Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types

Analysis of Fracture Behaviour of Exploded Metal Cylinders with Varied Charge

Explosively driven fragmentation of ductile metals cylinders is a highly complex phenomenon. In this work, the fracture characteristics of exploded TA2 titanium alloy cylinder with varied charge were investigated numerically and experimentally. The results show that the fracture surfaces of fragments lie along planes of maximum shear stress for either a higher or a lower detonation pressure, but their mechanism is different. The finite element analysis demonstrated that the equivalent plastic strain in the middle of the wall is always larger than that of inner and outer wall for metal cylinder during the stage of shock wave driven period. For the high explosive pressures, the micro-cracks originated firstly in middle zone of wall during the stage of shock wave driven, and extend to the inner and outer wall in the direction of maximum shear stress. Explosives which generate lower detonation pressures, the shear fracture of cylinder originated from the inner wall and propagate to the outer wall in an angle of 45° or 135° to radial, the crack begin at the stage of free expansion. The simulated analysis of the process of deformation and fragmentation for exploded metal cylinder agree with the experimental results

Analysis of Fracture Behaviour of Exploded Metal Cylinders with Varied Charge

Explosively driven fragmentation of ductile metals cylinders is a highly complex phenomenon. In this work, the fracture characteristics of exploded TA2 titanium alloy cylinder with varied charge were investigated numerically and experimentally. The results show that the fracture surfaces of fragments lie along planes of maximum shear stress for either a higher or a lower detonation pressure, but their mechanism is different. The finite element analysis demonstrated that the equivalent plastic strain in the middle of the wall is always larger than that of inner and outer wall for metal cylinder during the stage of shock wave driven period. For the high explosive pressures, the micro-cracks originated firstly in middle zone of wall during the stage of shock wave driven, and extend to the inner and outer wall in the direction of maximum shear stress. Explosives which generate lower detonation pressures, the shear fracture of cylinder originated from the inner wall and propagate to the outer wall in an angle of 45° or 135° to radial, the crack begin at the stage of free expansion. The simulated analysis of the process of deformation and fragmentation for exploded metal cylinder agree with the experimental results

First case report of PLA2R-related monotypic (IgG-κ positive) membranous nephropathy concurrent with leukocyte chemotactic factor 2 amyloidosis

Abstract Background Membranous nephropathy (MN) is a major pattern of nephrotic syndrome (NS) in adults. Some MN have secondary causes and some may be accompanied with other glomerular diseases. MN patients coexisting with amyloidosis are very rare, and mostly was polytypic MN. Herein, we describe the first report which identifying monotype PLA2R-MN (κ light chain) concurrent with leukocyte chemotactic factor 2 amyloidosis (ALECT2). This rare case highlights the importance of renal pathology for diagnosis. Case presentation We describe a case of a 60-year-old male patient with persistent proteinuria and low serum albumin for nine months. No monoclonal component was revealed by serum and urine immunofixation electrophoresis but serum PLA2R antibody was positive. The patient was empirically treated with Leflunomide and Losartan, but edema was not improved. The diagnosis of renal pathology is PLA2R-related monotypic (IgG-κ positive) MN concurrent with ALECT2. Methylprednisolone, cyclosporine A and anticoagulant (rivaroxaban) were prescribed resulting in a complete remission of NS. Conclusions MN patients concurrent with ALECT2 presented massive proteinuria or NS. When nephrotic range proteinuria is present in ALECT2, it is important to consider that it may be due to a concomitant underlying nephropathy especially MN and treated according to MN will get good therapeutic effect

Hong-Hui-Xiang Alleviates Pain Hypersensitivity in a Mouse Model of Monoarthritis

Background. Hong-Hui-Xiang (HHX) is a sterilized aqueous solution extracted from Illicium lanceolatum A.C. Smith widely used for pain relief in China. Despite its history, it is not well understood. In the present study, we used a mouse model of arthritic knee pain to investigate the antinociceptive effects of HHX and its potential side effects on weight and respiratory function, as well as on the liver, kidney, and heart. Methods. Mice were randomly assigned to four groups: saline and HHX at three doses (1 μl, 10 μl, and 50 μl). Each group was randomly divided to two subgroups: saline and CFA. After the first injection of HHX or saline on day 7, mechanical hyperalgesia was tested via the hind paw. Only after the tests had established that the analgesic effect had subsided was the next injection administered. A total of five injections were administered. Blood, knee joints, and other organs were collected for histopathological observation and biochemical detection. Objectives. We found that mechanical threshold of hind paw increased 2 h after of the initial injection HHX (10 μl and 50 μl), which lasted for at least 3 h. The analgesic effect lasted for three days after the second injection on day 8 and was approximately maintained for five days each time after the third injection. We also found a reduction in the diameter of the knee joint and suppression of synovial inflammation in response to treatment of HHX (10 μl and 50 μl). Meanwhile, HHX had no toxic effects on the liver, kidneys, and heart via histological and biochemical assays in all groups. Conclusion. HHX exerts antinociceptive and anti-inflammatory effects in a mouse model of arthritic knee pain. There were no obvious side effects on the liver, kidneys, or heart

Development of a Room Temperature SAW Methane Gas Sensor Incorporating a Supramolecular Cryptophane A Coating

