Quantum chemical study on the one-carbon unit transfer of imidazolinium

One-carbon unit transfer reaction of folate cofactor model compound, 1-acetyl-2-methyl-imidazolinium, with 1,2-diaminobenzene has been studied theoretically with ONIOM method. The result shows that there are two pathways to complete this reaction because the imidazolinium ring has two breaking patterns. Both the two pathways have six steps. They are combination of two reactants, proton migration, break of five-membered ring, formation of benzimidazole derivate, another proton migration, and formation of final products. In each of the above pathways, the two proton migration steps have higher energy, which illuminate that the reaction is catalyzed by general acid-base. This fact agrees with the experimental results of enzymatic one-carbon unit transfer at oxidation level of formate.     

One site fits both: A model for the ternary complex of folate + NADPH in R67 dihydrofolate reductase, a D2 symmetric enzyme

R67 dihydrofolate reductase (DHFR) is a novel enzyme that confers resistance to the antibiotic trimethoprim. The crystal structure of R67 DHFR displays a toroidal structure with a central active-site pore. This homotetrameric protein exhibits 222 symmetry, with only a few residues from each chain contributing to the active site, so related sites must be used to bind both substrate (dihydrofolate) and cofactor (NADPH) in the productive R67 DHFR?NADPH?dihydrofolate complex. Whereas the site of folate binding has been partially resolved crystallographically, an interesting question remains: how can the highly symmetrical active site also bind and orient NADPH for catalysis? To model this ternary complex, we employed DOCK and SLIDE, two methods for docking flexible ligands into proteins using quite different algorithms. The bound pteridine ring of folate (Fol I) from the crystal structure of R67 DHFR was used as the basis for docking the nicotinamide-ribose-P_i (NMN) moiety of NADPH. NMN was positioned by both DOCK and SLIDE on the opposite side of the pore from Fol I, where it interacts with Fol I at the pore's center. Numerous residues serve dual roles in binding. For example, Gln 67 from both the B and D subunits has several contacts with the pteridine ring, while the same residue from the A and C subunits has several contacts with the nicotinamide ring. The residues involved in dual roles are generally amphipathic, allowing them to make both hydrophobic and hydrophilic contacts with the ligands. The result is a `hot spot' binding surface allowing the same residues to co-optimize the binding of two ligands, and orient them for catalysis.     

过载作用下聚乙烯疲劳裂纹扩展行为研究

论文针对中密度聚乙烯材料(MDPE)，采用平板试样进行了I型疲劳裂纹扩展和单次过载下裂纹扩展试验．发现与金属材料类似，单次拉伸过载对聚乙烯(PE)的疲劳裂纹扩展有明显的迟滞作用，降低了裂纹扩展速率．试验还通过变载荷刻线法获取疲劳裂纹扩展前缘的实际形貌和变化规律，对常规变载荷刻线方法进行了调整和验证，其修正方法对高分子材料的疲劳裂纹扩展前缘刻线具有较好的效果．通过观察发现含楔形塑性区的裂尖钝化是裂纹迟滞的主要原因．过载引入的塑性区内残余应力对裂纹迟滞也起了重要作用．论文利用Dugdale模型计算了塑性区尺寸，使用基于残余应力的Wheeler模型对过载迟滞进行了很好的拟合．     

The Concept of Folic Acid in Health and Disease

Folates have a pterine core structure and high metabolic activity due to their ability to accept electrons and react with O-, S-, N-, C-bounds. Folates play a role as cofactors in essential one-carbon pathways donating methyl-groups to choline phospholipids, creatine, epinephrine, DNA. Compounds similar to folates are ubiquitous and have been found in different animals, plants, and microorganisms. Folates enter the body from the diet and are also synthesized by intestinal bacteria with consequent adsorption from the colon. Three types of folate and antifolate cellular transporters have been found, differing in tissue localization, substrate affinity, type of transferring, and optimal pH for function. Laboratory criteria of folate deficiency are accepted by WHO. Severe folate deficiencies, manifesting in early life, are seen in hereditary folate malabsorption and cerebral folate deficiency. Acquired folate deficiency is quite common and is associated with poor diet and malabsorption, alcohol consumption, obesity, and kidney failure. Given the observational data that folates have a protective effect against neural tube defects, ischemic events, and cancer, food folic acid fortification was introduced in many countries. However, high physiological folate concentrations and folate overload may increase the risk of impaired brain development in embryogenesis and possess a growth advantage for precancerous altered cells.     

Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.     

基于非齐次复合Poisson过程的正交异性钢桥面板细节疲劳裂纹随机扩展研究

传统的正交异性钢桥面板疲劳损伤评估常采用确定性和可靠性分析方法,忽略了疲劳裂纹扩展的随机性影响,针对这一问题,提出钢桥面板细节疲劳随机扩展分析方法。本文以南溪长江大桥为工程背景,基于长期车辆荷载监测数据,建立了车辆荷载非齐次复合Poisson过程模型。建立钢桥面板有限元模型,采用瞬态分析方法将随机车辆荷载转化成细节疲劳应力,基于线弹性断裂力学理论推导U肋-顶板焊接细节疲劳裂纹扩展时变微分方程,实现宏观关系式疲劳应力幅次数-疲劳损伤至微观表达式应力时间序列-疲劳损伤转换,讨论了车载次序及超载对疲劳裂纹扩展的影响。研究结果表明,非齐次复合泊松过程模型能够较好描述随机车流运营状态,车辆荷载的次序对疲劳裂纹扩展速率的影响不可忽略,重车排序靠前时能够促使疲劳裂纹扩展增速,南溪长江大桥细节点的车辆超载迟滞效应修正系数取值0.804。     

Nuclear magnetic resonance study of iron overload in liver tissue

Whole-tissue and homogenized samples of human liver were studied in a NMR spectrometer, T1 and T2 relaxation times were measured as a function of added inorganic or organic iron. When inorganic iron (Fe+3) was added, pronounced T1 and T2 shortening was noted. However, when organic iron, in the form of ferritin, was added, the amount of T1 and T2 relaxation enhancement was much reduced for the same amount of added iron. The in vitro ferritin results model the situation found in clinical studies of hemochromatosis. Only in cases of severe iron overload were significant decreases in relaxation times observed. The T2 relaxation time was the more reliable indicator of excessive levels of iron in the liver. The large range of T1 and T2 values encountered in normal volunteers precludes the use of MR to quantitatively measure iron levels in the liver. The T1 and T2 relaxation times measured at intervals for one individual tend to fluctuate as well, making the use of MR to follow the course of treatment of iron overload disorders unreliable.     

The overload phenomenon in gas chromatography

The usual concepts of the dynamics of an overloaded solute band fail to explain several phenomena such as the typical “leading-tail” shape and retention deviations exhibited by overloaded peaks, and why these defects are more commonly observed in short columns. These and other related deviations from theory can be rationalized by a non-classical approach to the overloading phenomenon.     

停歇对疲劳裂纹扩展超载迟滞效应影响的研究

本文用 16 Mn和 A 537 两种普通低合金钢试件,较系统地研究了停歇对疲劳超载迟滞效应的影响。研究表明,疲劳载荷中的停歇对超载迟滞效应有明显影响,其影响的程度大小与停歇时的载荷 P_H,停歇时间 t_H 等因素密切相关;不但可能使试件的疲劳寿命减少,也可能使试件的疲劳寿命增加。在工程结构疲劳设计、分析及应用超载迟滞效应时应予以注意。