Evolution of Vertebroplasty: A Biomechanical Perspective

This paper is a collection of computational, finite element studies on vertebroplasty performed in our laboratory, which attempts to provide new biomechanical evidence and a fresh perspective into how the procedure can be implemented more effectively toward the goal of preventing osteoporosis-related fractures. The percutaneous application of a bone cement to vertebral defects associated with osteoporotic vertebral compression fracture has proven clinical successful in alleviating back pain. When the biomechanical efficacy of the procedure was examined, however, vertebroplasty was found to be limited in its ability to provide sufficient augmentation to prevent further fractures without risking complications arising from cement extravasations. The procedure may instead be more efficient biomechanically as a prophylactic treatment, to mechanically reinforce osteoporotic vertebrae at risk for fracture. Patient selection for such intervention may be reliably achieved with the more accurate fracture risk assessments based on vertebral strength, predicted using geometrically detailed, specimen-specific finite element models, rather than on bone density alone. Optimal cement volume, placement, and material properties were also recommended. The future of vertebroplasty involving biodegradable augmentation material laced with osteogenic agents that upon release will stimulate new bone growth and increase bone mass was proposed.     

儿童退缩和同伴关系的相关

目的：用元分析方法对近20年关于儿童退缩和同伴关系相关的研究结果进行总结。方法：用多水平分析技术对儿童退缩和同伴接受的相关、退缩和同伴拒绝相关的研究结果进行总结分析。结果：儿童退缩和同伴接受之间有显著的负相关关系，退缩和同伴拒绝之间有低度的非负相关关系，各研究结果之间的变异显著。结论：退缩导致儿童不良的同伴关系。     

Computer Simulations of the “Hairy Rod” Model

Summary: Using extensive Molecular Dynamics simulations we study the behavior of very rigid polyelectrolytes with hydrophobic side chains that are known to form cylindrical micelles in aqueous solution. We investigate the stability of such micelles with respect to hydrophobicity, Coulomb interaction, and micellar size. We show that for the parameter range relevant for poly(p‐phenylene sulfonate)s (PPP) one finds a stable finite micellar size close to the experimental parameter region. We also point out that our model has some similarities to DNA solutions with added condensing agents, hinting to the possibility that the size of DNA aggregates is under certain circumstances thermodynamically limited.

DNA‐like morphologies of the polyelectrolytes.     

A mathematical model of thrombin production in blood coagulation,Part I: The sparsely covered membrane case

This paper presents the first attempt to model the blood coagulation reactions in flowing blood. The model focuses on the common pathway and includes activation of factor X and prothrombin, including feedback activation of cofactors VIII and V by thrombin, and plasma inhibition of factor Xa and thrombin. In this paper, the first of two, the sparsely covered membrane (SCM) case is presented. This considers the limiting situation where platelet membrane binding sites are in excess, such that no membrane saturation or binding competition occurs. Under these conditions, the model predicts that the two positive feedback loops lead to multiple steady-state behavior in the range of intermediate mass transfer rates. It will be shown that this results in three parameter regions exhibiting very different thrombin production patterns. The model predicts the effect of flow on steady-state and dynamic thrombin production and attempts to explain the difference between venous and arterial thrombi. The reliance of thrombin production on precursor procoagulant protein concentrations is also assessed.     

Computational biology insights into genotype-clinical phenotype-protein phenotype relationships between novel SLC26A2 variants identified in inherited skeletal dysplasias

BackgroundPathogenic variants in the transmembrane sulfate transporter protein SLC26A2 are associated with different phenotypes of inherited chondrodysplasias. As limited data is published from India, in this study we sought to elucidate the molecular basis of inherited chondrodysplasias in an Indian cohort.MethodsMolecular screening of 32 fetuses with antenatally diagnosed lethal skeletal dysplasia was performed by next generation sequencing and Sanger sequencing. The genotype-protein phenotype characterization was done using computational biology techniques like homology modelling, stability and pathogenicity predictions.ResultsWe identified five rare autosomal recessive SLC26A2 [NM_000112.4] variants, including three homozygous c.796dupA(p.Thr266Asnfs*12), c.1724delA(p.Lys575Serfs*10), and c.1375_1377dup(p.Val459dup) and two heterozygous variants (c.532C > T(p.Arg178*)) and (c.1382C > T(p.Ala461Val)) in compound heterozygous form in a total of four foetuses. Genotype-protein phenotype annotations highlighted that the clinically severe achondrogenesis 1B causative c.796dupA(p.Thr266Asnfs*12) and c.1724delA(p.Lys575Serfs*10)variants impact SLC26A2 protein structure by deletion of the protein core and transmembrane STAS domains, respectively. In clinically moderate atelosteogenesis type 2 phenotype, the c.1382C > T(p.Ala461Val) variant is predicted to distort alpha helix conformation and alter the bonding properties and free energy dynamics of transmembrane domains and the c.532C > T(p.Arg178*) variant results in loss of both core transmembrane and STAS domains of the SLC26A2 protein. The c.1375_1377dup(p.Val459dup) variant identified in clinically milder atelosteogenesis type II-diastrophic dysplasia spectrum lethal phenotype is predicted to decrease the Qualitative Model Energy Analysis (QMean), which affects major geometrical aspects of the SLC26A2 protein structure.ConclusionWe expand the spectrum of SLC26A2 related lethal chondrodysplasia and report three novel variants correlating clinical severity and protein phenotype within the lethal spectrum of this rare dysplasia. We demonstrate the relevance of structural characterization to aid novel variant reclassification to provide better prenatal management and reproductive options to families with lethal antenatal skeletal disorder.     

