An affine micro-sphere-based constitutive model,accounting for junctional sliding,can capture F-actin network mechanics

Actin filaments are a major component of the cytoskeleton and play a crucial role in cell mechanotransduction. F-actin networks can be reconstituted in vitro and their mechanical behaviour has been studied experimentally. Constitutive models that assume an idealised network structure, in combination with a non-affine network deformation, have been successful in capturing the elastic response of the network. In this study, an affine network deformation is assumed, in which we propose an alternative 3D finite strain constitutive model. The model makes use of a micro-sphere to calculate the strain energy density of the network, which is represented as a continuous distribution of filament orientations in space. By incorporating a simplified sliding mechanism at the filament-to-filament junctions, premature filament locking, inherent to affine network deformation, could be avoided. The model could successfully fit experimental shear data for a specific cross-linked F-actin network, demonstrating the potential of the novel model.     

Mechanics in human fibroblasts and progeria: Lamin A mutation E145K results in stiffening of nuclei

The lamina is a filamentous meshwork beneath the inner nuclear membrane that confers mechanical stability to nuclei. The E145K mutation in lamin A causes Hutchinson‐Gilford progeria syndrome (HGPS). It affects lamin filament assembly and induces profound changes in the nuclear architecture. Expression of wild‐type and E145K lamin A in Xenopus oocytes followed by atomic force microscopy (AFM) probing of isolated oocyte nuclei has shown significant changes in the mechanical properties of the lamina. Nuclei of oocytes expressing E145K lamin A are stiffer than those expressing wild‐type lamin A. Here we present mechanical measurements by AFM on dermal fibroblasts obtained from a 4‐year‐old progeria patient bearing the E145K lamin A mutation and compared it to fibroblasts obtained from 2 healthy donors of 10 and 61 years of age, respectively. The abnormal shape of nuclei expressing E145K lamin A was analyzed by fluorescence microscopy. Lamina thickness was measured using electron micrographs. Fluorescence microscopy showed alterations in the actin network of progeria cells. AFM probing of whole dermal fibroblasts did not demonstrate significant differences in the elastic moduli of nuclear and cytoplasmic cell regions. In contrast, AFM measurements of isolated nuclei showed that nuclei of progeria and old person's cells are significantly stiffer than those of the young person, indicating that the process of aging, be it natural or abnormal, increases nuclear stiffness. Our results corroborate AFM data obtained using Xenopus oocyte nuclei and prove that the presence of E145K lamin A abnormally increases nuclear stiffness.     

生境变化对集合种群系统生态效应的影响

通过大量的数值模拟发现 :生境恢复或扩展将导致集合种群的强弱序由自然数的顺序规律演变为奇数种群强 -偶数种群弱 ,同时集合种群里的最优秀种群将迅速扩张、发展为更为强大的最优势种。而当生境遭受到破坏 (毁坏 ) ,集合种群里的最优秀种群将迅速地伦为最弱者。如果栖息地的毁坏率大于集合种群优势种对栖息地的占有率 ,不仅集合种群里的优势种群将不可避免地灭绝 ,伴随最优秀种群走向灭绝的种群依次还有第二、第三、第四强等的种群。同时 ,将导致集合种群的强弱序由自然数的顺序规律演变为偶数种群强 -奇数种群弱。     

The function and evolution of male and female genitalia in Phyllophaga Harris scarab beetles (Coleoptera: Scarabaeidae)

Genitalia diversity in insects continues to fuel investigation of the function and evolution of these dynamic structures. Whereas most studies have focused on variation in male genitalia, an increasing number of studies on female genitalia have uncovered comparable diversity among females, but often at a much finer morphological scale. In this study, we analysed the function and evolution of male and female genitalia in Phyllophaga scarab beetles, a group in which both sexes exhibit genitalic diversity. To document the interaction between male and female structures during mating, we dissected flash‐frozen mating pairs from three Phyllophaga species and investigated fine‐scale morphology using SEM. We then reconstructed ancestral character states using a species tree inferred from mitochondrial and nuclear loci to elucidate and compare the evolutionary history of male and female genitalia. Our dissections revealed an interlocking mechanism of the female pubic process and male parameres that appears to improve the mechanical fit of the copulatory position. The comparative analyses, however, did not support coevolution of male and female structures and showed more erratic evolution of the female genitalia relative to males. By studying a group that exhibits obvious female genitalic diversity, we were able to demonstrate the relevance of female reproductive morphology in studies of male genital diversity.     

Protein side chain conformation predictions with an MMGBSA energy function

The prediction of protein side chain conformations from backbone coordinates is an important task in structural biology, with applications in structure prediction and protein design. It is a difficult problem due to its combinatorial nature. We study the performance of an “MMGBSA” energy function, implemented in our protein design program Proteus, which combines molecular mechanics terms, a Generalized Born and Surface Area (GBSA) solvent model, with approximations that make the model pairwise additive. Proteus is not a competitor to specialized side chain prediction programs due to its cost, but it allows protein design applications, where side chain prediction is an important step and MMGBSA an effective energy model. We predict the side chain conformations for 18 proteins. The side chains are first predicted individually, with the rest of the protein in its crystallographic conformation. Next, all side chains are predicted together. The contributions of individual energy terms are evaluated and various parameterizations are compared. We find that the GB and SA terms, with an appropriate choice of the dielectric constant and surface energy coefficients, are beneficial for single side chain predictions. For the prediction of all side chains, however, errors due to the pairwise additive approximation overcome the improvement brought by these terms. We also show the crucial contribution of side chain minimization to alleviate the rigid rotamer approximation. Even without GB and SA terms, we obtain accuracies comparable to SCWRL4, a specialized side chain prediction program. In particular, we obtain a better RMSD than SCWRL4 for core residues (at a higher cost), despite our simpler rotamer library. Proteins 2016; 84:803–819. © 2016 Wiley Periodicals, Inc.     

