目的

设计合成结构新颖的萘巯基氨基酸乙酯类组蛋白赖氨酸特异性去甲基化酶1(lysine specific demethylase 1,LSD1)抑制剂,评价其LSD1抑制活性与选择性,并通过分子对接和动力学模拟探讨结合机制。

基于先导化合物3a与LSD1蛋白的结合模式,在化合物结构中固定平面疏水性的萘环,同时引入具有亲水性的氨基片段,采用三组份一锅法构建α-萘巯基氨基酸乙酯小分子化合物。采用课题组自主构建的LSD1筛选平台测试化合物在5.0,1.0 μmol·L^–1浓度下对LSD1的抑制率,测试活性最好的化合物的IC₅₀值及对MAO-A和MAO-B的抑制活性,并通过分子对接和动力学模拟研究其结合机制。

共合成13个目标化合物,均对LSD1有很好的抑制作用,其中有9个化合物在1.0 μmol·L^–1浓度下对LSD1抑制率>50.0%,且化合物3l活性最佳,IC₅₀值为0.17 μmol·L^–1,是阳性对照的174倍,对MAO-A和MAO-B有很好的选择性。分子对接和动力学模拟表明化合物3l通过多重作用与LSD1结合来抑制其活性。

α-萘巯基氨基酸乙酯类结构可作为先导化合物或活性片段,为基于结构的药物设计进行后续LSD1抑制剂的设计打下良好基础。

     

Evaluación de la efectividad de la versión en español de un curso de comunicación de malas noticias

IntroductionGood communication by health professionals is associated with better patient outcomes. The Program to Enhance Relational and Communication Skills (PERCS) has been adapted to other cultures. The objective of this study is to describe the effectiveness of the Spanish version of the PERCS program, from the perspective of the participants, at the end of the course and 6 months after the course.MethodsA process of cultural and epidemiological adaptation of the PERCS program to the reality of Peru was carried out. A qualitative and quantitative approach was used to evaluate the educational impact of the program.ResultsThirty-nine professionals participated voluntarily. Participants found it more difficult to communicate ominous diagnoses (48.15%). Anxiety is the most frequent emotion when faced with difficult communications (77.78%). Almost all (92%) stated that the course improved their preparation, and 88.9% that it reduced their anxiety. At 6 months, participants recognised the importance of honesty and empathy, as well as some steps in conducting the patient-centred interview.DiscussionAn intensive training program in difficult communication can be adapted to Spanish, and positively impact the skills, self-confidence, and self-perception of learning in Peruvian professionals, in relation to promoting communication focused on the needs of the patient and family.     

Experimental and Numerical Study on the Mechanical Behavior of Composite Steel Structure under Explosion Load

Most engineering structures are composed of basic components such as plates, shells, and beams, and their dynamic characteristics under explosion load determine the impact resistance of the structure. In this paper, a three-dimensional composite steel structure was designed using a beam, plate, and other basic elements to study its mechanical behavior under explosion load. Subsequently, experiments on the composite steel structure under explosion load were carried out to study its mechanical behavior, and the failure mode and deformation data of the composite steel structure were obtained, which provided important experimental data regarding the dynamic response and mechanical behavior of the composite steel structure under explosion load. Then, we independently developed a parallel program with the coupled calculation method to solve the numerical simulation of the dynamic response and failure process of the composite steel structure under explosion load. This program adopts the Euler method as a whole, and Lagrange particles are used for materials that need to be accurately tracked. The numerical calculation results are in good agreement with the experimental data, indicating that the developed parallel program can effectively deal with the large deformation problems of multi-medium materials and the numerical simulation of the complex engineering structure failures subjected to the strong impact load.     

Computing simulated endolymphatic flow thermodynamics during the caloric test using normal and hydropic duct models

Conclusion: The obtained simulations support the underlying hypothesis that the hydrostatic caloric drive is dissipated by local convective flow in a hydropic duct.

Objective: To develop a computerized model to simulate and predict the internal fluid thermodynamic behavior within both normal and hydropic horizontal ducts.

Methods: This study used a computational fluid dynamics software to simulate the effects of cooling and warming of two geometrical models representing normal and hydropic ducts of one semicircular horizontal canal during 120?s.

