Acquired myasthenia gravis (MG) is a prototype autoimmune disease of the neuromuscular junction, caused in most patients by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). There ...seem to be ethnic and regional differences in the frequency and clinical features of MG seronegative for the AChR antibody. This study aimed to describe the autoantibody profiles and clinical features of Korean patients with generalized MG seronegative for the AChR antibody. A total of 62 patients with a high index of clinical suspicion of seronegative generalized MG were identified from 18 centers, and we examined their sera for antibodies to clustered AChR, muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) by cell-based assays (CBA) and to MuSK by radioimmunoprecipitation assay (RIPA). We also included 8 patients with ocular MG, 3 with Lambert-Eaton myasthenic syndrome, 5 with motor neuron disease, and 9 with other diagnoses as comparators for the serological testing. Antibodies were identified in 25/62 (40.3%) patients: 7 had antibodies to clustered AChR, 17 to MuSK, and 2 to LRP4. Three patients were double seropositive: 1 for MuSK and LRP4, and 2 for MuSK and clustered AChR. The patients with MuSK antibodies were mostly female (88.2%) and characterized by predominantly bulbar involvement (70%) and frequent myasthenic crises (58.3%). The patients with antibodies to clustered AChR, including 2 with ocular MG, tended to have a mild phenotype and good prognosis.
Vascular calcification is characterized by the accumulation of hydroxyapatite crystals, which is a result of aberrant mineral metabolism. Although many clinical studies have reported its adverse ...effects on cardiovascular morbidity, the molecular mechanism of vascular calcification, especially the involvement of long noncoding RNAs (lncRNAs), is not yet reported. From the transcriptomic analysis, we discovered hundreds of lncRNAs differentially expressed in rat vascular smooth muscle cells (VSMCs) treated with inorganic phosphate, which mimics vascular calcification. We focused on Lrrc75a-as1 and elucidated its transcript structure and confirmed its cytoplasmic localization. Our results showed that calcium deposition was elevated after knockdown of Lrrc75a-as1, while its overexpression inhibited calcium accumulation in A10 cells. In addition, Lrrc75a-as1 attenuated VSMCs calcification by decreasing the expression of osteoblast-related factors. These findings suggest that Lrrc75a-as1 acts as a negative regulator of vascular calcification, and may serve as a possible therapeutic target in vascular calcification.
MicroRNAs (miRNAs) regulate the expression of mRNA through sequence-specific binding of the 3′ untranslated region (UTR). The seed sequence of miRNAs is the key determinant for target site ...recognition. Paralogous miRNAs, which share the same seed sequences but differ in their 3′ regions, are known to regulate largely overlapping groups of mRNAs. However, no study has analyzed functional differences between paralogous miRNAs with proper experimental methods. In this study, we compared the targets of paralogous miRNAs, miR-221 and miR-222. Using a nuclease-mediated genome engineering technique, we established knockout cell lines for these miRNAs, and precisely analyzed differences in target regulation. We found that miR-221 and miR-222 suppress the previously identified targets, CDKN1B and CDKN1C, differentially. Whereas both miRNAs suppressed CDKN1B, only miR-221 suppressed CDKN1C. From transcriptome analyses, we found that several different target mRNAs were regulated by each of miR-221 and miR-222 independently, although a large number of mRNAs responded commonly to miR-221 and miR-222. This is the first study to compare the mRNA regulations by paralogous miRNAs and illustrate that paralogous miRNAs with the same seed sequence also have difference in target regulation.
The expression of microRNAs (miRNAs) is primarily regulated during their transcription. However, the transcriptional regulation of miRNA genes has not been studied extensively owing to the lack of ...sufficient information about the promoters and transcription start sites of most miRNAs.
In this study, we identified the transcription start sites of human primary miRNAs (pri-miRNAs) using DROSHA knockout cells. DROSHA knockout resulted in increased accumulation of pri-miRNAs and facilitated the precise mapping of their 5' end nucleotides using the rapid amplification of cDNA ends (RACE) technique. By analyzing the promoter region encompassing the transcription start sites of miRNAs, we found that the unrelated miRNAs in their sequences have many common elements in their promoters for binding the same transcription factors. Moreover, by analyzing intronic miRNAs, we also obtained comprehensive evidence that miRNA-harboring introns are spliced more slowly than other introns.
The precisely mapped transcription start sites of pri-miRNAs, and the list of transcription factors for pri-miRNAs regulation, will be valuable resources for future studies to understand the regulatory network of miRNAs.
