An advanced 3D multi-body system model for the human lumbar spine

Series : Mechanisms and machine science, ISSN 2211-0984, vol. 24A novel 3D multi-body system model of the human lumbar spine is presented, allowing the dynamic study of the all set but also to access mechanical demands, characteristics and performance under work of the individual intervertebral discs. An advanced FEM analysis was used for the most precise characterization of the disc 6DOF mechanical behavior, in order to build up a tool capable of predicting and assist in the design of disc recovery strategies – namely in the development of replace-ment materials for the degenerated disc nucleus – as well as in the analysis of variations in the me-chanical properties (disorders) at disc level or kinematic structure (e.g. interbody fusion, pedicle fixa-tion, etc.), and its influence in the overall spine dynamics and at motion segments individual level. Preliminary results of the model, at different levels of its development, are presented

Development of an unbiased statistical method for the analysis of unigenic evolution

BACKGROUND: Unigenic evolution is a powerful genetic strategy involving random mutagenesis of a single gene product to delineate functionally important domains of a protein. This method involves selection of variants of the protein which retain function, followed by statistical analysis comparing expected and observed mutation frequencies of each residue. Resultant mutability indices for each residue are averaged across a specified window of codons to identify hypomutable regions of the protein. As originally described, the effect of changes to the length of this averaging window was not fully eludicated. In addition, it was unclear when sufficient functional variants had been examined to conclude that residues conserved in all variants have important functional roles. RESULTS: We demonstrate that the length of averaging window dramatically affects identification of individual hypomutable regions and delineation of region boundaries. Accordingly, we devised a region-independent chi-square analysis that eliminates loss of information incurred during window averaging and removes the arbitrary assignment of window length. We also present a method to estimate the probability that conserved residues have not been mutated simply by chance. In addition, we describe an improved estimation of the expected mutation frequency. CONCLUSION: Overall, these methods significantly extend the analysis of unigenic evolution data over existing methods to allow comprehensive, unbiased identification of domains and possibly even individual residues that are essential for protein function

Estimating the evidence of selection and the reliability of inference in unigenic evolution

<p>Abstract</p> <p>Background</p> <p>Unigenic evolution is a large-scale mutagenesis experiment used to identify residues that are potentially important for protein function. Both currently-used methods for the analysis of unigenic evolution data analyze 'windows' of contiguous sites, a strategy that increases statistical power but incorrectly assumes that functionally-critical sites are contiguous. In addition, both methods require the questionable assumption of asymptotically-large sample size due to the presumption of approximate normality.</p> <p>Results</p> <p>We develop a novel approach, termed the Evidence of Selection (EoS), removing the assumption that functionally important sites are adjacent in sequence and and explicitly modelling the effects of limited sample-size. Precise statistical derivations show that the EoS score can be easily interpreted as an expected log-odds-ratio between two competing hypotheses, namely, the hypothetical presence or absence of functional selection for a given site. Using the EoS score, we then develop selection criteria by which functionally-important yet non-adjacent sites can be identified. An approximate power analysis is also developed to estimate the reliability of inference given the data. We validate and demonstrate the the practical utility of our method by analysis of the homing endonuclease <monospace>I-Bmol</monospace>, comparing our predictions with the results of existing methods.</p> <p>Conclusions</p> <p>Our method is able to assess both the evidence of selection at individual amino acid sites and estimate the reliability of those inferences. Experimental validation with <monospace>I-Bmol</monospace> proves its utility to identify functionally-important residues of poorly characterized proteins, demonstrating increased sensitivity over previous methods without loss of specificity. With the ability to guide the selection of precise experimental mutagenesis conditions, our method helps make unigenic analysis a more broadly applicable technique with which to probe protein function.</p> <p>Availability</p> <p>Software to compute, plot, and summarize EoS data is available as an open-source package called 'unigenic' for the 'R' programming language at <url>http://www.fernandes.org/txp/article/13/an-analytical-framework-for-unigenic-evolution</url>.</p