Integration from proteins to organs: the IUPS Physiome Project

The IUPS Physiome Project is an internationally collaborative open source project intended to provide a public domain framework for computational physiology, including the development of modeling standards, computational tools and web-accessible databases of models of structure and function at all spatial scales and across all organ systems. Here, we illustrate the application of this multi-scale modeling approach to three organ systems: the heart, the lungs and the musculo-skeletal system, and in each case we show how the organ level models incorporate tissue and cell-level physiology. Although the computational physiology framework presented here does not yet incorporate models of ageing processes, the model-based approach is certainly capable of describing ageing and disease-related processes both via parameter changes within the models of normal physiological processes and via models of additional processes added to the framework.     

Novel missense mutations in the human lysosomal sialidase gene in sialidosis patients and prediction of structural alterations of mutant enzymes

Three novel missense mutations in the human lysosomal sialidase gene causing amino acid substitutions (P80L, W240R, and P316S) in the coding region were identified in two Japanese sialidosis patients. One patient with a severe, congenital form of type 2 sialidosis was a compound heterozygote for 239C-to-T (P80L) and 718T-to-C (W240R). The other patient with a mild juvenile-onset phenotype (type 1) was a homozygote for the base substitution of 946C-to-T (P316S). None of these mutant cDNA products showed enzymatic activity toward an artificial substrate when coexpressed in galactosialidosis fibroblastic cells together with protective protein/cathepsin A (PPCA). All mutants showed a reticular immunofluorescence distribution when coexpressed with the PPCA gene in COS-1 cells, suggesting that the gene products were retained in the endoplasmic reticulum/Golgi area or rapidly degraded in the lysosomes. Homology modeling of the structural changes introduced by the mutations predicted that the P80L and P316S transversions cause large conformational changes including the active site residues responsible for binding the sialic acid carboxylate group. The W240R substitution was deduced to influence the molecular surface structure of a limited region of the constructed models, which was also influenced by previously identified V217M and G243R transversions. Received: Stptember 21, 2001 / Accepted: November 2, 2001     

Multivariate Genetic Analysis of Brain Structure in an Extended Twin Design

The hunt for genes influencing behavior may be aided by the study of intermediate phenotypes for several reasons. First, intermediate phenotypes may be influenced by only a few genes, which facilitates their detection. Second, many intermediate phenotypes can be measured on a continuous quantitative scale and thus can be assessed in affected and unaffected individuals. Continuous measures increase the statistical power to detect genetic effects (Neale et al., 1994), and allow studies to be designed to collect data from informative subjects such as extreme concordant or discordant pairs. Intermediate phenotypes for discrete traits, such as psychiatric disorders, can be neurotransmitter levels, brain function, or structure. In this paper we conduct a multivariate analysis of data from 111 twin pairs and 34 additional siblings on cerebellar volume, intracranial space, and body height. The analysis is carried out on the raw data and specifies a model for the mean and the covariance structure. Results suggest that cerebellar volume and intracranial space vary with age and sex. Brain volumes tend to decrease slightly with age, and males generally have a larger brain volume than females. The remaining phenotypic variance of cerebellar volume is largely genetic (88%). These genetic factors partly overlap with the genetic factors that explain variance in intracranial space and body height. The applied method is presented as a general approach for the analysis of intermediate phenotypes in which the effects of correlated variables on the observed scores are modeled through multivariate analysis.     

Cardiovascular patterns associated with threat and challenge appraisals: a within-subjects analysis

Previous studies demonstrated distinct cardiovascular patterns associated with threat and challenge appraisals for groups of participants. We extend these results by assessing whether appraisals continue to be associated with these cardiovascular response patterns within an individual as appraisals change. Participants completed four verbal mental arithmetic tasks for which they made appraisals before and after each task. Cardiac reactivity and total peripheral resistance (TPR) were calculated for the first and last minutes of each task, and the number of responses and percent correct were measured for each task. In line with our prediction, pretask appraisals were related to some task-related cardiac responses across the four tasks. In addition, task-related cardiovascular reactivity and behaviors both influenced appraisals following the task. Our findings suggest that an idiographic analysis of appraisals, cardiovascular physiology, and task-related behaviors provides a richer understanding of the appraisal process and reveals sex differences deserving further assessment.