Study on the disulfide bond and disulfide loop of native and mutated SOD1 protein

The superoxide anions in the human body are reduced into hydrogen peroxide and molecular oxygen by the metallo enzyme Cu–Zn superoxide dismutase 1. The disulfide bond in SOD1 is essential to maintain the structural stability of protein and its proper folding. A computational study on the disulfide bond with the addition of residues was made using three different level of theories viz., B3LYP/6-31G (d,p), M052X/6-31G (d,p) and MP2/6-31G (d,p). The nature of disulfide bond was found to be unaffected with the additional residues being attached to the termini of cysteine residues. This result was found to be in agreement with the experimental values. The results of Molecular Dynamics simulation illustrate the crinkled appearance caused in the disulfide loop of A4V mutation. The conformational change in the disulfide loop was found to have significant effect on the loss of dimerization, metal binding affinity and overall protein stability. It is also noted that the disulfide loop with more number of residues is found to have no effect on the disulfide bond characteristics, but the disulfide loop with less number of residues is found to have remarkable effect for mutation in any position of the wild type protein.     

Translational Read-Through Therapy of RPGR Nonsense Mutations

X-chromosomal retinitis pigmentosa (RP) frequently is caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. We evaluated the potential of PTC124 (Ataluren, Translama^TM) treatment to promote ribosomal read-through of premature termination codons (PTC) in RPGR. Expression constructs in HEK293T cells showed that the efficacy of read-through reagents is higher for UGA than UAA PTCs. We identified the novel hemizygous nonsense mutation c.1154T > A, p.Leu385* ({"type":"entrez-nucleotide","attrs":{"text":"NM_000328.3","term_id":"1677500221"}}NM_000328.3) causing a UAA PTC in RPGR and generated patient-derived fibroblasts. Immunocytochemistry of serum-starved control fibroblasts showed the RPGR protein in a dot-like expression pattern along the primary cilium. In contrast, RPGR was no longer detectable at the primary cilium in patient-derived cells. Applying PTC124 restored RPGR at the cilium in approximately 8% of patient-derived cells. RT-PCR and Western blot assays verified the pathogenic mechanisms underlying the nonsense variant. Immunofluorescence stainings confirmed the successful PTC124 treatment. Our results showed for the first time that PTC124 induces read-through of PTCs in RPGR and restores the localization of the RPGR protein at the primary cilium in patient-derived cells. These results may provide a promising new treatment option for patients suffering from nonsense mutations in RPGR or other genetic diseases.     

An efficient algorithm for low-order direct discrete-time implementation of fractional order transfer functions

Fractional order systems become increasingly popular due to their versatility in modelling and control applications across various disciplines. However, the bottleneck in deploying these tools in practice is related to their implementation on real-life systems. Numerical approximations are employed but their complexity no longer match the attractive simplicity of the original fractional order systems. This paper proposes a low-order, computationally stable and efficient method for direct approximation of general order (fractional order) systems in the form of discrete-time rational transfer functions, e.g. processes, controllers. A fair comparison to other direct discretization methods is presented, demonstrating its added value with respect to the state of art.     

How operators make use of wide-choice adaptable automation: observations from a series of experimental studies

The present paper is concerned with the design of adaptable automation. It analyses the aggregated data from five experiments (N = 154) to examine which automation levels operators prefer, how often they switch between them, and whether performance is associated with frequent switching or the automation levels being used. Using wide-choice adaptable automation (i.e. up to six levels were offered), the experiments were conducted using a PC-based simulation of a complex work environment. The results showed that about 95% of operators had a clearly preferred automation level, which they used for more than 50% of the time. They strongly preferred intermediate automation levels over levels at the higher and lower ends of the scale. Most operators switched rarely between levels and when they did, they usually made small adjustment rather than large changes. Several implications for the design of adaptable automation were derived from the empirical data.     