Circular RNAs (circRNAs) are generally formed by back splicing and are expressed in various cells. Vascular calcification (VC), a common complication of chronic kidney disease (CKD), is often ...associated with cardiovascular disease. The relationship between circRNAs and VC has not yet been studied. Inorganic phosphate (Pi) was used to treat rat vascular smooth muscle cells to induce VC. circRNAs were identified by analyzing RNA sequencing (RNA-seq) data, and their expression change during VC was validated. The selected circRNAs, including circSamd4a, circSmoc1-1, circMettl9, and circUxs1, were resistant to RNase R digestion and mostly localized in the cytoplasm. While silencing circSamd4a promoted VC, overexpressing it reduced VC in calcium assay and Alizarin red S (ARS) staining. In addition, microRNA (miRNA) microarray, luciferase reporter assay, and calcium assay suggested that circSamd4a could act as a miRNA suppressor. Our data show that circSamd4a has an anti-calcification role by functioning as a miRNA sponge. Moreover, mRNAs that can interact with miRNAs were predicted from RNA-seq and bioinformatics analysis, and the circSamd4a-miRNA-mRNA axis involved in VC was verified by luciferase reporter assay and calcium assay. Since circSamd4a is conserved in humans, it can serve as a novel therapeutic target in resolving VC.
Multilayered Au nanosheets are suggested as a novel class of material for fabricating stretchable electrodes suitable for organic‐based electronic devices. The electrodes show no difference in ...resistivity during repeated stretching cycles of up to ϵ = 40%.
Dielectric ceramic film capacitors, which store energy in the form of electric polarization, are promising for miniature pulsed power electronic device applications. For a superior energy storage ...performance of the capacitors, large recoverable energy density, along with high efficiency, high power density, fast charge/discharge rate, and good thermal/fatigue stability, is desired. Herein, we present highly dense lead-free 0.942Na0.535K0.480NbO3–0.058LiNbO3 (KNNLN) ferroelectric ceramic thick films (∼5 μm) demonstrating remarkable energy storage performance. The nanocrystalline KNNLN thick film fabricated by aerosol deposition (AD) process and annealed at 600 °C displayed a quasi-relaxor ferroelectric behavior, which is in contrast to the typical ferroelectric nature of the KNNLN ceramic in its bulk form. The AD film exhibited a large recoverable energy density of 23.4 J/cm3, with an efficiency of over 70% under the electric field of 1400 kV/cm. Besides, an ultrahigh power density of 38.8 MW/cm3 together with a fast discharge speed of 0.45 μs, good fatigue endurance (up to 106 cycles), and thermal stability in a wide temperature range of 20–160 °C was also observed. Using the AD process, we could make a highly dense microstructure of the film containing nano-sized grains, which gave rise to the quasi-relaxor ferroelectric characteristics and the remarkable energy storage properties.
Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 ...(Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n=30). Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P=0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.
The slow sodium-ion storage kinetics of battery-type electrodes limits the performance of sodium-ion capacitors (SICs) operating under high-power conditions. In this study, ultrafast laser ...micromachining was utilized to accelerate the sodium-ion storage kinetics of hard carbon/fumed silica (HC/f-SiO2) anodes. The ablation process involving an ultrafast femtosecond laser source enabled three-dimensional microstructuring of hot-short HC/f-SiO2 anodes with minimal photothermal damage. The microporous structure of the HC/f-SiO2 anodes facilitated the electrolyte wetting of the active materials as well as the diffusion-limited supply of sodium-ions from the bulk electrolytes. The microstructured HC/f-SiO2 anode exhibited a sodium-ion storage capacity of 370 mAh g−1, which was higher than those of unstructured HC/f-SiO2 anodes of comparable mass (298 mAh g−1) or thickness (248 mAh g−1). In addition, the rate capability of the microstructured HC/f-SiO2 anode was superior to that of the unstructured samples. Comparative full-cell tests with oxidized single-walled carbon nanotube cathodes confirmed that micromachining of the HC/f-SiO2 anode was crucial for improving the performance of the SIC full cells. This study demonstrates that ultrafast laser micromachining of HC/f-SiO2 electrodes is a facile and reliable strategy for the development of high-performance SICs.
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•Cold ablation of hard carbons using scalable femtosecond laser micromachining.•Micropatterned hard carbons facilitating electrolyte wetting and diffusion of Na-ion.•Demonstration of ultrafast laser micromachining for high performance Na-ion capacitor.
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