Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06

The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I₂ receptors (I₂-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I₂-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer’s disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson’s disease (PD). B06 rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I₂-IR as a fresh approach for the therapy of ND.     

SURFACE ROUGHNESS OF SPUTTERED SILICON. II. MODEL VERIFICATION

Experimental verification of the mathematical surface roughness model for sputtered silicon was performed. The beam shape and its significant level of intensity were determined first by measuring the topography of craters sputtered by focused ion beam (FIB). Then the beam function was generated for various combinations of beam parameters. The material function was developed both by theoretical and experimental analysis. These two functions were then used in the model to calculate the theoretical surface roughness. Microsurface analysis was formed by FIB sputtering of a (100) silicon wafer. The surface roughness at the bottom of the sputtered features was then measured using an atomic force microscope. The theoretical surface roughness was found to be within ±1 and ±5 nm of the measured surface roughness with the measurement uncertainty (standard deviation) of about ±0.36 and ±0.85 nm for R_a and R_t, respectively.     

Development and Use of a Kinetical and Real-Time Monitoring System to Analyze the Replication of Hepatitis C Virus

In microbiological research, it is important to understand the time course of each step in a pathogen’s lifecycle and changes in the host cell environment induced by infection. This study is the first to develop a real-time monitoring system that kinetically detects luminescence reporter activity over time without sampling cells or culture supernatants for analyzing the virus replication. Subgenomic replicon experiments with hepatitis C virus (HCV) showed that transient translation and genome replication can be detected separately, with the first peak of translation observed at 3–4 h and replication beginning around 20 h after viral RNA introduction into cells. From the bioluminescence data set measured every 30 min (48 measurements per day), the initial rates of translation and replication were calculated, and their capacity levels were expressed as the sums of the measured signals in each process, which correspond to the areas on the kinetics graphs. The comparison of various HuH-7-derived cell lines showed that the bioluminescence profile differs among cell lines, suggesting that both translation and replication capacities potentially influence differences in HCV susceptibility. The effects of RNA mutations within the 5′ UTR of the replicon on viral translation and replication were further analyzed in the system developed, confirming that mutations to the miR-122 binding sites primarily reduce replication activity rather than translation. The newly developed real-time monitoring system should be applied to the studies of various viruses and contribute to the analysis of transitions and progression of each process of their life cycle.     

基于有限元法的染污直流支柱复合绝缘子伞裙参数优化

直流支柱绝缘子污闪问题比交流支柱绝缘子要严重,通过伞裙优化能够明显改善其污闪特性。该文借鉴人工污秽试验研究伞裙优化的成果,利用有限元法对染污直流支柱绝缘子建模,研究伞间距、大伞伸出和大小伞伸出差对绝缘子沿面电场分布的影响。提出以爬电距离和电场强度作为伞裙参数优化的判断依据,研究表明,电场强度分布随着伞裙参数的变化呈有规律变化：随着伞间距的增加,绝缘子沿面平均电场强度逐渐减小;随着大伞伸出的增加,绝缘子沿面平均电场强度逐渐增大;随大小伞伸出差增加,爬电系数单调减小,沿面平均电场强度呈振荡减小的趋势。通过比较分析得出支柱绝缘子伞裙较优的参数范围,为进行伞裙优化试验研究提出试品伞裙的建议参数。     

基于通用型线的涡旋压缩腔几何模型

根据对应的节线类型把压缩腔分为a、b两类,定义涡旋压缩腔的宽度、长度和法面面积,用解析法建立以型线、压缩腔形状变化、生命周期和压缩腔数综合的涡旋压缩腔几何模型,分析压缩腔的宽度、长度、面积、体积、质心、啮合点的曲率半径等几何特性.研究表明:所建立的几何模型能真实反映压缩腔的形成、变形、破灭等过程,表征涡旋压缩腔的运动特征,可对压缩腔几何特性进行全面分析,是涡旋压缩腔几何学、运动学、动力学、热力学、仿真等研究以及设计的基础;Ⅲ类型线的压缩腔变化过于复杂,Ⅱ类型线的压缩腔变形及动力特性稳定,Ⅰ类型线的压缩腔变形效率高,加工相对容易,因此实践中宜采用以Ⅰ类型线为基础而中心啮合部分为Ⅱ类型线的组合型线.     