A new room temperature supra-molecular cryptophane A (CrypA)-coated surface acoustic wave (SAW) sensor for sensing methane gas is presented. The sensor is composed of differential resonator-oscillators, a supra-molecular CrypA coated along the acoustic propagation path, and a frequency signal acquisition module (FSAM). A two-port SAW resonator configuration with low insertion loss, single resonation mode, and high quality factor was designed on a temperature-compensated ST-X quartz substrate, and as the feedback of the differntial oscillators. Prior to development, the coupling of modes (COM) simulation was conducted to predict the device performance. The supramolecular CrypA was synthesized from vanillyl alcohol using a double trimerisation method and deposited onto the SAW propagation path of the sensing resonators via different film deposition methods. Experiential results indicate the CrypA-coated sensor made using a dropping method exhibits higher sensor response compared to the unit prepared by the spinning approach because of the obviously larger surface roughness. Fast response and excellent repeatability were observed in gas sensing experiments, and the estimated detection limit and measured sensitivity are ~0.05% and ~204 Hz/%, respectively

Variation in Leaf Type, Canopy Architecture, and Light and Nitrogen Distribution Characteristics of Two Winter Wheat (Triticum aestivum L.) Varieties with High Nitrogen-Use Efficiency

Studies of traits related to nitrogen (N)-use efficiency (NUE) in wheat cultivars are important for breeding N-efficient cultivars. Canopy structure has a major effect on NUE, as it determines the distribution of light and N. However, the mechanism by which canopy structure affects the distribution of light and N within the canopy remains unclear. The N-efficient winter wheat varieties YM49 and ZM27 and N-inefficient winter wheat varieties XN509 and AK58 were grown in the field under two N levels. Light transmittance was enhanced, and the leaf area index and photosynthetically active radiation were lower in the N-efficient cultivar population, which was characterized by moderately sized flag leaves, a low frequency of canopy leaf curling, a low light attenuation coefficient (KL), and high plant compactness. Reductions in the amount of shade increased the distribution of light and N resources to the middle and lower layers. The photosynthetic rate, transpiration rate, instant water-use efficiency, and canopy photosynthetic NUE were higher, N remobilization of the upper and middle canopy leaves was reduced, and the leaf N content was high in the N-efficient cultivars. A higher ratio of the N extinction coefficient (KN) to KL reflects the assimilation ability of the N-efficient winter wheat cultivars, resulting in improved canopy structure and distribution of light and N, higher 1000-grain weight and grain yield, and significantly increased light and NUE. An improved match between gradients of light and N in the leaf canopy promotes balanced C and N metabolism and reduces energy and nutrient losses. This should be a goal when breeding N-efficient wheat cultivars and implementing tillage regimes

Untargeted Metabolomics Revealed Potential Biomarkers of Small Yellow Follicles of Chickens during Sexual Maturation

Sexual maturation provides economically important traits in poultry production. Research on the initiation mechanism of sexual maturity is of great significance for breeding high-yield laying hens. However, the underlying mechanisms are not fully clear. Here, one hundred and fifty Chahua No. 2 laying hens (the CH2 group, which has precocious puberty) and one hundred and fifty Wu Liang Shan black-bone laying hens (the WLS group, a late-maturing chicken breed) with similar weights and ages were randomly selected. ELISA was used to determine the secretion levels of luteinizing hormone (LH), estradiol (E2), and progesterone (P4) in 150-day-old serum and small yellow follicle (SYF) tissues. A histology examination, immunohistochemistry, and quantitative real-time PCR (qPCR) were used to explore the molecular mechanism of how some genes related to oxidative stress affect sexual maturation. The results showed that the secretion levels of LH, E2, and P4 in the CH2 group serum and SYF were higher than those in the WLS group. The results of the real-time PCR of all genes showed that the expression levels of cytochrome P450 family 11 subfamily A member 1, steroidogenic acute regulatory protein, follicle-stimulating hormone receptor, and cytochrome P450 family 19 subfamily A member 1 in the CH2 group were significantly higher than those in the WLS groups (p < 0.001). Untargeted metabolomics combined with multivariate statistical analysis was used to identify biomarkers of SYF tissues in the CH2 and WLS groups. A trajectory analysis of the principal component analysis (PCA) results showed that the samples within the group were clustered and that the samples were dispersed between the CH2 and the WLS groups, indicating that the results of the measured data were reliable and could be used for further research. Further analysis showed that a total of 319 metabolites in small yellow follicles of the CH2 and WLS groups were identified, among which 54 downregulated differential metabolites were identified. These 54 metabolites were found as potential CH2 biomarkers compared with WLS at 150 days, and the different expressions of L-arginine, L-prolinamide, (R)-4-hydroxymandelate, glutathione, and homovanillic acid were more significant. Twenty metabolic pathways were found when significantly differential metabolites were queried in the KEGG database. According to the impact values of the metabolic pathways, eighteen differential metabolites belonged to the mTOR signaling pathway, glutathione metabolism, ABC transporters, the cell ferroptosis pathway, and D-arginine and D-ornithine metabolism. Interestingly, we identified that the cell ferroptosis pathway played an important role in chicken follicle selection for the first time. The histology and immunohistochemistry of SYF showed that the number of granulosa cells increased in the CH2 groups and the expression levels of glutathione peroxidase 4, tumor protein p53, ribosomal protein S6 kinase, and sterol regulatory element binding protein 1 in the granulosa cell layer were upregulated in the CH2 group at the time of sexual maturation. Furthermore, we also speculated that the antioxidant system may play an indispensable role in regulating sexual maturity in chickens. Overall, our findings suggest differentially expressed metabolites and metabolic pathways between CH2 and WLS chickens, providing new insights into the initiation mechanism of sexual maturation