogenesis. Among these genes, the Tnni3 gene was also present in the downregulated model. Hypermethylation of Tnni3 at 72 h after MI may be an important cause of exacerbation of MI.

Nogo-B promotes angiogenesis and improves cardiac repair after myocardial infarction via activating Notch1 signaling.

Nogo-B (Reticulon 4B) is reportedly a regulator of angiogenesis during the development and progression of cancer. However, whether Nogo-B regulates angiogenesis and post-myocardial infarction (MI) cardiac repair remains elusive. In the present study, we aimed to explore the role and underlying mechanisms of Nogo-B in cardiac repair during MI. We observed an increased expression level of Nogo-B in the heart of mouse MI models, as well as in isolated cardiac microvascular endothelial cells (CMECs). Moreover, Nogo-B was significantly upregulated in CMECs exposed to oxygen-glucose deprivation (OGD). Nogo-B overexpression in the endothelium via cardiotropic adeno-associated virus serotype 9 (AAV9) with the mouse endothelial-specific promoter Tie2 improved heart function, reduced scar size, and increased angiogenesis. RNA-seq data indicated that Notch signaling is a deregulated pathway in isolated CMECs along the border zone of the infarct with Nogo-B overexpression. Mechanistically, Nogo-B activated Notch1 signaling and upregulated Hes1 in the MI hearts. Inhibition of Notch signaling using a specific siRNA and γ-secretase inhibitor abolished the promotive effects of Nogo-B overexpression on network formation and migration of isolated cardiac microvascular endothelial cells (CMECs). Furthermore, endothelial Notch1 heterozygous deletion inhibited Nogo-B-induced cardioprotection and angiogenesis in the MI model. Collectively, this study demonstrates that Nogo-B is a positive regulator of angiogenesis by activating the Notch signaling pathway, suggesting that Nogo-B is a novel molecular target for ischemic disease.