Vascular calcification is highly prevalent in end-stage renal diseases and is predictive of cardiovascular events and mortality. Poly(ADP-ribose) polymerase 1 (PARP1) inhibition or deletion is ...vasoprotective in several disease models. Here we show that PARP activity is increased in radial artery samples from patients with chronic renal failure, in arteries from uraemic rats, and in calcified vascular smooth muscle cells (VSMCs) in vitro. PARP1 deficiency blocks, whereas PARP1 overexpression exacerbates, the transdifferentiation of VSMCs from a contractile to an osteogenic phenotype, the expression of mineralization-regulating proteins, and calcium deposition. PARP1 promotes Runx2 expression, and Runx2 deficiency offsets the pro-calcifying effects of PARP1. Activated PARP1 suppresses miRNA-204 expression via the IL-6/STAT3 pathway and thus relieves the repression of its target, Runx2, resulting in increased Runx2 protein. Together, these results suggest that PARP1 counteracts vascular calcification and that therapeutic agents that influence PARP1 activity may be of benefit to treat vascular calcification.
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) with a crucial function in innate immune responses. Activation of TLR4 signaling at the plasma membrane by ...lipopolysaccharide (LPS) stimulates proinflammatory signaling pathways dependent on the E3 ubiquitin ligase TRAF6. Here we show the LPS-induced long non-coding RNA (lncRNA) Mirt2 functions as a checkpoint to prevent aberrant activation of inflammation, and is a potential regulator of macrophage polarization. Mirt2 associates with, and attenuates Lys63 (K63)-linked ubiquitination of, TRAF6, thus inhibiting activation of NF-κB and MAPK pathways and limiting production of proinflammatory cytokines. Adenovirus mediated gene transfer of Mirt2 protects mice from endotoxemia induced fatality and multi-organ dysfunction. These findings identify lncRNA Mirt2 as a negative feedback regulator of excessive inflammation.
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multisystem fibroinflammatory disease. We previously reported that a circulating cell population expressing CD19
CD24
CD38
was increased in ...patients with IgG4-RD. In this study, we aimed to document that this cell population represented circulating plasmablasts/plasma cells, to identify the detailed phenotype and gene expression profile of these IgG4-secreting plasmablasts/plasma cells, and to determine whether this B-cell lineage subset could be a biomarker in IgG4-related disease (IgG4-RD).
A total of 42 untreated patients with IgG4-RD were evaluated. Peripheral B-cell subsets, including CD19
CD24
CD38
plasmablasts/plasma cells, CD19
CD24
CD38
memory B cells, CD19
CD24
CD38
naïve B cells, and CD19
CD24
CD38
regulatory B cells, were assessed and sorted by flow cytometry. Microarray analysis was used to measure gene expression of circulating B-cell lineage subsets. Further characterization of CD19
CD24
CD38
plasmablasts/plasma cells was carried out by evaluating additional surface markers, including CD27, CD95, and human leukocyte antigen (HLA)-DR, by flow cytometric assay. In addition, various B-cell lineage subsets were cultured in vitro and IgG4 concentrations were measured by cytometric bead array.
In untreated patients with IgG4-RD, the peripheral CD19
CD24
CD38
plasmablast/plasma cell subset was increased and positively correlated with serum IgG4 levels, the number of involved organs, and the IgG4-related Disease Responder Index. It decreased after treatment with glucocorticoids. Characterization of the plasmablast/plasma cell population by gene expression profiling documented a typical plasmablast/plasma cell signature with higher expression of X-box binding protein 1 and IFN regulatory factor 4, but lower expression of paired box gene 5 and B-cell lymphoma 6 protein. In addition, CD27, CD95, and HLA-DR were highly expressed on CD19
CD24
CD38
plasmablasts/plasma cells from patients with IgG4-RD. Furthermore, CD19
CD24
CD38
plasmablasts/plasma cells secreted more IgG4 than other B-cell populations.
Circulating CD19
CD24
CD38
plasmablasts/plasma cells are elevated in active IgG4-RD and decreased after glucocorticoid treatment. This IgG4-secreting plasmablast/plasma cell population might be a potentially useful biomarker for diagnosis and assessing response to treatment.
Abstract
In order to improve the electrical tree resistance of epoxy resin, composites were prepared using dihydroxydiphenylsilane and a novel silicone modifier modified epoxy resin and micron ...silica, and the composites were subjected to accelerated thermal aging test and electrical tree test and recorded the growth process of electrical trees to further obtain the characteristic parameters of electrical trees in the experimental samples. The results show that the silicone‐modified epoxy resin/silica composite has better thermal stability and electrical tree resistance than the unmodified epoxy resin/silica composite and pure epoxy resin. Analysis of the scanning electron microscope (SEM) and breakdown field strength results show that the introduction of the modifier enhanced interfacial properties between the epoxy resin and silica. At the end of the electrical tree test, the length of the electrical tree in the silicone‐modified epoxy resin/silica composite was at a minimum 25.31% of the length of the electrical tree in the unmodified epoxy resin/silica composite with the same silica filling ratio, and 9.19% of the length of the electrical tree in the pure epoxy, while the electrical trees in the silicone‐modified epoxy resin/silica composite have lower expansion factors, as well as higher fractal dimensions, compared to those in the resin without added silica.
Abstract
Objectives
To further investigate the clinical characteristics and circulating lymphocyte profiles of patients with early-onset primary Sjögren’s syndrome (pSS).