Evolutionarily Conserved Linkage between Enzyme Fold, Flexibility, and Catalysis

Proteins are intrinsically flexible molecules. The role of internal motions in a protein's designated function is widely debated. The role of protein structure in enzyme catalysis is well established, and conservation of structural features provides vital clues to their role in function. Recently, it has been proposed that the protein function may involve multiple conformations: the observed deviations are not random thermodynamic fluctuations; rather, flexibility may be closely linked to protein function, including enzyme catalysis. We hypothesize that the argument of conservation of important structural features can also be extended to identification of protein flexibility in interconnection with enzyme function. Three classes of enzymes (prolyl-peptidyl isomerase, oxidoreductase, and nuclease) that catalyze diverse chemical reactions have been examined using detailed computational modeling. For each class, the identification and characterization of the internal protein motions coupled to the chemical step in enzyme mechanisms in multiple species show identical enzyme conformational fluctuations. In addition to the active-site residues, motions of protein surface loop regions (>10 Å away) are observed to be identical across species, and networks of conserved interactions/residues connect these highly flexible surface regions to the active-site residues that make direct contact with substrates. More interestingly, examination of reaction-coupled motions in non-homologous enzyme systems (with no structural or sequence similarity) that catalyze the same biochemical reaction shows motions that induce remarkably similar changes in the enzyme–substrate interactions during catalysis. The results indicate that the reaction-coupled flexibility is a conserved aspect of the enzyme molecular architecture. Protein motions in distal areas of homologous and non-homologous enzyme systems mediate similar changes in the active-site enzyme–substrate interactions, thereby impacting the mechanism of catalyzed chemistry. These results have implications for understanding the mechanism of allostery, and for protein engineering and drug design

Characterisation of SEQ0694 (PrsA/PrtM) of Streptococcus equi as a functional peptidyl-prolyl isomerase affecting multiple secreted protein substrates

YesPeptidyl-prolyl isomerase (PPIase) lipoproteins have been shown to influence the virulence of a number of Gram-positive bacterial human and animal pathogens, most likely through facilitating the folding of cell envelope and secreted virulence factors. Here, we used a proteomic approach to demonstrate that the Streptococcus equi PPIase SEQ0694 alters the production of multiple secreted proteins, including at least two putative virulence factors (FNE and IdeE2). We demonstrate also that, despite some unusual sequence features, recombinant SEQ0694 and its central parvulin domain are functional PPIases. These data add to our knowledge of the mechanisms by which lipoprotein PPIases contribute to the virulence of streptococcal pathogens

New Political Ecologies of Renewable Energy

The critique of fossil fuel regimes has been a foundational concern for the field of political ecology, in its drives to expose the injustices and harms of energy extractivism and its early warnings of the climate crisis. However, it is increasingly evident that renewable energy sources and their infrastructures will carry their own costs and trade-offs, and that critique, resistance and alternative movement-building are needed to forge a truly just renewable energy transition. This theme issue underlines the many ways in which political ecology is well-positioned to lead critical and engaged scholarship in support of energy/climate justice. In this introduction and survey, we draw on new research collected here to reflect on political ecology's distinctive analytical capacities and forms of praxis for this task. We argue that the collection advances political ecology's intellectual and political purchase on renewable transition in several crucial ways. These include (1) Theorizing Renewables-Driven Land Transformations, (2) Advancing Industrial Political Ecologies of Renewables, (3) Locating Power within Technical and Artifactual Politics and (4) Generating Knowledge and Tools for Just Transitions. We conclude with reflections on further pressing concerns for the field: for example, rising debates over scale, ownership and accountability models within renewable energy justice and democracy movements and critical conversations growing around renewable energy's own extraction geographies and diverse forms of racialization

Development of an unbiased statistical method for the analysis of unigenic evolution-0

<p><b>Copyright information:</b></p><p>Taken from "Development of an unbiased statistical method for the analysis of unigenic evolution"</p><p>BMC Bioinformatics 2006;7():150-150.</p><p>Published online 17 Mar 2006</p><p>PMCID:PMC1434776.</p><p>Copyright © 2006 Behrsin et al; licensee BioMed Central Ltd.</p> of individual residues was averaged over a window of 1, 5, 11 or 25 codons. The hypo- or hypermutability was then plotted as a bar in the center of the specified window and the window was shifted downstream one codon at a time. Individual hypomutable regions, designated A, B, C, and D are indicated on the plot for the 11 codon window. For comparison, the difference between mutability calculated by previous methods (5) and mutability as described in this manuscript is also shown (circles)

Development of an unbiased statistical method for the analysis of unigenic evolution-1

<p><b>Copyright information:</b></p><p>Taken from "Development of an unbiased statistical method for the analysis of unigenic evolution"</p><p>BMC Bioinformatics 2006;7():150-150.</p><p>Published online 17 Mar 2006</p><p>PMCID:PMC1434776.</p><p>Copyright © 2006 Behrsin et al; licensee BioMed Central Ltd.</p>d against region length and amino acid residue number. Calculations were performed as described in the text. Only regions that are significant at the 0.005 level are plotted; the whole window is plotted whenever this significance level is achieved. If a residue is involved in more than one significant region of the same length, the region with the highest χvalue is plotted. Colours indicate χof the region and range from deep red (χ> 15, corresponding to α < 0.0001) to pale green (χ> 8, α < 0.005). Four hypomutable regions approximating regions A-D (Figure 1) are evident