Probing the Binding Requirements of Modified Nucleosides with the DNA Nuclease SNM1A

SNM1A is a nuclease that is implicated in DNA interstrand crosslink repair and, as such, its inhibition is of interest for overcoming resistance to chemotherapeutic crosslinking agents. However, the number and identity of the metal ion(s) in the active site of SNM1A are still unconfirmed, and only a limited number of inhibitors have been reported to date. Herein, we report the synthesis and evaluation of a family of malonate-based modified nucleosides to investigate the optimal positioning of metal-binding groups in nucleoside-derived inhibitors for SNM1A. These compounds include ester, carboxylate and hydroxamic acid malonate derivatives which were installed in the 5′-position or 3′-position of thymidine or as a linkage between two nucleosides. Evaluation as inhibitors of recombinant SNM1A showed that nine of the twelve compounds tested had an inhibitory effect at 1 mM concentration. The most potent compound contains a hydroxamic acid malonate group at the 5′-position. Overall, our studies advance the understanding of requirements for nucleoside-derived inhibitors for SNM1A and indicate that groups containing a negatively charged group in close proximity to a metal chelator, such as hydroxamic acid malonates, are promising structures in the design of inhibitors.     

Characterization of a Novel CaCO3-Forming Alkali-Tolerant Rhodococcus erythreus S26 as a Filling Agent for Repairing Concrete Cracks

Biomineralization, a well-known natural phenomenon associated with various microbial species, is being studied to protect and strengthen building materials such as concrete. We characterized Rhodococcus erythreus S26, a novel urease-producing bacterium exhibiting CaCO₃-forming activity, and investigated its ability in repairing concrete cracks for the development of environment-friendly sealants. Strain S26 grown in solid medium formed spherical and polygonal CaCO₃ crystals. The S26 cells grown in a urea-containing liquid medium caused culture fluid alkalinization and increased CaCO₃ levels, indicating that ureolysis was responsible for CaCO₃ formation. Urease activity and CaCO₃ formation increased with incubation time, reaching a maximum of 2054 U/min/mL and 3.83 g/L, respectively, at day four. The maximum CaCO₃ formation was achieved when calcium lactate was used as the calcium source, followed by calcium gluconate. Although cell growth was observed after the induction period at pH 10.5, strain S26 could grow at a wide range of pH 4–10.5, showing its high alkali tolerance. FESEM showed rhombohedral crystals of 20–60 µm in size. EDX analysis indicated the presence of calcium, carbon, and oxygen in the crystals. XRD confirmed these crystals as CaCO₃ containing calcite and vaterite. Furthermore, R. erythreus S26 successfully repaired the artificially induced large cracks of 0.4–0.6 mm width.     

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.     

Evaluation of 3- and 4-Phenoxybenzamides as Selective Inhibitors of the Mono-ADP-Ribosyltransferase PARP10

Intracellular ADP-ribosyltransferases catalyze mono- and poly-ADP-ribosylation and affect a broad range of biological processes. The mono-ADP-ribosyltransferase PARP10 is involved in signaling and DNA repair. Previous studies identified OUL35 as a selective, cell permeable inhibitor of PARP10. We have further explored the chemical space of OUL35 by synthesizing and investigating structurally related analogs. Key synthetic steps were metal-catalyzed cross-couplings and functional group modifications. We identified 4-(4-cyanophenoxy)benzamide and 3-(4-carbamoylphenoxy)benzamide as PARP10 inhibitors with distinct selectivities. Both compounds were cell permeable and interfered with PARP10 toxicity. Moreover, both revealed some inhibition of PARP2 but not PARP1, unlike clinically used PARP inhibitors, which typically inhibit both enzymes. Using crystallography and molecular modeling the binding of the compounds to different ADP-ribosyltransferases was explored regarding selectivity. Together, these studies define additional compounds that interfere with PARP10 function and thus expand our repertoire of inhibitors to further optimize selectivity and potency.     

