scholarly journals Allostery and Epistasis: Emergent Properties of Anisotropic Networks

Entropy ◽  
2020 ◽  
Vol 22 (6) ◽  
pp. 667 ◽  
Author(s):  
Paul Campitelli ◽  
S. Banu Ozkan
Keyword(s):  
Random Force ◽  
Biological Properties ◽  
Functional Site ◽  
Emergent Properties ◽  
Dynamic Coupling ◽  
Functional Sites ◽  
Coupling Index ◽  
The Difference ◽  
Underlying Mechanisms ◽  
Anisotropic Network

Understanding the underlying mechanisms behind protein allostery and non-additivity of substitution outcomes (i.e., epistasis) is critical when attempting to predict the functional impact of mutations, particularly at non-conserved sites. In an effort to model these two biological properties, we extend the framework of our metric to calculate dynamic coupling between residues, the Dynamic Coupling Index (DCI) to two new metrics: (i) EpiScore, which quantifies the difference between the residue fluctuation response of a functional site when two other positions are perturbed with random Brownian kicks simultaneously versus individually to capture the degree of cooperativity of these two other positions in modulating the dynamics of the functional site and (ii) DCIasym, which measures the degree of asymmetry between the residue fluctuation response of two sites when one or the other is perturbed with a random force. Applied to four independent systems, we successfully show that EpiScore and DCIasym can capture important biophysical properties in dual mutant substitution outcomes. We propose that allosteric regulation and the mechanisms underlying non-additive amino acid substitution outcomes (i.e., epistasis) can be understood as emergent properties of an anisotropic network of interactions where the inclusion of the full network of interactions is critical for accurate modeling. Consequently, mutations which drive towards a new function may require a fine balance between functional site asymmetry and strength of dynamic coupling with the functional sites. These two tools will provide mechanistic insight into both understanding and predicting the outcome of dual mutations.

scholarly journals CATH functional families predict functional sites in proteins

2020 ◽  
Author(s):  
Sayoni Das ◽  
Harry M Scholes ◽  
Neeladri Sen ◽  
Christine Orengo
Keyword(s):  
Functional Characterization ◽  
Functional Site ◽  
Training Data ◽  
Supplementary Information ◽  
Conserved Residues ◽  
Functional Sites ◽  
Protein Protein Interaction ◽  
Evolutionary Features ◽  
Functional Families

Abstract Motivation Identification of functional sites in proteins is essential for functional characterization, variant interpretation and drug design. Several methods are available for predicting either a generic functional site, or specific types of functional site. Here, we present FunSite, a machine learning predictor that identifies catalytic, ligand-binding and protein–protein interaction functional sites using features derived from protein sequence and structure, and evolutionary data from CATH functional families (FunFams). Results FunSite’s prediction performance was rigorously benchmarked using cross-validation and a holdout dataset. FunSite outperformed other publicly available functional site prediction methods. We show that conserved residues in FunFams are enriched in functional sites. We found FunSite’s performance depends greatly on the quality of functional site annotations and the information content of FunFams in the training data. Finally, we analyze which structural and evolutionary features are most predictive for functional sites. Availabilityand implementation https://github.com/UCL/cath-funsite-predictor. Contact [email protected] or [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

Linguistic cues facilitate children’s understanding of belief-reporting sentences

2021 ◽  
pp. 014272372110486
Author(s):  
Xiaowen Zhang ◽  
Peng Zhou
Keyword(s):  
Gold Medal ◽  
Judgment Task ◽  
False Belief ◽  
Value Judgment ◽  
Additional Information ◽  
Linguistic Cues ◽  
Truth Value ◽  
The Difference ◽  
Underlying Mechanisms ◽  
Mental Verbs

It has been well-documented that although children around 4 years start to attribute false beliefs to others in classic false-belief tasks, they are still less able to evaluate the truth-value of propositional belief-reporting sentences, especially when belief conflicts with reality. This article investigates whether linguistic cues, verb factivity in particular, can facilitate children’s understanding of belief-reporting sentences. Two experiments were implemented, one testing children’s knowledge of verb factivity using a gold medal task, and one investigating children’s interpretation of belief-reporting sentences using a truth-value-judgment task. Both experiments took advantage of the contrast between neutral non-factive mental verbs and strong negatively biased mental verbs. What sets the two apart is that the complement clause following a strong negatively biased mental verb is definitely false, whereas the one following a neutral non-factive mental verb remains indeterminate in the absence of additional information. The findings were that, first, 4-year-old children were able to tell the difference between the two types of mental verbs in factivity, and second, children’s performance was significantly improved when a strong negatively biased mental verb than when a neutral non-factive mental verb was used as the main verb of the belief-reporting sentences. The findings suggest that the use of strong negatively biased mental verbs facilitates children’s understanding of belief-reporting sentences. Implications of the findings are discussed in relation to the underlying mechanisms connecting verb factivity and false-belief understanding.

