A Scalable Computational Approach for Simulating Complexes of Multiple Chromosomes

Significant efforts have been recently made to obtain the three-dimensional (3D) structure of the genome with the goal of understanding how structures may affect gene regulation and expression. Chromosome conformational capture techniques such as Hi-C, have been key in uncovering the quantitative information needed to determine chromatin organization. Complementing these experimental tools, co-polymers theoretical methods are necessary to determine the ensemble of three-dimensional structures associated to the experimental data provided by Hi-C maps. Going beyond just structural information, these theoretical advances also start to provide an understanding of the underlying mechanisms governing genome assembly and function. Recent theoretical work, however, has been focused on single chromosome structures, missing the fact that, in the full nucleus, interactions between chromosomes play a central role in their organization. To overcome this limitation, MiChroM (Minimal Chromatin Model) has been modified to become capable of performing these multi-chromosome simulations. It has been upgraded into a fast and scalable software version, which is able to perform chromosome simulations using GPUs via OpenMM Python API, called Open-MiChroM. To validate the efficiency of this new version, analyses for GM12878 individual autosomes were performed and compared to earlier studies. This validation was followed by multi-chain simulations including the four largest human chromosomes (C1-C4). These simulations demonstrated the full power of this new approach. Comparison to Hi-C data shows that these multiple chromosome interactions are essential for a more accurate agreement with experimental results. Without any changes to the original MiChroM potential, it is now possible to predict experimentally observed inter-chromosome contacts. This scalability of Open-MiChroM allow for more audacious investigations, looking at interactions of multiple chains as well as moving towards higher resolution chromosomes models.     

A Computational Approach for Modeling the Allele Frequency Spectrum of Populations with Arbitrarily Varying Size

The allele frequency spectrum (AFS), or site frequency spectrum, is commonly used to summarize the genomic polymorphism pattern of a sample, which is informative for inferring population history and detecting natural selection. In 2013, Chen and Chen developed a method for analytically deriving the AFS for populations with temporally varying size through the coalescence time-scaling function. However, their approach is only applicable to population history scenarios in which the analytical form of the time-scaling function is tractable. In this paper, we propose a computational approach to extend the method to populations with arbitrary complex varying size by numerically approximating the time-scaling function. We demonstrate the performance of the approach by constructing the AFS for two population history scenarios: the logistic growth model and the Gompertz growth model, for which the AFS are unavailable with existing approaches. Software for implementing the algorithm can be downloaded at http://chenlab.big.ac.cn/software/.     

Rigorous Approach to Modeling of a Continuous Aerobic Membrane Bioreactor

A rigorous approach to mathematical modeling of a continuous aerobic membrane bioreactor (MBR) for the treatment of wastewater is reported. The idea is to apply the activated sludge model ASM3 to the special configuration of a membrane bioreactor. Therefore, the biochemical processes modeled by the ASM3 were implemented together with mass balances typical of a MBR running at constant TSS. The model parameters were adapted to the properties of an artificial wastewater by using a global search algorithm. The model could be validated by comparing effluent chemical oxygen demand (COD), sludge production and CO₂ concentration in the exhaust to the experimental data.     

A Computational Modeling and Simulation Approach to Investigate Mechanisms of Subcellular cAMP Compartmentation

Subcellular compartmentation of the ubiquitous second messenger cAMP has been widely proposed as a mechanism to explain unique receptor-dependent functional responses. How exactly compartmentation is achieved, however, has remained a mystery for more than 40 years. In this study, we developed computational and mathematical models to represent a subcellular sarcomeric space in a cardiac myocyte with varying detail. We then used these models to predict the contributions of various mechanisms that establish subcellular cAMP microdomains. We used the models to test the hypothesis that phosphodiesterases act as functional barriers to diffusion, creating discrete cAMP signaling domains. We also used the models to predict the effect of a range of experimentally measured diffusion rates on cAMP compartmentation. Finally, we modeled the anatomical structures in a cardiac myocyte diad, to predict the effects of anatomical diffusion barriers on cAMP compartmentation. When we incorporated experimentally informed model parameters to reconstruct an in silico subcellular sarcomeric space with spatially distinct cAMP production sites linked to caveloar domains, the models predict that under realistic conditions phosphodiesterases alone were insufficient to generate significant cAMP gradients. This prediction persisted even when combined with slow cAMP diffusion. When we additionally considered the effects of anatomic barriers to diffusion that are expected in the cardiac myocyte dyadic space, cAMP compartmentation did occur, but only when diffusion was slow. Our model simulations suggest that additional mechanisms likely contribute to cAMP gradients occurring in submicroscopic domains. The difference between the physiological and pathological effects resulting from the production of cAMP may be a function of appropriate compartmentation of cAMP signaling. Therefore, understanding the contribution of factors that are responsible for coordinating the spatial and temporal distribution of cAMP at the subcellular level could be important for developing new strategies for the prevention or treatment of unfavorable responses associated with different disease states.     