Evolution on neutral networks accelerates the ticking rate of the molecular clock

Large sets of genotypes give rise to the same phenotype, because phenotypic expression is highly redundant. Accordingly, a population can accept mutations without altering its phenotype, as long as the genotype mutates into another one on the same set. By linking every pair of genotypes that are mutually accessible through mutation, genotypes organize themselves into neutral networks (NNs). These networks are known to be heterogeneous and assortative, and these properties affect the evolutionary dynamics of the population. By studying the dynamics of populations on NNs with arbitrary topology, we analyse the effect of assortativity, of NN (phenotype) fitness and of network size. We find that the probability that the population leaves the network is smaller the longer the time spent on it. This progressive ‘phenotypic entrapment’ entails a systematic increase in the overdispersion of the process with time and an acceleration in the fixation rate of neutral mutations. We also quantify the variation of these effects with the size of the phenotype and with its fitness relative to that of neighbouring alternatives.     

一种混合多边缘型LDPC码密度进化算法

在二进制输入加性高斯白噪声信道下，研究了基于多边缘型低密度奇偶校验码（Multi-edge Low Density Parity Check，MET-LDPC）的密度进化算法。针对高斯近似算法在前期迭代中的不准确问题，提出了一种改进算法。在分析MET-LDPC码的密度进化的基础上，将全密度进化与高斯近似算法结合，通过设置切换限制条件，弥补早期迭代的不准确，提高编码阈值估计的准确性。仿真结果表明,与MET-LDPC全密度进化算法相比，所提算法可以有效提高编码阈值估计的准确性，对LDPC编码的设计有一定的参考价值。     

基于弱变异准则的测试用例约简方法

针对为数较多的测试用例增加了回归测试成本的问题，提出一种基于弱变异准则的测试用例约简方法。首先，基于弱变异准则获得测试用例和变异分支关系矩阵；然后，重复约简4种无效测试需求和子集测试用例；最后，结合人工鱼群算法选择当前最优测试用例，并且交替执行简化和测试用例选择操作直至覆盖所有测试需求。该方法针对6个经典程序与贪心算法和HGS算法相比，基于弱变异准则并且不改变或稍微改变变异评分的条件下，约简率分别提高了73.4%和8.2%，且耗时分别降低了25.3%和56.1%。实验结果表明，所提方法在回归测试中可有效约简测试用例，降低测试代价。     

Exponential ergodicity of some Markov dynamical systems with application to a Poisson-driven stochastic differential equation

We are concerned with the asymptotics of the Markov chain given by the post-jump locations of a certain piecewise-deterministic Markov process with a state-dependent jump intensity. We provide sufficient conditions for such a model to possess a unique invariant distribution, which is exponentially attracting in the dual-bounded Lipschitz distance. Having established this, we generalize a result of J. Kazak on the jump process defined by a Poisson-driven stochastic differential equation with a solution-dependent intensity of perturbations.     

An interval-valued exceedance method in MCDM with uncertain satisfactions

Multicriteria decision-making problems have been applied to many applications for its practicality. Nevertheless, when the evaluated satisfactions are more complex, such as interval-valued distributions, how to reasonably obtain the aggregation results of alternatives is still an open issue. In this paper, an interval-valued exceedance method is proposed to solve such a question based on the Golden Rule representative value and probabilistic exceedance method. Due to good performance of expressing uncertain information, the Golden Rule representative value method is used to order interval-valued satisfactions after an effective normalization process. In addition, a quantifier-based ordered weighted averaging operator is also introduced to consider the preferences of decision makers. A realistic application of supplier selection is shown to illustrate the practicality of the proposed method.     

改进的区间犹豫算子应用于物流企业选择决策

针对现有区间犹豫模糊Hamacher算子存在的缺陷，构建了一种基于改进的区间犹豫模糊Hamacher加权算子的群决策方法。在分析现有区间犹豫模糊Hamacher算子不能满足幂等性的基础上，定义新的区间犹豫模糊Hamacher四则运算；提出两种改进的区间犹豫模糊Hamacher加权算子，包括改进的区间犹豫模糊Hamacher有序加权平均（I-IVHFHOWA）算子和改进的区间犹豫模糊Hamacher有序加权几何（I-IVHFHOWG）算子，并详细探究它们的常用算子形式以及算子之间的内在联系；建立基于I-IVHFHOWA算子和I-IVHFHOWG算子的物流企业选择决策模型，并通过实例说明模型的有效性。