Piezo channels in the urinary system

The Piezo channel family, including Piezo1 and Piezo2, includes essential mechanosensitive transduction molecules in mammals. Functioning in the conversion of mechanical signals to biological signals to regulate a plethora of physiological processes, Piezo channels, which have a unique homotrimeric three-blade propeller-shaped structure, utilize a cap-motion and plug-and-latch mechanism to gate their ion-conducting pathways. Piezo channels have a wide range of biological roles in various human systems, both in vitro and in vivo. Currently, there is a lack of comprehensive understanding of their antagonists and agonists, and therefore further investigation is needed. Remarkably, increasingly compelling evidence demonstrates that Piezo channel function in the urinary system is important. This review article systematically summarizes the existing evidence of the importance of Piezo channels, including protein structure, mechanogating mechanisms, and pharmacological characteristics, with a particular focus on their physiological and pathophysiological roles in the urinary system. Collectively, this review aims to provide a direction for future clinical applications in urinary system diseases.Subject terms: Bladder disease, Bladder cancer, Prostate cancer, Oncogenesis     

Anisotropic Superconducting Properties of Kagome Metal CsV_3Sb_5

We systematically measure the superconducting(SC) and mixed state properties of high-quality CsV_3 Sb_5 single crystals with T_c～3.5 K.We find that the upper critical field H_(c2)(T) exhibits a large anisotropic ratio of H_(c2)~(ab)/H_(c2)~c～9 at zero temperature and fitting its temperature dependence requires a minimum two-band effective model.Moreover,the ratio of the lower critical field,H_(c1)~(ab)/H_(c1)~c,is also found to be larger than 1,which indicates that the in-plane energy dispersion is strongly renormalized near Fermi energy.Both H_(c1)(T) and SC diamagnetic signal are found to change little initially below T_c～3.5 K and then to increase abruptly upon cooling to a characteristic temperature of ～2.8 K.Furthermore,we identify a two-fold anisotropy of in-plane angular-dependent magnetoresistance in the mixed state.Interestingly,we find that,below the same characteristic T～2.8 K,the orientation of this two-fold anisotropy displays a peculiar twist by an angle of 60° characteristic of the Kagome geometry.Our results suggest an intriguing superconducting state emerging in the complex environment of Kagome lattice,which,at least,is partially driven by electron-electron correlation.     

In Vitro and In Vivo Antibacterial Activity,Toxicity and Resistance Analysis of Pleuromutilin Derivative Z33 against Methicillin-Resistant Staphylococcus aureus

The novel pleuromutilin derivative, which showed excellent in vitro antibacterial activity against MRSA, 22-(2-(2-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamido)phenyl)thioacety-l-yl-22-deoxypleuromutilin (Z33), was synthesized and characterized in our previous work. In this study, the preliminary pharmacodynamics and safety of Z33 were further evaluated. In in vitro antibacterial activity assays, Z33 was found to be a potent bactericidal antibiotic against MRSA that induced dose-dependent growth inhibition and long-term post-antibiotic effect (PAE). The drug-resistance test demonstrated that Z33 possessed a narrow mutant selection window and lower propensities to select resistance than that of tiamulin. Cytochrome P450 (CYP450) inhibition assay determined that the inhibitory effect of Z33 was similar to that of tiamulin against the activity of CYP3A4, and was lower than that of tiamulin on the activity of CYP2E1. Toxicity determination showed that both Z33 and tiamulin displayed low cytotoxicity of RAW264.7 cells. Furthermore, Z33 was found to be a high-security compound with a 50% lethal dose (LD₅₀) above 5000 mg/kg in the acute oral toxicity test in mice. In an in vivo antibacterial activity test, Z33 displayed better therapeutic effectiveness than tiamulin in the neutropenic mouse thigh infection model. In summary, Z33 was worthy of further development as a highly effective and safe antibiotic agent against MRSA infection.     