基于图像配准分析物种进化关系的新方法

图像配准是图像处理的一个重要技术,可用于分析两幅图像之间的相似度。本文提出了一种基于图像配准分析物种进化关系的新方法:首先利用一阶马尔可夫链方法计算不同基因组序列的寡聚核苷酸转移概率矩阵;然后将转移概率矩阵转换为彩色图像矩阵,并绘制物种两两之间彩色图像矩阵的联合直方图;最后分析联合直方图点集的分布情况,引入直方图点集的散度公式,将其作为相似性测度的标准,从而鉴定物种亲缘关系的远近。100种细菌全基因组的计算结果表明,相较于单基因法或基于基因组寡聚核苷酸频率组分差异信息的方法,本文提出的新方法具有更高的准确度和分辨力,它不仅能够很好地分辨科以下的分类单元,而且对科以上的分类单元同样具有较好的区分效果。该方法有望发展成为物种鉴定及系统发育推断的有效手段。     

A finite element model of stress-mediated vascular adaptation: application to abdominal aortic aneurysms

Despite rapid expansion of our knowledge of vascular adaptation, developing patient-specific models of diseased arteries is still an open problem. In this study, we extend existing finite element models of stress-mediated growth and remodelling of arteries to incorporate a medical image-based geometry of a healthy aorta and, then, simulate abdominal aortic aneurysm. Degradation of elastin initiates a local dilatation of the aorta while stress-mediated turnover of collagen and smooth muscle compensates the loss of elastin. Stress distributions and expansion rates during the aneurysm growth are studied for multiple spatial distribution functions of elastin degradation and kinetic parameters. Temporal variations of the degradation function are also investigated with either direct time-dependent degradation or stretch-induced degradation as possible biochemical and biomechanical mechanisms for elastin degradation. The results show that this computational model has the capability to capture the complexities of aneurysm progression due to variations of geometry, extent of damage and stress-mediated turnover as a step towards patient-specific modelling.     

Computationally guided identification of Akt-3, a serine/threonine kinase inhibitors: Insights from homology modelling,structure-based screening,molecular dynamics and quantum mechanical calculations

Abstract

Chemical entities targeting kinase signalling pathways serve as a potential strategy to combat malignancies. Protein Kinase B or Akt is a validated target for various malignancies and Akt3 remains the least explored isoform among all its isoforms. Initially, homology modelling technique was used for generating protein structure and further validation was performed using molecular dynamics simulation and Ramachandran plot. The validated protein structure was then subjected for active site analysis which led to identification of active site residues based on metrics provided by site score. The important residues in binding site were identified as Thr81, Asp271 and Asp289 for binding energetics and inhibition. Subsequently, virtual screening methodologies were used for identification of novel hits for inhibition of Protein Kinase B or Akt3. This led to the identification of two hits, i.e. thiophene derivative and thieno-pyridine derivative which were selected on the basis of their binding affinity and drug likeliness. These identified hits were subjected for molecular dynamics simulations, quantum mechanical and synthetic accessibility studies. The role of crucial residues in binding site stood validated as suggested by molecular dynamics simulations studies.

Communicated by Ramaswamy H. Sarma     

Using linkage models to explore skull kinematic diversity and functional convergence in arthrodire placoderms

Biomechanical models offer a powerful set of tools for quantifying the diversity of function across fossil taxa. A computer‐based four‐bar linkage model previously developed to describe the potential feeding kinematics of Dunkleosteus terrelli is applied here to several other arthrodire placoderm taxa from different lineages. Arthrodire placoderms are a group of basal gnathostomes showing one of the earliest diversifications of jaw structures. The linkage model allows biomechanical variation to be compared across taxa, identify trends in skull morphology among arthrodires that potentially influence function and explore the role of linkage systems in the early evolution of jaw structures. The linkage model calculates various kinematic metrics including gape angle, effective mechanical advantage, and kinematic transmission coefficients. Results indicate that the arthrodire feeding system may be more diverse and complex than previously thought. A range of potential kinematic profiles among arthrodire taxa illustrate a diversity of feeding function comparable with modern teleost fishes. Previous estimates of bite force in Dunkleosteus are revised based on new morphological data. High levels of kinematic transmission among arthrodires suggest the potential for rapid gape expansion and possible suction feeding. Morphological comparisons indicate that there were several morphological solutions for obtaining these fast kinematics, which allowed different taxa to achieve similar kinematic profiles while varying other aspects of the feeding apparatus. Mapping of key morphological components of the linkage system on a general placoderm phylogeny illustrates the potential importance of four‐bar systems to the early evolution of jaw structures. J. Morphol. 271:990–1005, 2010. © 2010 Wiley‐Liss, Inc.