工艺参数对马氏体不锈钢激光冲击区表面轮廓的影响

激光功率密度和搭接率对马氏体不锈钢的激光冲击区的表面轮廓有较大影响.激光功率密度从3.79 GW/cm2到7.25 GW/cm2,冲击区塑性变形程度随功率密度增大而增大,当激光功率密度为6.09 GW/cm2时,冲击区塑性变形程度适中,其残余应力平均值达-569.1 MPa.搭接率试验结果表明,搭接率为33%时,可获得较大面积无挤出的激光冲击区,无挤出区域的塑性均匀,变形深度波动幅度在2μm以内,而且此搭接率下冲击区挤出面积较小,分布具有规律,便于再次冲击以降低冲击区的表面波纹度.     

Design and Development of a Bimodal Optical Instrument for Simultaneous Vibrational Spectroscopy Measurements

Vibrational spectroscopy techniques are widely used in analytical chemistry, physics and biology. The most prominent techniques are Raman and Fourier-transform infrared spectroscopy (FTIR). Combining both techniques delivers complementary information of the test sample. We present the design, construction, and calibration of a novel bimodal spectroscopy system featuring both Raman and infrared measurements simultaneously on the same sample without mutual interference. The optomechanical design provides a modular flexible system for solid and liquid samples and different configurations for Raman. As a novel feature, the Raman module can be operated off-axis for optical sectioning. The calibrated system demonstrates high sensitivity, precision, and resolution for simultaneous operation of both techniques and shows excellent calibration curves with coefficients of determination greater than 0.96. We demonstrate the ability to simultaneously measure Raman and infrared spectra of complex biological material using bovine serum albumin. The performance competes with commercial systems; moreover, it presents the additional advantage of simultaneously operating Raman and infrared techniques. To the best of our knowledge, it is the first demonstration of a combined Raman-infrared system that can analyze the same sample volume and obtain optically sectioned Raman signals. Additionally, quantitative comparison of confocality of backscattering micro-Raman and off-axis Raman was performed for the first time.     

Determination of IgG1 and IgG3 SARS-CoV-2 Spike Protein and Nucleocapsid Binding—Who Is Binding Who and Why?

The involvement of immunoglobulin (Ig) G3 in the humoral immune response to SARS-CoV-2 infection has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) in COVID-19. The exact molecular mechanism is unknown, but it is thought to involve this IgG subtype’s differential ability to fix, complement and stimulate cytokine release. We examined the binding of convalescent patient antibodies to immobilized nucleocapsids and spike proteins by matrix-assisted laser desorption/ionization–time of flight (MALDI-ToF) mass spectrometry. IgG3 was a major immunoglobulin found in all samples. Differential analysis of the spectral signatures found for the nucleocapsid versus the spike protein demonstrated that the predominant humoral immune response to the nucleocapsid was IgG3, whilst for the spike protein it was IgG1. However, the spike protein displayed a strong affinity for IgG3 itself, as it would bind from control plasma samples, as well as from those previously infected with SARS-CoV-2, similar to the way protein G binds IgG1. Furthermore, detailed spectral analysis indicated that a mass shift consistent with hyper-glycosylation or glycation was a characteristic of the IgG3 captured by the spike protein.     

Dynamic Decoupling for Combined Shape and Gauge Control System in Wide Strip Rolling Process

The precision of profile and thickness is the most important target for wide strip rolling,but the coupling of profile control and thickness control is ignored in rolling schedule,which holds down the simultaneous quality improvement of profile and thickness.A cross-coupled process control model for combined shape and gauge control was developed on the basis of the fact that both controls for profile and thickness are realized by controlling the rolling gap.A dynamic decoupling controller was then proposed to decouple the model.Both the simulation results and the online production data are valid and ensure the quality of the decoupling controller.     

Non-Cytokine Protein Profile of the Mesenchymal Stem Cell Secretome That Regulates the Androgen Production Pathway

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-aged women, and it typically involves elevated androgen levels. Recently, it has been reported that human bone marrow mesenchymal stem cells (hBM-MSCs) can regulate androgen synthesis pathways. However, the details of the mechanism are still unclear. hBM-MSC-derived secreted factors (the secretome) are promising sources of cell-based therapy as they consist of various types of proteins. It is thus important to know which proteins interact with disease-implicated biomolecules. This work aimed to investigate which secretome components contain the key factor that inhibits testosterone synthesis. In this study, we fractionated hBM-MSC-conditioned media into three fractions based on their molecular weights and found that, of the three fractions, one had the ability to inhibit the androgen-producing genes efficiently. We also analyzed the components of this fraction and established a protein profile of the hBM-MSC secretome, which was shown to inhibit androgen synthesis. Our study describes a set of protein components present in the hBM-MSC secretome that can be used therapeutically to treat PCOS by regulating androgen production for the first time.