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MicroRNA-495 downregulates AQP1 and facilitates proliferation and differentiation of osteoblasts in mice with tibial fracture through activation of p38 MAPK signaling pathway

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Osteoblasts are implicated in the building of the vertebrate skeleton. The current study aimed to investigate the role of microRNA-495 (miR-495) in the osteoblasts of mice with tibial fractures and the underlying mechanism involving in aquaporin-1 (AQP1) and the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Initially, a microarray-based analysis was performed to screen the differentially expressed genes and miRNAs associated with tibial fracture. Following the establishment of a tibial fracture mouse model, the positive rate of the AQP1 protein in the fracture tissue was detected by immunohistochemistry (IHC). Next, to verify the binding site between miR-495 on AQP1, bioinformatics data were employed in addition to the application of a dual-luciferase reporter gene assay. The osteoblast cell line MC3T3-E1 was treated with miR-495 mimic, miR-495 inhibitor and Anisomycin to explore the potent effects of miR-495 on proliferation and differentiation of osteoblasts in mice with tibial fracture. The expression of miR-495, AQP1, p38 MAPK, PCNA, Cyclin D1, OCN, and OPN was subsequently evaluated by RT-qPCR and Western blot analysis. Cell viability, the number of calcium nodules and alkaline phosphatase (ALP) activity were detected by MTT assay, alizarin red staining, and ALP activity assay, respectively. Our results revealed that miR-495 was down-regulated while AQP1 was up-regulated in the mice with tibial fractures. AQP1 was verified as a target gene of miR-495. When the cells were treated with overexpressed miR-495 or activated p38 MAPK signaling pathway, elevated expression of PCNA, Cyclin, D1, OCN, and OPN along with an increased amount of calcium nodules, higher cell viability, and enhanced ALP activity was detected, while the expression of AQP1 was reduced. Collectively, the key findings of the present study support the notion that overexpressed miR-495 may activate the p38 MAPK signaling pathway to inhibit AQP1 and to promote the proliferation and differentiation of osteoblasts in mice with tibial fracture.

IF:4.01

Gut Microbiota-Mediated Drug-Drug Interaction between Amoxicillin and Aspirin

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

The effects of antibiotics on the intestinal flora can create potential drug-drug interactions. The combination of amoxicillin and aspirin is high and there is a high probability of interaction. We used 16S rRNA, incubation experiments and liquid chromatography-tandem mass spectrometry to analyze rat biological samples to characterize the effect of amoxicillin on the pharmacokinetics of aspirin metabolites. We first discovered that amoxicillin reduced the species and number of intestinal flora in rats, such as reducing the abundance of Helicobacter pylori and Prevotella_copri. After 12, 24, and 36 hours of incubation, the remaining amount of aspirin in the aspirin and amoxicillin treatment groups decreased, and salicylic acid production increased, suggesting that aspirin is metabolized by the intestinal flora, and the main metabolite is salicylic acid. As the incubation time prolonged, the reduction of aspirin and the production of salicylic acid in the amoxicillin treatment group were slower. It is indicated that the metabolic activity of aspirin through the intestinal flora is slowed down after administration of amoxicillin. The pharmacokinetic experiments showed that after administration of amoxicillin, the area under the salicylic acid curve increased by 91.38%, the peak concentration increased by 60.43%, and the clearance rate decreased by 43.55%.The results demonstrated that amoxicillin affected the pharmacokinetics of aspirin active metabolite salicylic acid by slowing down the metabolic activity of intestinal flora on aspirin. The interaction between amoxicillin and aspirin mediated by the intestinal flora may affect the efficacy of aspirin and cause more significant adverse effects.

IF:4.01

The integration of metabolome and proteome reveals bioactive polyphenols and hispidin in ARTP mutagenized Phellinus baumii

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Phellinus baumii, also called "Sang Huang" in China, is broadly used as a kind of health food or folk medicine in Asia for its high biological activities, e.g. anti-tumor, anti-oxidation and anti-inflammatory activities. Although some previous studies have indicated that polysaccharides and flavonoids showed the activity of inhibiting tumor cells, the active metabolites of P. baumii needs further research. In our study, a stable P. baumii mutant (A67), generated by ARTP mutagenesis strategy, showed more significantly inhibiting tumor cells and enhancing antioxidant activity. Our further studies found that the increase of polyphenols content, especially hispidin, was an important reason of the biological activity enhancement of A67. According to the results of the integrated metabolome and proteome study, the increase of polyphenol content was caused by upregulation of the phenylpropanoid biosynthesis. This study expanded the understanding of active compounds and metabolic pathway of P. baumii.