Method
Data of 333 patients ...with pSS were analysed retrospectively. Early onset was defined as a pSS diagnosis at an age of 35 years or younger. The clinical, laboratory and immunophenotypic profiles of peripheral blood lymphocyte subsets were compared between early- and later-onset pSS.
Results
Thirty-six (10.81%) patients matched the definition of early-onset pSS, with age at disease onset being 28.97 (5.53) years. Elevated serum IgG level (77.14% vs 31.16%, P <0.001), low C3 (41.67% vs 20.20%, P =0.004) and C4 levels (27.78% vs 6.40%, P <0.001), anti-SSA positivity (91.67% vs 51.85%, P <0.001) and anti-SSB positivity (50% vs 20.54%, P <0.001) were more frequent in early-onset patients. The frequencies of hematological (80.56% vs 52.53%, P =0.001), renal (19.44% vs 5.05%, P =0.005) and mucocutaneous involvement (50% vs 22.56%, P <0.001) were significantly higher in the early-onset pSS group, which showed a higher 2010 EULAR SS Disease Activity Index (ESSDAI) 11(6.25–17) vs 7(3–12); P =0.003, compared with the later-onset group. In addition, profound CD4+ T-cell lymphopenia was found in patients with early-onset.
Conclusions
Patients with early-onset pSS have distinctive clinical manifestations and greater activation of the cellular immune system, present with more severe clinical symptoms and immunological features, have increased activation of circulating T cells and have an unfavourable prognosis. Thus, they require more positive treatment with glucocorticoids and/or immunosuppressants and merit closer follow-up and regular monitoring.
The ability of the adult mammalian heart to regenerate can save the cardiac muscle from a loss of function caused by injury. Cardiomyocyte regeneration is a key aspect of research for the treatment ...of cardiovascular diseases. The mouse heart shows temporary regeneration in the first week after birth; thus, the newborn mouse heart is an ideal model to study heart muscle regeneration. In this study, proteomic analysis was used to investigate the differences in protein expression in the hearts of neonatal mice at days 1 (P1 group), 4 (P4 group), and 7 (P7 group). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed changes in several groups of proteins, including the protein kinase A (PKA) signaling pathway. Moreover, it was found that PKA inhibitors and agonists regulated cardiomyocyte replication in neonatal mouse hearts. These findings suggest that PKA may be a target for the regulation of the cardiomyocyte cell cycle.
Neuromuscular disorders (NMD), many of which are hereditary, affect muscular function. Due to advances in high-throughput sequencing technologies, the diagnosis of hereditary NMDs has dramatically ...improved in recent years.
In this study, we report an family with two siblings exhibiting two different NMD, Miyoshi muscular dystrophy (MMD) and early onset primary dystonia (EOPD). Whole exome sequencing (WES) identified a novel monoallelic frameshift deletion mutation (
: c.4404delC/p.I1469Sfs
17) in the Dysferlin gene in the index patient who suffered from MMD. This deletion was inherited from his unaffected father and was carried by his younger sister with EOPD. However, immunostaining staining revealed an absence of dysferlin expression in the proband's muscle tissue and thus suggested the presence of the second underlying mutant allele in dysferlin. Using integrated RNA sequencing (RNA-seq) and whole genome sequencing (WGS) of muscle tissue, a novel deep intronic mutation in
(
: c.5341-415A > G) was discovered in the index patient. This mutation caused aberrant mRNA splicing and inclusion of an additional pseudoexon (PE) which we termed PE48.1. This PE was inherited from his unaffected mother. PE48.1 inclusion altered the Dysferlin sequence, causing premature termination of translation.
Using integrated genome and transcriptome sequencing, we discovered hereditary MMD and EOPD affecting two siblings of same family. Our results added further weight to the combined use of RNA-seq and WGS as an important method for detection of deep intronic gene mutations, and suggest that integrated sequencing assays are an effective strategy for the diagnosis of hereditary NMDs.
Abstract
Background
Mitral regurgitation (MR) is a rather common valvular heart disease. The aim of this systematic review and meta-analysis was to compare the outcomes, and complications of mitral ...valve (MV) replacement with surgical MV repair of non-ischemic MR (NIMR)
Methods
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched until October, 2020. Studies were eligible for inclusion if they included patients with MR and reported early (30-day or in-hospital) or late all-cause mortality. For each study, data on all-cause mortality and incidence of reoperation and operative complications in both groups were used to generate odds ratios (ORs) or hazard ratios (HRs). This study is registered with PROSPERO, CRD42018089608.
Results
The literature search yielded 4834 studies, of which 20 studies, including a total of 21,898 patients with NIMR, were included. The pooled analysis showed that lower age, less female inclusion and incident of hypertension, significantly higher rates of diabetes and atrial fibrillation in the MV replacement group than MV repair group. No significant differences in the rates of pre-operative left ventricle ejection fraction (LVEF) and heart failure were observed between groups. The number of patients in the MV repair group was lower than in the MV replacement group. We found that there were significantly increased risks of mortality associated with replacement of MR. Moreover, the rate of re-operation and post-operative MR in the MV repair group was lower than in the MV replacement group.
Conclusions
In patients with NIMR, MV repair achieves higher survival and leads to fewer complications than surgical MV replacement. In light of these results, we suggest that MV repair surgery should be a priority for NIMR patients.
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