Results: Temperature maps, vorticity, and velocity fields were successfully obtained to characterize the endolymphatic flow during the caloric test in the developed models. In the normal semicircular canal, a well-defined endolymphatic linear flow was obtained, this flow has an opposite direction depending only on the cooling or warming condition of the simulation. For the hydropic model a non-effective endolymphatic flow was predicted; in this model the velocity and vorticity fields show a non-linear flow, with some vortices formed inside the hydropic duct.     

Interlaminar Microstructure and Mechanical Properties of Narrow Gap Laser Welding of 40-mm-Thick Ti-6Al-4V Alloy

Narrow gap laser welding (NGLW) is a common solution for the welding of thick structures. NGLW was carried out on narrow-gap butt joints of 40 mm-thick Ti-6Al-4V alloy plates with a U-shaped groove. The distribution characteristics of the interlaminar microstructure in different height ranges of the joint were investigated, and the evolution behavior and formation mechanism of the interlaminar microstructure of the joint were also revealed. This showed that a large amount of short needle martensite nucleated and grew up near the fusion line and the upper boundary of the remelting zone. The “softening” phenomenon occurred in all welds except the cover layer weld. The microstructure evolution and defect migration, induced by multiple welding thermal cycles in the upper weld forming process, were the main reasons for the “softening” of the lower weld. The tensile strength of each sample changed in the range of 920~990 MPa; the fracture mode of the sample belongs to a transgranular ductile fracture. In addition, compared with the upper part of the joint, the plasticity and toughness of the weld area in the lower part of the joint was improved.     

Study of the Magnetized Hybrid Nanofluid Flow through a Flat Elastic Surface with Applications in Solar Energy

The main theme of the present study is to analyze numerically the effects of the magnetic field on the hybrid nanofluid flow over a flat elastic surface. The effects of the thermal and velocity slips are also analyzed in view of the hybrid nanofluid flow. It is considered a combination of titanium oxide (TiO₂) and copper oxide (CuO) nanoparticles that are suspended in the incompressible and electrically conducting fluid (water). The behavior of the Brownian motion of the nanoparticles and the thermophoretic forces are contemplated in the physical and mathematical formulations. Moreover, the impact of the Joule heating and viscous dissipation are also discussed using the energy equation. The mathematical modeling is simulated with the help of similarity variables. The resulting equations are solved using the Keller–Box method with a combination of finite difference schemes (FDSs). Hybrid nanofluids provide significant advantages over the usual heat transfer fluids. Therefore, the use of nanofluids is beneficial to improve the thermophysical properties of the working fluid. All of the results are discussed for the various physical parameters involved in governing the flow. From the graphical results, it is found that the hybrid nanoparticles improve the concentration, temperature, and velocity profiles, as well as the thickness of the relevant boundary layer. The conjunction of a magnetic field and the velocity slip, strongly opposes the fluid motion. The boundary layer thickness and concentration profile are significantly reduced with the higher levels of the Schmidt number.     

Defect Detection and Characterization in Concrete Based on FEM and Ultrasonic Techniques

In order to estimate the crack depth in concrete using time-of-flight, finite element analysis and experiments were performed on non-cracked concrete blocks and 45 mm and 70 mm vertical cracks. As a result of measuring the time-of-flight change by changing the positions of the transmitter and receiver, it was confirmed that the finite element analysis results agreed with the experimental results, and high accuracy was confirmed by various formulas for calculating the depth of defects using the obtained experimental measurements for comparison. In addition to the verification of the simulation and experimental theory, research was conducted through actual field cases, and methodologies for crack detection and depth evaluation for concrete structures were presented, and furthermore, the expected effects of improving the soundness and safety of structures were shown.     

Elastic Moduli of Non-Chiral Singe-Walled Silicon Carbide Nanotubes: Numerical Simulation Study

Silicon carbide nanotubes (SiCNTs) have generated significant research interest due to their potential use in the fabrication of electronic and optoelectronic nanodevices and biosensors. The exceptional chemical, electrical and thermal properties of SiCNTs are beneficial for their application in high-temperature and harsh-environments. In view of the limited thermal stability of carbon nanotubes, they can be replaced by silicon carbide nanotubes in reinforced composites, developed for operations at high temperatures. However, fundamentally theoretical studies of the mechanical properties of the silicon carbide nanotubes are at an early stage and their results are still insufficient for designing and exploiting appropriate nanodevices based on SiCNTs and reinforced composites. In this context, the present study deals with the determination of Young’s and shear moduli of non-chiral single-walled silicon carbide nanotubes, using a three-dimensional finite element model.