IF:4.01

Recombinant B2L and Kisspeptin-54 DNA Vaccine Induces Immunity Against Orf Virus and Inhibits Spermatogenesis In Rats

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Orf is a highly contagious zoonotic disease of small ruminants caused by Parapoxvirus. Kisspeptin, encoded by the KISS1 gene with its cognate receptor GPR-54 is recognized as an upstream orchestrator in the hypothalamic-pituitary-gonadal axis. This study was designed to construct a DNA vaccine that produces a fused peptide composed of a major immunodominant protein of the orf virus (B2L) and kisspeptin-54, a neuropeptide with recognized roles in mammalian reproductive biology. The administration of this recombinant vaccine is shown to produce a significant antibody and cell-mediated immune response directed against B2L compared to the control group (p < 0.05). Furthermore, we found that rats inoculated with PBK-asd vaccine up-regulated antigen-mediated splenocyte proliferation and significantly raised antigen-specific tumor necrosis factor-alpha (TNF alpha-), interferongamma (IFN-gamma) and interleukin (IL-2) compared to the control group (p < 0.05). This recombinant vaccine also stimulated antibody responses to kisspeptin and decreased serum luteinizing hormone and testosterone levels. Moreover, the current recombinant vaccine caused testicular atrophy and arrested spermatogenesis. It is concluded that this recombinant B2L and Kisspeptin-54 vaccine could be a promising approach for construction of bivalent orf virus and immunocastration vaccine. Furthermore, we concluded that the orf virus envelope protein (B2L) could be used as an immunomodulator for kisspeptin-54 to produce a strong antibody response.

IF:4.01

Seasonal variation of idiopathic benign paroxysmal positional vertigo correlates with serum 25-hydroxyvitamin D levels: a six-year registry study in Shanghai, China

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Seasonal variation of benign paroxysmal positional vertigo (BPPV) occurrence has been reported in recent years. Whether the seasonality of BPPV also exists in Chinese patients and whether it correlates with serum vitamin D levels is unexplored. We retrospectively analyzed the data of 1269 new-onset idiopathic BPPV patients registered in our vertigo outpatient clinic over a six-year period. Additionally, serum 25-hydroxyvitamin D levels during this period were measured in 877 patients by chemiluminescence immunoassay. We delineated the changing trend of the monthly BPPV patient numbers and serum 25-hydroxyvitamin D levels, and the correlation between them was explored. December to next March is the top 4 months with higher BPPV patient numbers. The median BPPV patient numbers in winter group were higher than those in summer group (20 vs. 16 patients, p < 0.05). Median 25-hydroxyvitamin D levels in winter group were much lower than those in summer group (16.3 vs. 20.8 ng/ml, p < 0.001) and autumn group (16.3 vs. 19.3 ng/ml, p < 0.05). A moderate negative correlation was observed between median serum 25-hydroxyvitamin D levels and BPPV patient numbers each month. The onset of BPPV also shows a seasonal fluctuation in Chinese patients. This phenomenon may be related to serum vitamin D levels.