An Exploration of the Effect of the Kleier Model and Carrier-Mediated Theory to Design Phloem-Mobile Pesticides Based on Researching the N-Alkylated Derivatives of Phenazine-1-Carboxylic Acid-Glycine

The Kleier model and Carrier-mediated theory are effective for molecularly designing pesticides with phloem mobility. However, the single Kleier model or Carrier-mediated theory cannot achieve a reliable explanation of the phloem mobility of all exogenous substances. A detailed investigation of the two models and the scope of their applications can provide a more accurate and highly efficient basis for the guidance of the design and development of phloem-mobile pesticides. In the present paper, a strategy using active ingredient-amino acid conjugates as mode compounds is developed based on Carrier-mediated theory. An N-alkylated amino acid is used to improve the pesticide’s physicochemical properties following the Kleier model, thus allowing the conjugates to fall on the predicted and more accessible transportation region of phloem. Moreover, the influence of this movement on phloem is inspected by the Kleier model and Carrier-mediated theory. To verify this strategy, a series of N-alkylated phenazine-1-carboxylic acid-glycine compounds (PCA-Gly) were designed and synthesized. The results related to the castor bean seeds (R. communis L.) indicated that all the target compounds (4a–4f) had phloem mobility. The capacity for phloem mobility shows that N-alkylated glycine containing small substituents can significantly improve PCA phloem mobility, such as 4c(i-C₃H₇-N) > 4a(CH₃-N) ≈ 4b(C₂H₅-N) > 4d (t-C₄H₉-N) > PCA-Gly > 4e(C₆H₅-N) > 4f(CH₂COOH-N), with an oil–water partition coefficient between 1.2~2.5. In particular, compounds 4a(CH₃-N), 4b(C₂H₅-N), and 4c(i-C₃H₇-N) present better phloem mobility, with the average concentrations in phloem sap of 14.62 μΜ, 13.98 μΜ, and 17.63 μΜ in the first 5 h, which are 8 to 10 times higher than PCA-Gly (1.71 μΜ). The results reveal that the Kleier model and Carrier-mediated theory play a guiding role in the design of phloem-mobile pesticides. However, the single Kleier model or Carrier-mediated theory are not entirely accurate. Still, there is a synergism between Carrier-mediated theory and the Kleier model for promoting the phloem transport of exogenous compounds. Therefore, we suggest the introduction of endogenous plant compounds as a promoiety to improve the phloem mobility of pesticides through Carrier-mediated theory. It is necessary to consider the improvement of physicochemical properties according to the Kleier model, which can contribute to a scientific theory for developing phloem-mobile pesticides.     

基于双混沌置乱和扩频调制的彩色图像盲水印算法

提出了一种新的适应彩色图像的盲水印算法,先对宿主图像的绿色分量以8×8像素分块进行离散余弦变换(DCT)变换,用logistic映射生成两个混沌序列,然后用混沌序列置乱加密二值水印图像,并用两个互不相关的伪随机序列扩频调制水印,最后将调制好的水印嵌入到DCT变换域的中频子带系数上,进行分块DCT反变换得到水印化图像.提取水印时,通过比较两个伪随机序列和水印化图像的相关性大小来提取水印,不需要原始图像的参与,为盲提取水印算法.实验结果证明本文算法能有效地抵抗JPEG压缩、加噪、剪切等常见攻击,绿色分量嵌入水印比红色和蓝色分量嵌入水印能更好地抵抗JPEG压缩的攻击.     

碱金属氟化物对掺Yb3+氟磷酸盐玻璃析晶稳定性和光谱性质的影响

研究了碱金属氟化物对掺Yb3 氟磷玻璃的光谱性质和析晶稳定性能的影响.运用倒易法计算了Yb3 的发射截面.结果显示,LiF的引入对吸收和发射截面的提高作用较大并出现最佳引入量极值,其次为KF.碱金属氟化物的引入可提高二元体系的析晶稳定性能,使玻璃网络结构得到改善;拉曼光谱显示二元体系中引入YbF<,3>后玻璃网络结构得到增强,而在引入碱金属氟化物的三元体系中掺杂YbF<,3>后破坏了网络完整性,降低系统析晶稳定性能.     

