Comparison of dynamics of wildtype and V94M human UDP-galactose 4-epimerase—A computational perspective on severe epimerase-deficiency galactosemia

UDP-galactose 4′-epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose, an important step in galactose catabolism. Type III galactosemia, an inherited metabolic disease, is associated with mutations in human GALE. The V94M mutation has been associated with a very severe form of type III galactosemia. While a variety of structural and biochemical studies have been reported that elucidate differences between the wildtype and this mutant form of human GALE, little is known about the dynamics of the protein and how mutations influence structure and function. We performed molecular dynamics simulations on the wildtype and V94M enzyme in different states of substrate and cofactor binding. In the mutant, the average distance between the substrate and both a key catalytic residue (Tyr157) and the enzyme-bound NAD⁺ cofactor and the active site dynamics are altered making substrate binding slightly less stable. However, overall stability or dynamics of the protein is not altered. This is consistent with experimental findings that the impact is largely on the turnover number (k_cat), with less substantial effects on K_m. Active site fluctuations were found to be correlated in enzyme with substrate bound to just one of the subunits in the homodimer suggesting inter-subunit communication. Greater active site loop mobility in human GALE compared to the equivalent loop in Escherichia coli GALE explains why the former can catalyze the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine while the bacterial enzyme cannot. This work illuminates molecular mechanisms of disease and may inform the design of small molecule therapies for type III galactosemia.     

Contrasting patterns of genetic differentiation in Macaronesian lineages of Ilex (Aquifoliaceae)

Islands offer an interesting framework in which to study the effect of geographical isolation on population genetic differentiation. For plant species with high dispersal abilities, however, oceanic barriers may not represent a factor promoting strong population structure. In this work, we analysed seven nuclear microsatellite loci in Ilex (Aquifoliaceae), a bird‐dispersed plant group, to infer patterns of genetic differentiation among Macaronesian taxa: I. canariensis, I. perado ssp. lopezlilloi, I. perado ssp. platyphylla (Canary Islands) and I. perado ssp. azorica (Azores). In agreement with current taxonomic classification, our results revealed a high genetic differentiation between Ilex lineages (I. canariensis and the I. perado complex), and also supported previous hypotheses that these are the result of independent dispersal events to the islands. In contrast, genetic differentiation between I. perado ssp. azorica and the two subspecies from the Canaries was high, suggesting that taxonomic revision may be necessary. Levels of genetic variation at microsatellite loci in ssp. azorica were, in addition, the lowest reported among Macaronesian bird‐dispersed taxa. Lastly, low genetic differentiation was observed between subspecies occurring on the same island (sspp. platyphylla and lopezlilloi). In summary, our results revealed contrasting patterns between Macaronesian Ilex lineages: I. canariensis displayed moderate population structure across islands, whereas the I. perado complex showed strong differentiation among populations sampled on different islands. Thus, the Macaronesian Ilex taxa show that long‐distance dispersal syndromes (ornithochory) do not always ensure genetic connectivity across large areas in island systems. Plant groups that successfully colonized the islands on multiple occasions may have found barriers to gene flow within certain lineages. © 2013 The Linnean Society of London, Botanical Journal of the Linnean Society, 2013, 173 , 258–268.     

EXAMINING THE FULL EFFECTS OF LANDSCAPE HETEROGENEITY ON SPATIAL GENETIC VARIATION: A MULTIPLE MATRIX REGRESSION APPROACH FOR QUANTIFYING GEOGRAPHIC AND ECOLOGICAL ISOLATION

Understanding the effects of landscape heterogeneity on spatial genetic variation is a primary goal of landscape genetics. Ecological and geographic variables can contribute to genetic structure through geographic isolation, in which geographic barriers and distances restrict gene flow, and ecological isolation, in which gene flow among populations inhabiting different environments is limited by selection against dispersers moving between them. Although methods have been developed to study geographic isolation in detail, ecological isolation has received much less attention, partly because disentangling the effects of these mechanisms is inherently difficult. Here, I describe a novel approach for quantifying the effects of geographic and ecological isolation using multiple matrix regression with randomization. I explored the parameter space over which this method is effective using a series of individual‐based simulations and found that it accurately describes the effects of geographic and ecological isolation over a wide range of conditions. I also applied this method to a set of real‐world datasets to show that ecological isolation is an often overlooked but important contributor to patterns of spatial genetic variation and to demonstrate how this analysis can provide new insights into how landscapes contribute to the evolution of genetic variation in nature.     

THE EFFECT OF 40 HOURS OF CONSTANT WAKEFULNESS ON NUMBER COMPARISON PERFORMANCE

We investigated the effects of sleep loss and circadian rhythm on number comparison performance. Magnitude comparison of single-digits is robustly characterized by a distance effect: Close numbers (e.g., 5 versus 6) produce longer reaction times than numbers further apart (e.g., 2 versus 8). This distance effect is assumed to reflect the difficulty of a comparison process based on an analogous representation of general magnitude. Twelve male participants were required to stay awake for 40?h in a quasi-constant-routine protocol. Response speed and accuracy deteriorated between 00:00 and 06:00?h but recovered afterwards during the next day, indicating a circadian rhythm of elementary cognitive function (i.e., attention and speed of mental processing). The symbolic distance effect, however, did not increase during the nighttime, indicating that neither cumulative sleep loss nor the circadian clock prolongs numerical comparison processes. The present findings provide first evidence for a relative insensitivity of symbolic magnitude processing against the temporal variation in energy state. (Author correspondence: michael.steinborn@uni-tuebingen.de)     