IF:4.01

LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Ferroptosis is a non-apoptotic, iron-dependent oxidative form of cell death that is specifically induced by erastin in RAS mutant cancer cells. Ferroptotic cell death is the result of membrane lipid peroxide damage caused by the accumulation of hydroxyl radicals derived from H2O2 by the Fenton reaction. Peroxidases are key cellular antioxidant enzymes that block such damaging processes. Few studies have examined the roles of long non-coding RNAs (lncRNAs) in the regulation of cellular oxidative stress, especially in ferroptosis. Here, we demonstrated that erastin upregulated the lncRNA GABPB1-AS1, which downregulated GABPB1 protein levels by blocking GABPB1 translation, leading to the downregulation of the gene encoding Peroxiredoxin-5 (PRDX5) peroxidase and the eventual suppression of the cellular antioxidant capacity. Such effects critically inhibited the cellular antioxidant capacity and cell viability. Additionally, high expression levels of GABPB1 were correlated with poor prognosis of hepatocellular carcinoma (HCC) Patients, while high GABPB1-AS1 levels in HCC patients correlated with improved overall survival. Collectively, these data demonstrate a mechanistic link between GABPB1 and its antisense lncRNA GABPB1-AS1 in erastin-induced ferroptosis and establish GABPB1 and GABPB1-AS1 as attractive therapeutic targets for HCC.

IF:4.01

Preferential Paths of Air-water Two-phase Flow in Porous Structures with Special Consideration of Channel Thickness Effects

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Accurate understanding and predicting the flow paths of immiscible two-phase flow in rocky porous structures are of critical importance for the evaluation of oil or gas recovery and prediction of rock slides caused by gas-liquid flow. A 2D phase field model was established for compressible air-water two-phase flow in heterogenous porous structures. The dynamic characteristics of air-water two-phase interface and preferential paths in porous structures were simulated. The factors affecting the path selection of two-phase flow in porous structures were analyzed. Transparent physical models of complex porous structures were prepared using 3D printing technology. Tracer dye was used to visually observe the flow characteristics and path selection in air-water two-phase displacement experiments. The experimental observations agree with the numerical results used to validate the accuracy of phase field model. The effects of channel thickness on the air-water two-phase flow behavior and paths in porous structures were also analyzed. The results indicate that thick channels can induce secondary air flow paths due to the increase in flow resistance; consequently, the flow distribution is different from that in narrow channels. This study provides a new reference for quantitatively analyzing multi-phase flow and predicting the preferential paths of immiscible fluids in porous structures.

IF:4.01

Recent Lake Area Changes in Central Asia

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Using Moderate Resolution Imaging Spectroradiometer (MODIS) 500 m spatial resolution global water product data, Least Squares Method (LSM) was applied to analyze changes in the area of 14 lakes in Central Asia from 2001 to 2016. Interannual changes in lake area, along with seasonal change trends and influencing factors, were studied for the months of April, July and September. The results showed that the total lakes area differed according to interannual variations and was largest in April and smallest in September, measuring -684.9 km(2)/a, -870.6 km(2)/a and -827.5 km(2)/a for April, July and September, respectively. The change rates for the total area of alpine lakes during the same three months were 31.1 km(2)/a, 29.8 km(2)/a and 30.6 km(2)/a, respectively, while for lakes situated on plains, the change rates were -716.1 km(2)/a, -900.5 km(2)/a, and -858 km(2)/a, respectively. Overall, plains lakes showed a declining trend and alpine lakes showed an expanding trend, the latter likely due to the warmer and wetter climate. Furthermore, there was a high correlation (r = 0.92) between area changes rate of all alpine lakes and the lakes basin supply coefficient, although there was low correlation (r = 0.43) between area changes rate of all alpine lakes area and glacier area/lake area. This indicates that lakes recharge via precipitation may be greater than lakes recharge via glacier meltwater. The shrinking of area changes for all plains lakes in the study region was attributable to climate change and human activities.

IF:4.01

A New Chloroplast DNA Extraction Protocol Significantly Improves the Chloroplast Genome Sequence Quality of Foxtail Millet (Setaria italica (L.) P. Beauv.)