Cardiac-specific overexpression of Ndufs1 ameliorates cardiac dysfunction after myocardial infarction by alleviating mitochondrial dysfunction and apoptosis

Myocardial infarction (MI) is the leading cause of premature death among adults. Cardiomyocyte death and dysfunction of the remaining viable cardiomyocytes are the main pathological factors of heart failure after MI. Mitochondrial complexes are emerging as critical mediators for the regulation of cardiomyocyte function. However, the precise roles of mitochondrial complex subunits in heart failure after MI remain unclear. Here, we show that NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) expression is decreased in the hearts of heart failure patients and mice with myocardial infarction. Furthermore, we found that cardiac-specific Ndufs1 overexpression alleviates cardiac dysfunction and myocardial fibrosis in the healing phase of MI. Our results demonstrated that Ndufs1 overexpression alleviates MI/hypoxia-induced ROS production and ROS-related apoptosis. Moreover, upregulation of Ndufs1 expression improved the reduced activity of complex I and impaired mitochondrial respiratory function caused by MI/hypoxia. Given that mitochondrial function and cardiomyocyte apoptosis are closely related to heart failure after MI, the results of this study suggest that targeting Ndufs1 may be a potential therapeutic strategy to improve cardiac function in patients with heart failure.Subject terms: Heart failure, Myocardial infarction, Myocardial infarction     

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

Chlorogenic acid (CGA), an important metabolite in natural plant medicines such as honeysuckle and eucommia, has been shown to have potent antinociceptive effects. Nevertheless, the mechanism by which CGA relieves chronic pain remains unclear. α-amino-3-hydroxy-5-methyl-4-isooxazolpropionic acid receptor (AMPAR) is a major ionotropic glutamate receptor that mediates rapid excitatory synaptic transmission and its glutamate ionotropic receptor AMPA type subunit 1 (GluA1) plays a key role in nociceptive transmission. In this study, we used Western blot, surface plasmon resonance (SPR) assay, and the molecular simulation technologies to investigate the mechanism of interaction between CGA and AMPAR to relieve chronic pain. Our results indicate that the protein expression level of GluA1 showed a dependent decrease as the concentration of CGA increased (0, 50, 100, and 200 μM). The SPR assay demonstrates that CGA can directly bind to GluA1 (K_D = 496 μM). Furthermore, CGA forms a stable binding interaction with GluA1, which is validated by molecular dynamics (MD) simulation. The binding free energy between CGA and GluA1 is −39.803 ± 14.772 kJ/mol, where van der Waals interaction and electrostatic interaction are the major contributors to the GluA1–CGA binding, and the key residues are identified (Val-32, Glu-33, Ala-36, Glu-37, Leu-48), which play a crucial role in the binding interaction. This study first reveals the structural basis of the stable interaction between CGA and GluA1 to form a binding complex for the relief of chronic pain. The research provides the structural basis to understand the treatment of chronic pain and is valuable to the design of novel drug molecules in the future.     

双间隙输出腔开放腔的高频特性分析

 建立了S波段相对论速调管放大器双间隙输出腔开放腔的3维模型。采用时域有限差分法,通过监测激励电流源的响应计算了该双间隙输出腔的谐振频率、有载Q值、场分布以及特性阻抗,并分析了腔体结构尺寸对谐振频率、有载Q值和特性阻抗的影响。研究表明：腔体半径对开放腔的谐振频率影响很大,耦合孔尺寸对腔体谐振频率的影响较小;随着耦合孔张角增加,有载Q值逐渐减小;随着腔体半径增大、间隙的减小,腔体特性阻抗降低。研究结果可为S波段强流相对论速调管放大器双间隙输出腔的设计提供理论依据。     

Transition-metal-free synthesis of 1,4-benzoxazepines via [4+3]-cycloaddition of para-quinone methides with azaoxyallyl cations

A formal[4+3]-cycloaddition reaction of ortho-hydroxyphenyl-substituted para-quinone methides(p-QMs)with in-situ generated azaoxyallyl cations is reported.The reaction occurs under very mild reaction conditions(transition-metal free,room temperature,cheap inorganic base)and provides a very efficient route to a series of biologically important 1,4-benzoxazepine derivatives in good to excellent yields.