Computational methods for the analysis of swimming biomechanics

A series of computer programs is presented which enables the analysis of fish body shape and mass distributions, spine positions, spine curvatures and coordinates for the centre of mass. Data are derived from silhouette outlines of swimming fish, white muscle strains during swimming, white muscle force-time development functions for body bending cycles, muscle force and power production along the whole fish body and hydrodynamic efficiencies for fast-start swimming behaviours.     

The Obstacle-Set Method for Representing Muscle Paths in Musculoskeletal Models

A computational method is introduced for modeling the paths of muscles in the human body. The method is based on the premise that the resultant muscle force acts along the locus of the transverse cross-sectional centroids of the muscle. The path of the muscle is calculated by idealizing its centroid path as a frictionless elastic band, which moves freely over neighboring anatomical constraints such as bones and other muscles. The anatomical constraints, referred to as obstacles, are represented in the model by regular-shaped, rigid bodies such as spheres and cylinders. The obstacles, together with the muscle path, define an obstacle set. It is proposed that the path of any muscle can be modeled using one or more of the following four obstacle sets: single sphere, single cylinder, double cylinder, and sphere-capped cylinder. Assuming that the locus of the muscle centroids is known for an arbitrary joint configuration, the obstacle-set method can be used to calculate the path of the muscle for all other joint configurations. The obstacle-set method accounts not only for the interaction between a muscle and a neighboring anatomical constraint, but also for the way in which this interaction changes with joint configuration. Consequently, it is the only feasible method for representing the paths of muscles which cross joints with multiple degrees of freedom such as the deltoid at the shoulder.     

Specificity in Computational Protein Design

A long-standing goal of computational protein design is to create proteins similar to those found in Nature. One motivation is to harness the exquisite functional capabilities of proteins for our own purposes. The extent of similarity between designed and natural proteins also reports on how faithfully our models represent the selective pressures that determine protein sequences. As the field of protein design shifts emphasis from reproducing native-like protein structure to function, it has become important that these models treat the notion of specificity in molecular interactions. Although specificity may, in some cases, be achieved by optimization of a desired protein in isolation, methods have been developed to address directly the desire for proteins that exhibit specific functions and interactions.     

Linking Changes in Epithelial Morphogenesis to Cancer Mutations Using Computational Modeling

Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini). In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the relationship between the histopathology of neoplastic lesions and their underlying molecular defects.     

A Framework for Structured Modeling of Skeletal Muscle

The aim of this study is to present a detailed continuum mechanics formulation, and the corresponding algorithms, to predict the deformation of skeletal muscle at different structural levels, starting from the muscle fiber level. The model is used to investigate force production and structural changes during isometric and dynamic contractions of the cat medial gastrocnemius. From a comparison with experimental data obtained in our own laboratories, we conclude that the model faithfully predicts all of the observations pertaining to force production, fascicle length and angle of pennation under various test conditions.     

A Computational Approach for Deciphering the Organization of Glycosaminoglycans

Background

Increasing evidence has revealed important roles for complex glycans as mediators of normal and pathological processes. Glycosaminoglycans are a class of glycans that bind and regulate the function of a wide array of proteins at the cell-extracellular matrix interface. The specific sequence and chemical organization of these polymers likely define function; however, identification of the structure-function relationships of glycosaminoglycans has been met with challenges associated with the unique level of complexity and the nontemplate-driven biosynthesis of these biopolymers.

Methodology/Principal Findings

To address these challenges, we have devised a computational approach to predict fine structure and patterns of domain organization of the specific glycosaminoglycan, heparan sulfate (HS). Using chemical composition data obtained after complete and partial digestion of mixtures of HS chains with specific degradative enzymes, the computational analysis produces populations of theoretical HS chains with structures that meet both biosynthesis and enzyme degradation rules. The model performs these operations through a modular format consisting of input/output sections and three routines called chainmaker, chainbreaker, and chainsorter. We applied this methodology to analyze HS preparations isolated from pulmonary fibroblasts and epithelial cells. Significant differences in the general organization of these two HS preparations were observed, with HS from epithelial cells having a greater frequency of highly sulfated domains. Epithelial HS also showed a higher density of specific HS domains that have been associated with inhibition of neutrophil elastase. Experimental analysis of elastase inhibition was consistent with the model predictions and demonstrated that HS from epithelial cells had greater inhibitory activity than HS from fibroblasts.