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

The complexity of the leaf constitution of foxtail millet (Setaria italica (L.) P. Beauv.) makes it difficult to obtain high-purity cpDNA. Here, we developed a protocol to isolate high-quality cpDNA from foxtail millet and other crops. The new protocol replaces previous tissue grinding and homogenization by enzyme digestion of tiny leaf strips to separate protoplasts from leaf tissue and protects chloroplasts from damage by undue grinding and homogenization and from contamination of cell debris and nuclear DNA. Using the new protocol, we successfully isolated high-quality cpDNAs for whole-genome sequencing from four foxtail millet cultivars, and comparative analysis revealed that they were approximately 27 parts per thousand longer than their reference genome. In addition, six cpDNAs of four other species with narrow and thin leaf blades, including wheat (Triticum aestivum L.), maize (Zea may L.), rice (Oryza sativa L.) and sorghum (Sorghum bicolor (L.) Moench), were also isolated by our new protocol, and they all exhibited high sequence identities to their corresponding reference genomes. A maximum-likelihood tree based on the chloroplast genomes we sequenced here was constructed, and the result was in agreement with previous reports, confirming that these cpDNA sequences were available for well-supported phylogenetic analysis and could provide valuable resources for future research.

IF:4.01

Active control on switchable waveguide of elastic wave metamaterials with the 3D printing technology

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Propagation of elastic waves along a direction has special interests in practical applications. These concerns generate the design of an elastic wave metamaterial with electrically switchable properties, which is studied in this work. The structure contains a T-shaped waveguide in a plate with the 3D printing technology; and the active control system is used to tune the propagation direction of the flexural wave. The piezoelectric patches which are connected by the negative capacitance circuits are applied to behave as the active control system. The finite element simulation is performed to give the theoretical prediction of the switchable waveguide and the tunable equivalent parameters are achieved by the electrical circuits. The active control experiments are finally carried out to support the numerical design.

IF:4.01

Two-dimensional Peripheral Refraction and Retinal Image Quality in Emmetropic Children

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

The relationship between the optical properties of the eye in the periphery and myopia development is still under debate. To further clarify this issue, we provide here baseline data of two-dimensional peripheral optics results in a group of emmetropic Chinese children. Peripheral aberrations were measured under cycloplegia by using an open-view Hartmann-Shack wavefront sensor (VPR, Voptica SL, Spain). This instrument allows to measure fast in the horizontal visual field from temporal 30 degrees to nasal 30 degrees every 1 degrees. Two-dimensional (2D) maps were retrieved from a series of horizonal scans taken every 4 degrees from 20 degrees superior to 16 degrees inferior covering a visual field of 60 x 36 degrees. A relatively homogeneous pattern of the 2D relative peripheral refraction was found across all these emmetropic subjects. Using cluster analysis followed by manual visual refinement, the 2D maps were identified to fit into four categories. More than 70% of the subjects showed a nearly flat horizontal refraction with a slightly myopic shift in the superior retina. Peripheral astigmatism was quite constant across subjects and similar to that expected theoretically. Peripheral aberrations were also similar to those in the fovea for a large retinal area. These baseline data would offer an important reference to compare with the future evolution with time, as well as with other refractive or age groups of subjects, to better understand the role of peripheral optical properties in myopia development.

IF:4.01

Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Angiotensin II type-1 receptor-neprilysin inhibitor (ARNi) is consisted of Angiotensin II type-1 receptor (AT1) antagonist and neprilysin (NEP) inhibitor, which could simultaneously increase the vasodilators of the natriuretic peptides and antagonize vasoconstrictors of Ang II. ARNi has been proved a superior effect and lower risks of death on chronic heart failure (CHF) and hypertension. In this paper, ARNi from Traditional Chinese Medicines (TCM) was discovered based on target combination of AT1 and NEP by virtual screening, biological assay and molecular dynamics (MD) simulations. Two customized strategies of combinatorial virtual screening were implemented to discover AT1 antagonist and NEP inhibitor based on pharmacophore modeling and docking computation respectively. Gyrophoric acid (PubChem CID: 135728) from Parmelia saxatilis was selected as AT1 antagonist and assayed with IC50 of 29.76 mu M by calcium influx assay. And 3,5,3'-triiodothyronine (PubChem CID: 861) from Bos taurus domesticus was screened as NEP inhibitor and has a dose dependent inhibitory activity by biochemistry fluorescence assay. Combined with MD simulations, these compounds can generate interaction with the target, key interactive residues of ARG167, TRP84, and VAL108 in AT1, and HIS711 in NEP were also identified respectively. This study designs the combinatorial strategy to discover novel frames of ARNi from TCM, and gyrophoric acid and 3,5,3'-triiodothyronine could provide the clues and revelations of drug design and therapeutic method of CHF and hypertension for TCM clinical applications.

