Whole-genome transcription and DNA methylation analysis of peripheral blood mononuclear cells identified aberrant gene regulation pathways in systemic lupus erythematosus

Hypermethylated CpG sites in PBMC of SLE patients comparing normal controls by genome-wide DNA methylation analysis. Three group comparisons, SLE LN+ vs. NC (S3-1), SLE LN− vs. NC (S3-2), and SLE (LN− and LN+) vs. NC (S3-3), were performed to identify hypermethylated DNA CpG sites by fold change (FC) > 1.2 and q value < 5% within each group. The 1813 common hypermethylated sites identified in each of the three group comparisons were then selected and listed in S3-4. (XLSX 814 kb

Ubiquitination in Scleroderma Fibrosis and Its Treatment

Scleroderma (systemic sclerosis, SSc) is a highly heterogeneous rheumatic disease, and uncontrolled fibrosis in visceral organs is the major cause of death in patients. The transforming growth factor-β (TGF-β) and WNT/β-catenin signaling pathways, along with signal transducer and activator of transcription 3 (STAT3), play crucial roles in this fibrotic process. Currently, no therapy is available that effectively arrests or reverses the progression of fibrosis in patients with SSc. Ubiquitination is an important post-translational modification that controls many critical cellular functions. Dysregulated ubiquitination events have been observed in patients with systemic lupus erythematosus, rheumatoid arthritis and fibrotic diseases. Inhibitors targeting the ubiquitination pathway have considerable potential for the treatment of rheumatic diseases. However, very few studies have examined the role and mechanism of ubiquitination in patients with SSc. In this review, we will summarize the molecular mechanisms of ubiquitination in patients with SSc and explore the potential targets for treatment

Expression of Mipu1 in Response to Myocardial Infarction in Rats

Myocardial ischemic preconditioning up-regulated protein 1 (Mipu1) was cloned in our laboratory. Male Wistar rats were subjected to left anterior coronary artery ligation and sham-operation and sacrificed at 1 h, 3 h, 6 h, 12 h, 24 h, 3 d or 5 d after ligation. Expression of Mipu1 mRNA and protein were assessed by Northern blotting, real-time quantitative RT-PCR, In Situ hybridization and Western blotting. Expression of Mipu1 was up-regulated at 3 h and lasted to 12 h with a peak at 6 h. Mipu1 mRNA and protein signals express in the endothelium and myocardium in normal and infarcted heart, mainly in infarcted zone. Fluorescent immunocytochemistry showed that Mipu1 protein was localized to the nuclei of H9c2 myogenic cells and was upregulated after the cells being exposed to H2O2. These observations indicates that Mipu1 may play a role in maintaining vascular homeostasis and protecting the myogenic cells from being injured by ischemia-reperfusion or oxidation stress

Multicenter validation of the value of BASFI and BASDAI in Chinese ankylosing spondylitis and undifferentiated spondyloarthropathy patients

The objectives of this study were to evaluate the reliability of Bath ankylosing spondylitis functional index (BASFI) and Bath ankylosing spondylitis disease activity index (BASDAI) in Chinese ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA) patients. 664 AS patients by the revised New York criteria for AS and 252 USpA patients by the European Spondyloarthropathy Study Group criteria were enrolled. BASDAI and BASFI questionnaires were translated into Chinese. Participants were required to fill in BASFI and BASDAI questionnaires again after 24 h. Moreover, BASDAI and BASFI were compared in AS patients receiving Enbrel or infliximab before and after treatment. For AS group, BASDAI ICC: 0.9502 (95% CI: 0.9330–0.9502, α = 0.9702), BASFI ICC: 0.9587 (95% CI: 0.9521–0.9645, α = 0.9789). For USpA group, BASDAI ICC: 0.9530 (95% CI: 0.9402–0.9632, α = 0.9760), BASFI ICC: 0.9900 (95% CI: 0.9871–0.9922, α = 0.9950). In the AS group, disease duration, occipital wall distance, modified Schober test, chest expansion, ESR, and CRP showed significant correlation with BASDAI and BASFI (all P < 0.01). In the USpA group, onset age, ESR, and CRP were significantly correlated with BASDAI (all P < 0.05), while modified Schober test, ESR, and CRP were significantly associated with BASFI (all P < 0.05). The change in BASDAI and BASFI via Enbrel or infliximab treatment showed a significant positive correlation (P < 0.01). The two instruments have good reliability and reference value regarding the evaluation of patient’s condition and anti-TNF-α treatment response