Conclusions/Significance

This model establishes the conceptual framework for a new class of computational tools to use to assess patterns of domain organization within glycosaminoglycans. These tools will provide a means to consider high-level chain organization in deciphering the structure-function relationships of polysaccharides in biology.     

Validation of a simplified method for muscle volume assessment

The present study investigated the validity of a simplified muscle volume assessment that uses only the maximum anatomical cross-sectional area (ACSA_max), the muscle length (L_M) and a muscle-specific shape factor for muscle volume calculation ( Albracht et al., 2008, J Biomech 41, 2211–2218). The validation on the example of the triceps surae (TS) muscles was conducted in two steps. First L_M, ACSA_max, muscle volume and shape factor were calculated from magnet resonance image muscle reconstructions of the soleus (SO), gastrocnemius medialis (GM) and lateralis (GL) of a group of untrained individuals (n=13), endurance (n=9) and strength trained (n=10) athletes. Though there were significant differences in the muscle dimensions, the shape factors were similar across groups and were in average 0.497±0.026, 0.596±0.030, and 0.556±0.041 for the SO, GM and GL respectively. In a second step, the shape factors were applied to an independent recreationally active group (n=21) to compare the muscle volume assessed by the simplified method to the results from whole muscle reconstructions. There were no significant differences between the volumes assessed by the two methods. In conclusion, assessing TS muscle volume on the basis of the reported shape factors is valid across populations and the root mean square differences to whole muscle reconstruction of 7.9%, 4.8% and 8.3% for SO, GM and GL show that the simplified method is sensitive enough to detect changes in muscle volume in the context of degeneration, atrophy or hypertrophy.     

Muscle Strength,Muscle Mass and Physical Impairment in Women with hypermobile Ehlers-Danlos syndrome and Hypermobility Spectrum Disorder

Objectives:To evaluate differences in physical impairment, muscle strength, muscle mass and muscle density between patients with hypermobile Ehlers Danlos Syndrome (hEDS), hypermobile spectrum disorder (HSD), and healthy controls.Methods:Female adults with hEDS (n=20) and HSD (n=23), diagnosed to the most recent criteria, and age-matched healthy controls (n=28) completed the Arthritis Impact Measurement Scale (physical functioning) and performed maximal muscle strength and strength endurance tests of lower and upper limbs (hand grip, posture maintenance, 30 seconds chair rise and isokinetic tests). Muscle mass and density were evaluated by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography.Results:No differences in physical functioning and muscle strength were found between adults with hEDS and HSD. Furthermore, no differences in muscle mass and density were observed between the three groups. Nevertheless, when both patient groups were compared to controls, physical functioning, maximal muscle strength and muscle strength endurance were significantly lower (all p<0.001), except for the hand flexors.Conclusion:Physical functioning, muscle strength, density and mass did not significantly differ between individuals with hEDS and HSD. Compared to controls, physical functioning and muscle strength (maximal and endurance) were significantly lower. Consequently, (functional) strength training in individuals with hEDS and HSD is necessary.     

数种鱼类肌肉中氨基酸成分及含量的比较研究

综述了１２科２９种鱼类肌肉氨基酸成分及含量。结果表明,鱼类肌肉氨基酸种类齐全,约１７－２０种;总氨基酸含量较高,占９．６２－９３．６０％,其中必需氨基酸储量丰富,占总氨基酸含量的３７．７５－５８．４４％。通过比较发现乌鳢、团头鲂、矛尾复虾虎鱼、鳙、鲤和虹鳟等６种鱼类肌肉氨基酸总量高于其他２３种鱼类,确为鱼中佳品。     

Developmental Changes in Lactate Dehydrogenase and Aldolase Activity of the A2G-adr Mouse with Abnormal Muscle Function: Further Comparison with the 129Re-dy Mutant

Abstract: Lactate dehydrogenase and aldolase activity were reduced in lateral gastrocnemius muscle from two mouse mutants, A2G- adr and 129Re- dy , with abnormal muscle function. The activities of both of these enzymes were significantly reduced in the lateral gastrocnemius muscle from the A2G- adr mice at ages varying from 2 weeks to 32 weeks, whereas the activities in the soleus, heart, liver, and brain were the same as in the control animals. The lactate dehydrogenase isoenzymes in the lateral gastrocnemius and soleus muscles from the A2G mice were quantified, and although those of the soleus were comparable in mutant and control muscle, the lateral gastrocnemius from the adr mutant had reduced activity of LDH 5 and increased activities of the other four isoenzymes. The findings suggest that the adr mutation is expressed in the white (Type II) muscle fibres and not in the red (Type I) fibres or in any of the organs studied. It is suggested that the initiation of differentiation into Type II fibres from the embryonic form is absent or delayed in the A2G mutant. The reduced activities of lactate dehydrogenase and aldolase in 129Re- dy muscle confirm the findings of other workers.     