IF:4.01

Characterization and Identification of Lysine Succinylation Sites based on Deep Learning Method

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Succinylation is a type of protein post-translational modification (PTM), which can play important roles in a variety of cellular processes. Due to an increasing number of site-specific succinylated peptides obtained from high-throughput mass spectrometry (MS), various tools have been developed for computationally identifying succinylated sites on proteins. However, most of these tools predict succinylation sites based on traditional machine learning methods. Hence, this work aimed to carry out the succinylation site prediction based on a deep learning model. The abundance of MS-verified succinylated peptides enabled the investigation of substrate site specificity of succinylation sites through sequence-based attributes, such as position-specific amino acid composition, the composition of k-spaced amino acid pairs (CKSAAP), and position-specific scoring matrix (PSSM). Additionally, the maximal dependence decomposition (MDD) was adopted to detect the substrate signatures of lysine succinylation sites by dividing all succinylated sequences into several groups with conserved substrate motifs. According to the results of ten-fold cross-validation, the deep learning model trained using PSSM and informative CKSAAP attributes can reach the best predictive performance and also perform better than traditional machine-learning methods. Moreover, an independent testing dataset that truly did not exist in the training dataset was used to compare the proposed method with six existing prediction tools. The testing dataset comprised of 218 positive and 2621 negative instances, and the proposed model could yield a promising performance with 84.40% sensitivity, 86.99% specificity, 86.79% accuracy, and an MCC value of 0.489.

IF:4.01

Relationship between left ventricular isovolumic relaxation flow patterns and mitral inflow patterns studied by using vector flow mapping

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

The purpose of this study was to investigate the relationship between isovolumic relaxation flow (IRF) patterns in left ventricle (LV) and mitral inflow patterns. Color Doppler loops were acquired for vector flow mapping in apical long-axis view in 57 patients with coronary artery disease, 31 patients with dilated cardiomyopathy, and 58 healthy controls. IRF patterns were classified into three categories: pattern A, apically directed flow; pattern B, bidirectional flow with small scattered vortices; and pattern C, a large vortex. All normals and patients with normal LV filling (n = 10) showed pattern A. Patients with impaired relaxation consisted of 31 (66%) patients having pattern A, 11 (23%) having pattern B, and 5 (11%) having pattern C. Patients with pseudonormal filling included 4 (31%) patients having pattern A, 7 (54%) having pattern B, and 2 (15%) having pattern C. In patients with restrictive filling, 14 (78%) showed pattern C, 4 (22%) showed pattern B, and no patient showed pattern A. IRF patterns were associated with LV filling patterns (chi(2) = 52.026, p < 0.001). There are significant relationships between LV filling and IRF patterns. IRF patterns may provide an index for evaluation of LV diastolic function.

IF:4.01

Neural correlates of theory of mind in typically-developing youth: Influence of sex, age and callous-unemotional traits

期刊: SCIENTIFIC REPORTS, 2019; 9 ()

Theory of mind (ToM), or the ability to infer and predict the intentions, thoughts and beliefs of others, involves cognitive perspective taking (cognitive ToM/cToM) and understanding emotions (affective ToM/aToM). While behavioral evidence indicates that ToM is influenced by sex and age, no study has examined the influence of these variables on the neural correlates of cToM and aToM in late childhood/adolescence. Using fMRI with 35 typically-developing youths (aged 9-18 years, 12 males), we investigated the influence of sex and age on the neural correlates of cToM and aToM. We also examined how callous-unemotional traits, indexing a lack of empathy, were related to brain responses during aToM. Across both conditions, we found convergent activity in ToM network regions, such as superior temporal sulcus/temporoparietal junction (TPJ) and precuneus across males and females, but males recruited the left TPJ significantly more than females during cToM. During aToM, age was negatively correlated with brain responses in frontal, temporal and posterior midline regions, while callous-unemotional traits were positively correlated with right anterior insula responses. These results provide the first evidence in youth that sex influences the neural correlates of cToM, while age and callous-unemotional traits are specifically related to brain responses during aToM.

IF:4.01

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