Small nucleolar RNA host gene 18 controls vascular smooth muscle cell contractile phenotype and neointimal hyperplasia.

AIMS: Long non-coding RNA (LncRNA) small nucleolar RNA host gene 18 (SNHG18) has been widely implicated in cancers. However, little is known about its functional involvement in vascular diseases. Herein, we attempted to explore a role for SNHG18 in modulating vascular smooth muscle cell (VSMC) contractile phenotype and injury-induced neointima formation. METHODS AND RESULTS: Analysis of single-cell RNA sequencing and transcriptomic datasets showed decreased levels of SNHG18 in injured and atherosclerotic murine and human arteries, which is positively associated with VSMC contractile genes. SNHG18 was upregulated in VSMCs by TGFß1 through transcription factors Sp1 and SMAD3. SNHG18 gene gain/loss-of-function studies revealed that VSMC contractile phenotype was positively regulated by SNHG18. Mechanistic studies showed that SNHG18 promotes a contractile VSMC phenotype by up-regulating miR-22-3p. SNHG18 up-regulates miR-22 biogenesis and miR-22-3p production by competitive binding with the A-to-I RNA editing enzyme, adenosine deaminase acting on RNA-2 (ADAR2). Surprisingly, we observed that ADAR2 inhibited miR-22 biogenesis not through increasing A-to-I editing within primary miR-22, but by interfering with the binding of microprocessor complex subunit DGCR8 to primary miR-22. Importantly, perivascular SNHG18 overexpression in the injured vessels dramatically up-regulated the expression levels of miR-22-3p and VSMC contractile genes, and prevented injury-induced neointimal hyperplasia. Such modulatory effects were reverted by miR-22-3p inhibition in the injured arteries. Finally, we observed a similar regulator role for SNHG18 in human VSMCs and a decreased expression level of both SNHG18 and miR-22-3p in diseased human arteries; and we found that the expression level of SNHG18 was positively associated with that of miR-22-3p in both healthy and diseased human arteries. CONCLUSION: We demonstrate that SNHG18 is a novel regulator in governing VSMC contractile phenotype and preventing injury-induced neointimal hyperplasia. Our findings have important implications for therapeutic targeting snhg18/miR-22-3p signalling in vascular diseases.

Lipid nanoparticles for local delivery of mRNA to the respiratory tract: Effect of PEG-lipid content and administration route.

Design of inhalable mRNA therapeutics is promising because local administration in the respiratory tract is minimally invasive and induces a local response. However, several challenges related to administration via inhalation and respiratory tract barriers have so far prevented the progress of inhaled mRNA therapeutics. Here, we investigated factors of importance for lipid nanoparticle (LNP)-mediated delivery of mRNA to the respiratory tract. We hypothesized that: (i) the PEG-lipid content is important for providing colloidal stability during aerosolization and for mucosal delivery, (ii) the PEG-lipid contentinfluences the expression of mRNA-encoded protein in the lungs, and (iii) the route of administration (nasal versus pulmonary) affects mRNA delivery in the lungs. In this study, we aimed to optimize the PEG-lipid content for mucosal delivery and to investigatethe effect of administration route on the kinetics of protein expression. Our results show that increasing the PEG-lipid content improves the colloidal stability during the aerosolization process, but has a negative impact on the transfection efficiencyin vitro. The kinetics of protein expressionin vivois dependent on the route of administration, and we found that pulmonaryadministration of mRNA-LNPs to mice results inmore durable protein expression than nasaladministration. These results demonstrate that the design of the delivery system and the route of administration are importantfor achieving high mRNA transfection efficiency in the respiratory tract.

FunSwin: A deep learning method to analysis diabetic retinopathy grade and macular edema risk based on fundus images.

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are forms of degenerative retinal disorders that may result in vision impairment or even permanent blindness. Early detection of these conditions is essential to maintaining a patient's quality of life. The fundus photography technique is non-invasive, safe, and rapid way of assessing the function of the retina. It is widely used as a diagnostic tool for patients who suffer from fundus-related diseases. Using fundus images to analyze these two diseases is a challenging exercise, since there are rarely obvious features in the images during the incipient stages of the disease. In order to deal with these issues, we have proposed a deep learning method called FunSwin. The Swin Transformer constitutes the main framework for this method. Additionally, due to the characteristics of medical images, such as their small number and relatively fixed structure, transfer learning strategy that are able to increase the low-level characteristics of the model as well as data enhancement strategy to balance the data are integrated. Experiments have demonstrated that the proposed method outperforms other state-of-the-art approaches in both binary and multiclass classification tasks on the benchmark dataset.