Dissecting the Catalytic Mechanism of Trypanosoma brucei Trypanothione Synthetase by Kinetic Analysis and Computational Modeling

In pathogenic trypanosomes, trypanothione synthetase (TryS) catalyzes the synthesis of both glutathionylspermidine (Gsp) and trypanothione (bis(glutathionyl)spermidine (T(SH)₂)). Here we present a thorough kinetic analysis of Trypanosoma brucei TryS in a newly developed phosphate buffer system at pH 7.0 and 37 °C, mimicking the physiological environment of the enzyme in the cytosol of bloodstream parasites. Under these conditions, TryS displays K_m values for GSH, ATP, spermidine, and Gsp of 34, 18, 687, and 32 μm, respectively, as well as K_i values for GSH and T(SH)₂ of 1 mm and 360 μm, respectively. As Gsp hydrolysis has a K_m value of 5.6 mm, the in vivo amidase activity is probably negligible. To obtain deeper insight in the molecular mechanism of TryS, we have formulated alternative kinetic models, with elementary reaction steps represented by linear kinetic equations. The model parameters were fitted to the extensive matrix of steady-state data obtained for different substrate/product combinations under the in vivo-like conditions. The best model describes the full kinetic profile and is able to predict time course data that were not used for fitting. This system''s biology approach to enzyme kinetics led us to conclude that (i) TryS follows a ter-reactant mechanism, (ii) the intermediate Gsp dissociates from the enzyme between the two catalytic steps, and (iii) T(SH)₂ inhibits the enzyme by remaining bound at its product site and, as does the inhibitory GSH, by binding to the activated enzyme complex. The newly detected concerted substrate and product inhibition suggests that TryS activity is tightly regulated.     

Fixed Dystonia in Complex Regional Pain Syndrome: a Descriptive and Computational Modeling Approach

Background  

Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback.     

陆地生态系统碳循环模型研究概述

陆地碳循环研究是全球变化研究中的一个重要组成部分,而碳循环模型已成为目前研究陆地碳循环的必要手段.本文针对有关碳循环研究方面的进展,介绍了陆地碳循环模型的基本结构、碳循环过程中涉及的两个基本模型以及目前陆地生态系统碳循环模型的两大类型,并通过对现有主要陆地生态系统碳收支模式的分析,指出了未来陆地碳循环模型的研究方向可能是发展基于动态植被的生物物理模型.这种耦合模型也可能是地球系统模式的重要组成部分.     

剪切波弹性成像技术对脑卒中偏瘫患者肌张力和肌肉硬度的评估价值研究

摘要 目的：研究应用剪切波弹性成像技术对脑卒中偏瘫患者肌张力、肌硬度进行评估的临床价值。方法：选取2019年3月到2021年2月在我院进行治疗的79例脑卒中偏瘫患者作为研究对象,应用超声仪检测所有研究对象健康侧（健侧）和患病侧（患侧）肱二头肌、肱肌和肱桡肌放松位和拉伸位下杨氏模量值,进行对比分析。结果：在放松位下,脑卒中偏瘫患者患侧肱二头肌和肱桡肌杨氏模量与健康侧肌肉相比无显著差异（P>0.05）,而患侧肱肌杨氏模量显著低于健侧（P<0.05）。在拉伸位下,脑卒中偏瘫患者患侧肱二头肌、肱肌和肱桡肌杨氏模量均显著高于健康侧肌肉（P<0.05）;脑卒中偏瘫患者放松位与拉伸位肱二头肌、肱肌和肱桡肌杨氏模量差值也均显著高于健康侧肌肉（P<0.05）。此外,不同改良Ashworth肌张力分级的脑卒中偏瘫患者患侧肱二头肌、肱肌和肱桡肌杨氏模量均存在显著差异（P<0.05）,并且患侧肱二头肌、肱肌和肱桡肌杨氏模量值随改良Ashworth肌张力分级升高而增加。结论：剪切波弹性成像技术可用于评估脑卒中偏瘫患者肌张力、肌硬度,以指导临床康复。