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

MicroRNAs Regulating Signaling Pathways: Potential Biomarkers in Systemic Sclerosis

AbstractSystemic sclerosis (SSc) is a multisystem fibrotic and autoimmune disease. Both genetic and epigenetic elements mediate SSc pathophysiology. This review summarizes the role of one epigenetic element, known as microRNAs (miRNAs), involved in different signaling pathways of SSc pathogenesis. The expression of key components in transforming growth factor-β (TGF-β) signaling pathway has been found to be regulated by miRNAs both upstream and downstream of TGF-β. We are specifically interested in the pathway components upstream of TGF-β, while miRNAs in other signaling pathways have not been extensively studied. The emerging role of miRNAs in vasculopathy of SSc suggests a promising new direction for future investigation. Elucidation of the regulatory role of miRNAs in the expression of signaling factors may facilitate the discovery of novel biomarkers in SSc and improve the understanding and treatment of this disease

Classification of Transcription Boundary-Associated RNAs (TBARs) in Animals and Plants

There is increasing evidence suggesting the contribution of non-coding RNAs (ncRNAs) to the phenotypic and physiological complexity of organisms. A novel ncRNA species has been identified near the transcription boundaries of protein-coding genes in eukaryotes, bacteria, and archaea. This review provides a detailed description of these transcription boundary-associated RNAs (TBARs), including their classification. Based on their genomic distribution, TBARs are divided into two major groups: promoter-associated RNAs (PARs) and terminus-associated RNAs (TARs). Depending on the sequence length, each group is further classified into long RNA species (&gt;200 nt) and small RNA species (&lt;200 nt). According to these rules of TBAR classification, divergent ncRNAs with confusing nomenclatures, such as promoter upstream transcripts (PROMPTs), upstream antisense RNAs (uaRNAs), stable unannotated transcripts (SUTs), cryptic unstable transcripts (CUTs), upstream non-coding transcripts (UNTs), transcription start site-associated RNAs (TSSaRNAs), transcription initiation RNAs (tiRNAs), and transcription termination site-associated RNAs (TTSaRNAs), were assigned to specific classes. Although the biogenesis pathways of PARs and TARs have not yet been clearly elucidated, previous studies indicate that some of the PARs have originated either through divergent transcription or via RNA polymerase pausing. Intriguing findings regarding the functional implications of the TBARs such as the long-range “gene looping” model, which explains their role in the transcriptional regulation of protein-coding genes, are also discussed. Altogether, this review provides a comprehensive overview of the current research status of TBARs, which will promote further investigations in this research area

Nuclear-Targeting Delivery of CRISPRa System for Upregulation of β-Defensin against Virus Infection by Dexamethasone and Phenylalanine Dual-Modified Dendrimer

The dual-modified dendrimer containing dexamethasone (DET) and phenylalanine (Phe) was prepared to deliver plasmid DNA encoding dCas9 and single-guide RNA (sgRNA) for specific upregulation of β-defensin. DET and Phe moieties synergistically enhanced the transfection efficiency and reduced cytotoxicity of dendrimers. Combination of three sgRNAs targeting β-defensin gene demonstrated higher activation efficacy of β-defensin than any single sgRNA and combinations of any two sgRNAs, showing an efficient inhibition of virus infection and replication. The titer of vesicular stomatitis virus (VSV) in the cells treated with dCas9-sgRNA targeting β-defensin was reduced by about 100-fold compared to that of cells treated with dCas9-scramble sgRNA (dCas9-scr sgRNA). In vivo experiments demonstrated that the DET- and Phe-modified dendrimer effectively delivered plasmid DNA encoding dCas9 protein into the airway epithelium, inducing β-defensin expression. Delivery of the CRISPR activation system by a dendrimer modified with DET and Phe was a promising approach against viral disease