Effect of Nanostructured TiO2 on Rheological Properties of Fresh Cement Slurry.

Rheological properties have a great influence on mechanical behavior and durability of fresh cement slurry after construction and hardening. For this reason, a series of experiments were carried out in this study to investigate the effects of different nanostructured TiO2 (NT) contents on rheological properties of nanostructured TiO2-cement (NTC) composite slurries. Moreover, the microstructure of NTC was analyzed by means of scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD). Results showed that the shear stress was increased followed by increased NT content. Variation of viscosity with time was divided into initial decline period, initial stable period, growth period and final stable period. During the first two periods, the viscosity decreased first and then increased with increased NT content. Moreover, the viscosity showed a reverse variation during the latter two periods. In addition, it was also noted that the reasonable range for NT content of cement slurry was 0%-1.5%.

An Improved Time-Series Model Considering Rheological Parameters for Surface Deformation Monitoring of Soft Clay Subgrade.

Building deformation models consistent with reality is a crucial step for time-series deformation monitoring. Most deformation models are empirical mathematical models, lacking consideration of the physical mechanisms of observed objects. In this study, we propose an improved time-series deformation model considering rheological parameters (viscosity and elasticity) based on the Kelvin model. The functional relationships between the rheological parameters and deformation along the Synthetic Aperture Radar ( SAR) line of sight are constructed, and a method for rheological parameter estimation is provided. To assess the feasibility and accuracy of the presented model, both simulated and real deformation data over a stretch of the Lungui highway (built on soft clay subgrade in Guangdong province, China) are investigated with TerraSAR-X satellite imagery. With the proposed deformation model, the unknown rheological parameters over all the high coherence points are obtained and the deformation time-series are generated. The high-pass (HP) deformation component and external leveling ground measurements are utilized to assess the modeling accuracy. The results show that the root mean square of the residual deformation is ±1.6 mm, whereas that of the ground leveling measurements is ±5.0 mm, indicating an improvement in the proposed model by 53%, and 34% compared to the pure linear velocity model. The results indicate the reliability of the presented model for the application of deformation monitoring of soft clay highways. The estimated rheological parameters can be provided as a reference index for the interpretation of long-term highway deformation and the stability control of subgrade construction engineering.

MSNCs and MgO-MSNCs as drug delivery systems to control the adsorption kinetics and release rate of indometacin.

Mesoporous silica cocoon materials (MSNCs) and MgO doped mesoporous silica cocoons (MgO-MSNCs) with the cocoon-like hierarchical morphology and different alkalinities were synthesized as carriers for acidic drugs. Indomethacin (IMC) was selected as a model drug and loaded into carriers. All materials and the drug-loaded samples were characterized by nitrogen adsorption, FTIR spectroscopy, transmission electron microscopy (TEM), powder X-Ray diffraction (XRD) and differential scanning calorimetry (DSC). The effect of the Mg/Si molar ratio on the kinetics and equilibrium of IMC adsorption on MgO-MSNCs was thoroughly examined, and it was found that the increase in the Mg/Si molar ratio resulted in an increasing IMC adsorption rate due to the increased affinity between alkaline MgO-MSNCs and weak acid IMC. The adsorption kinetics fitted a pseudo second-order model well. The Freundlich isotherm showed a better fit, indicating that the coverage of IMC on the surface of MgO-MSNCs was heterogeneous. The maximum adsorption capacity of adsorbent was calculated by the Langmuir isotherm equation. The Temkin equation provided further support that the IMC adsorption on MgO-MSNCs was dominated by a chemisorption process. MgO-MSNCs also have the advantage of allowing an adjustment of the drug release rate of weak acid drug. The cytotoxicity assay indicated good biocompatibility of MgO-MSNCs. Our research on MgO-MSNCs carriers demonstrated their potential therapeutic benefit for safe and effective management of IMC adsorption and in vitro release.