MECHANICAL ANALYSIS OF THE ROUNDHOUSE KICK ACCORDING TO HEIGHT AND DISTANCE IN TAEKWONDO

Competition regulation in taekwondo has experienced several changes during the last few years, for example, kicks to the head score more points than kicks to the chest. In addition, some external factors such as the height of target and execution distance seem to affect the kick performance. The aim of this study was to analyse selected biomechanical parameters (impact force, reaction time, and execution time) according to the height and execution distance in two different male groups (experts (n = 12) and novices (n = 21)). Athletes kicked twice from every execution distance (short, normal and long) and towards two different heights of target (chest and head) in a random order. Novices kicked to the head with a longer reaction time than to the chest (p < 0.05) but experts were able to kick with similar performance for both heights. From short and normal distances experts kicked with similar performance; whereas from the normal distance novices had longer reaction and execution time than from the short distance (p < 0.05). In conclusion, in counterattacking situations, experts should perform the roundhouse kick to the head instead of to the chest, because it produces better scores with similar performance; whereas novice athletes should avoid kicking to the head because they are not able to kick with similar performance. Moreover, it is recommended that during counterattacks higher-level taekwondo athletes should intend to kick from normal distances.     

Mechanism of flexibility control for ATP access of hepatitis C virus NS3 helicase

Hepatitis C virus (HCV) NS3 helicase couples adenosine triphosphate (ATP) binding and hydrolysis to polynucleotide unwinding. Understanding the regulation mechanism of ATP binding will facilitate targeting of the ATP-binding site for potential therapeutic development for hepatitis C. T324, an amino acid residue connecting domains 1 and 2 of NS3 helicase, has been suggested as part of a flexible hinge for opening of the ATP-binding cleft, although the detailed mechanism remains largely unclear. We used computational simulation to examine the mutational effect of T324 on the dynamics of the ATP-binding site. A mutant model, T324A, of the NS3 helicase apo structure was created and energy was minimized. Molecular dynamics simulation was conducted for both wild type and the T324A mutant apo structures to compare their differences. For the mutant structure, histogram analysis of pairwise distances between residues in domains 1 and 2 (E291-Q460, K210-R464 and R467-T212) showed that separation between the two domains was reduced by ～10% and the standard deviation by ～33%. Root mean square fluctuation (RMSF) analysis demonstrated that residues in close proximity to residue 324 have at least 30% RMSF value reductions in the mutant structure. Solvent RMSF analysis showed that more water molecules were trapped near D290 and H293 in domain 1 to form an extensive interaction network constraining cleft opening. We also demonstrated that the T324A mutation established a new atomic interaction with V331, revealing that an atomic interaction cascade from T324 to residues in domains 1 and 2 controls the flexibility of the ATP-binding cleft.     

生态保护价值的距离衰减性——以三江平原湿地为例

应用二分式条件价值评估法对三江平原湿地生态保护价值进行定量评价。运用支付意愿函数模型构建双边界二分式CVM数据分析模型,应用生存分析中的参数回归模型建立支付意愿影响因素分析模型。建立具有距离变量及个人社会、经济属性变量的支付意愿函数,验证支付意愿具有"距离衰减性"。研究采用以面访调查为主、网上调查为辅的方式,进行支付意愿问卷调查,得出2010年三江平原湿地生态保护的人均支付意愿为134.582元/a,三江平原湿地的生态保护价值为33.412亿元/a。研究结论为政府相关政策的制定提供参考依据。     

Predicting the structural integrity of bone defects repaired using bone graft materials

Bone defects create stress concentrations which can cause fracture under impact or cyclic loading. Defects are often repaired by filling them with a bone graft material; this will reduce the stress concentration, but not completely, because these materials have lower stiffness than bone. The fracture risk decreases over time as the graft material is replaced by living bone. Many new bone graft materials are being developed, using tissue engineering and other techniques, but currently there is no rational way to compare these materials and predict their effectiveness in repairing a given defect. This paper describes, for the first time, a theoretical model which can be used to predict failure by brittle fracture or fatigue, initiating at the defect. Preliminary results are presented, concentrating on the prediction of stress fracture during the crucial post-operative period. It is shown that the likelihood of fracture is strongly influenced by the shape of the defect as well as its size, and also by the level of post-operative exercise. The most important finding is that bone graft materials can be successful in preventing fracture even when their mechanical properties are greatly inferior to those of bone. Future uses of this technique include pre-clinical assessment of bone replacement materials and pre-operative planning in orthopaedic surgery.     

Irreversibility and Interatomic Potentials in One-dimensional Lattice Models

Abstract

Since the computational work on the relaxation process toward the equilibrium state by Fermi, Pasta, and Ulam (FPU) [1], the stochastic behaviors in one dimensional lattice models have been studied by many physicists numerically and theoretically. The objective of those studies is to understand the origin of thermodynamical properties from the microscopic particle motions which are determined by the deterministic equations of motion. In the FPU work, since the given energy was too small and anharmonicity was too weak, thermodynamic irreversibility phenomena, which lead to the equipartition of energy among modes, were not observed. Many studies after this work confirmed the existence of the threshold for the chaotic motions [2] [3]. However, the relation of the chaotic motion in the system with many degrees of freedom to the thermodynamical properties is not well understood [4]. The steady lattice thermal conduction in one dimensional lattice poses an interesting problem in this; respect. A clear linear internal temperature gradient was not observed in the FPU model [5], while it was observed in the the ding-a-ling model by Casati et al. [6] and the diatomic Toda lattice (DTL) by Mokross and Büttner [7]. Recently, the system size dependence of the coefficient of thermal conductivity has been studied [8][9] and the Fourier's law of heat conduction is begining to be confirmed in the DTL.