侧胸皮瓣修复顽固性扁平疣一例

介绍了治疗顽固性扁平疣的有效方法。本例患者起病两年多来由右手中指背针尖大的一个部位，发展到三个部位，且右中指创面发展到整个指甲边缘。期间曾行冷冻治疗、电灼治疗多次，内服、外用及肌注药物多种，均未奏效。最终行病灶切除缝合及侧胸部带蒂皮瓣移植，术后半年复查病灶未复发。可见手术切除方法是根治顽固性扁平疣的有效方法，侧胸部皮瓣为手指创面修复较理想部位。     

激光沉积修复BT20合金的显微组织和力学性能

针对BT20钛合金锻件当量孔损伤进行激光沉积修复试验,考察了修复试样的组织和力学特点。修复区与基材之间形成了致密冶金结合,Al,Zr,Mo,V合金元素由锻件基体到激光修复区均匀分布,无宏观偏析,硬度分布从基材到修复区依次提高。热影响区组织是由基材的双态组织过渡到网篮组织;修复区组织为粗大的原始柱状β晶,晶粒内为α/β网篮组织,晶内α片层取向随机,宽0.4~0.5μm。修复过程中发现,激光加工工艺参数选择不当、坡度过大等原因会造成修复区组织形成气孔和熔合不良等缺陷,但是通过优化工艺参数可以获得无缺陷修复试样。修复试样的室温静拉伸结果表明,试样的抗拉强度接近锻件基体强度,但修复件的韧性比锻件稍有提高。     

三维激光扫描系统中曲面空洞的识别与修复

为了解决三维激光扫描系统中重构曲面存在的空洞问题,提出了基于Floyd最短路径选择算法的空洞识别与修复方法。该方法对三维曲面中所有可能构成空洞的边界点进行逐个处理,采用树搜索算法获得与处理点直接或间接相连的边界点;将搜索到的边界点作为路径选择的节点,将连接节点的边界边作为路径选择的边并根据节点的搜索级别设置边的长度。当新搜索到的边界点与已搜索点发生重复时,首先,利用Floyd算法处理距离矩阵和路由矩阵找到空洞端点;然后,根据重复点与空洞端点生成空洞边集,最后,采用波前法对空洞边集进行处理。实验结果表明:本文所提方法能够准确识别连接有孤立边的空洞以及两个相邻空洞的特殊空洞结构,与传统方法相比,该方法具有更强的通用性和鲁棒性,空洞修复数量与两个传统方法相比分别提高了54.1%和21.3%。     

Reliability analysis of Polytube industry using supplementary variable technique

The purpose of this paper is to compute reliability of Polytube manufacturing plant having four units using supplementary variable technique. The failure and repair rates of the sub-systems are variable. The mathematical equations are derived using Chapman-Kolmogorov differential equations which are formed using mnemonic rule from the transition diagram of Polytube manufacturing plant. The system of partial differential equations obtained has been solved using Lagrange’s method and reliability of the system for the various choices of constant transition rates is solved numerically using Runge-Kutta fourth order. A sensitive analysis of subsystem is finally carried out to improve overall availability.     

Structural Basis for Bulky‐Adduct DNA‐Lesion Recognition by the Nucleotide Excision Repair Protein Rad14

Heterocyclic aromatic amines react with purine bases and result in bulky DNA adducts that cause mutations. Such structurally diverse lesions are substrates for the nucleotide excision repair (NER). It is thought that the NER machinery recognises and verifies distorted DNA conformations, also involving the xeroderma pigmentosum group A and C proteins (XPA, XPC) that act as a scaffold between the DNA substrate and several other NER proteins. Here we present the synthesis of DNA molecules containing the polycyclic, aromatic amine C8‐guanine lesions acetylaminophenyl, acetylaminonaphthyl, acetylaminoanthryl, and acetylaminopyrenyl, as well as their crystal structures in complex with the yeast XPA homologue Rad14. This work further substantiates the indirect lesion‐detection mechanism employed by the NER system that recognises destabilised and deformable DNA structures.     

考虑不完全检测的冲击模型最优维修策略

针对制造系统中设备检测不完全的情形,研究基于不完全检测的冲击模型的周期检测、维修联合策略．通过定期检测获知系统的劣化状态以进行必要的预防性维修．在假设系统是退化的且有k个不同故障状态的条件下,以最小化系统运行成本为目标,以检测周期T、系统更换前故障次数Ⅳ为联合决策变量,利用更新过程理论建立了系统平均费用率C（T,N）的数学模型,并且给出最优联合策略的数值算法．最后借助数值例子演示了该模型,分析了检测水平对系统运行成本的影响．