scholarly journals Isolation of humic acid from oxidized lignite and complexation with metal cations

2017 ◽  
Vol 71 (4) ◽  
pp. 319-327
Author(s):  
Benjamin Catovic ◽  
Minela Sisic ◽  
Majda Srabovic ◽  
Melita Huremovic
Keyword(s):  
Humic Acid ◽  
Metal Ions ◽  
Humic Acids ◽  
Metal Binding ◽  
Base Material ◽  
Metal Cations ◽  
Biological Properties ◽  
Metal Nitrate ◽  
Chemical Difference ◽  
The Difference

Lignite is brown coal, which in its composition contains humic acids. Humic acids are produced by coal combustion, which leads to the enrichment of coal humic acids. Lignite, from the opet pit mine Sikulje, lignite ore ?Kreka?, Bosnia and Herzegovina, was fragmented and sieved to the appropriate size and used as a base material. The isolation of humic acid was carried out from pre-oxidized and dried lignite after which it was refined. Identification thus obtained humic acids was carried out by FTIR spectroscopy and its characterization of UV analysis which is determined by optical density of isolated humic acid and its complexation with metal cations. Data obtained by FTIR spectroscopic analysis of isolated humic acids show no significant structural and chemical difference in relation to the spectrum obtained for standard humic acids (Sigma Aldrich). UV analysis showed that isolated and standard humic acid have E4/E6 ratio in an appropriate range of 3?5, which indicates the presence of a large number of aliphatic structure. Based on the degree of humification was found that the isolated humic acids belong to the type B standard while humic acids belong to type A. The most important property of the humic substances is the ability to interact with the metal ions forming soluble or insoluble complexes which possess different chemical and biological properties and stability. The nature of the complex between humic acid and metal cation derived from the heterogeneous, polyelectric and polydispersive character humic acids that occurs due to the presence of a large number of functional groups. Complexation of humic acid is carried out with different concentrations of metal nitrate solutions and at different pH values. Different amounts of humic acids were used for the complexation. The amount of the free metal ions was measured with the ICP-OES methode. The data were also statistically analyzed with ANOVA. The results showed that increasing the pH reduces the concentration of metal ions adsorbed on humic acid and by increasing the concentrations and amounts of metal humic acid that power increases. On the basis of the difference in absorbance between metals and humic acids can be said that there is an interaction between the metal and the ligand and is based on absorbance values obtained can be determine the next set of metal binding to humic acids Pb>Zn>Ni>Cu.

scholarly journals Towards a Validation Methodology for Macroeconomic Agent-Based Models

2021 ◽  
Author(s):  
Sebastiaan Tieleman
Keyword(s):  
Emergent Properties ◽  
Agent Based Models ◽  
Important Distinction ◽  
Agent Based ◽  
Model Classification ◽  
Classification Framework ◽  
The Difference ◽  
To Come

AbstractAgent-based models provide a promising new tool in macroeconomic research. Questions have been raised, however, regarding the validity of such models. A methodology of macroeconomic agent-based model (MABM) validation, that provides a deeper understanding of validation practices, is required. This paper takes steps towards such a methodology by connecting three elements. First, is a foundation of model validation in general. Second is a classification of models dependent on how the model is validated. An important distinction in this classification is the difference between mechanism and target validation. Third, is a framework that revolves around the relationship between the structure of models of complex systems with emergent properties and validation in practice. Important in this framework is to consider MABMs as modelling multiple non-trivial levels. Connecting these three elements provides us with a methodology of the validation of MABMs and allows us to come to the following conclusions regarding MABM validation. First, in MABMs, mechanisms at a lower level are distinct from, but provide input to higher levels of mechanisms. Since mechanisms at different levels are validated in different ways we can come to a specific characterization of MABMs within the model classification framework. Second, because the mechanisms of MABMs are validated in a direct way at the level of the agent, MABMs can be seen as a move towards a more realist approach to modelling compared to DSGE.

Emergent Corporate Mind

2020 ◽  
pp. 110-140
Author(s):  
Lisa Siraganian
Keyword(s):  
Stock Exchange ◽  
Daily Life ◽  
Emergent Properties ◽  
Prose Poem ◽  
Publicly Traded ◽  
Publicly Traded Companies ◽  
Oliver Wendell Holmes ◽  
Lively Debate ◽  
The Difference ◽  
Business Entities

A lively debate over “corporate mind” materialized in legal, philosophical, and political scientific guises throughout the first decades of the twentieth century. Legal theorists such as Harold Laski, Jethro Brown, and Frederic Maitland sought to ascribe intentions to mindful corporations to understand why corporations acted as they did and to treat them accordingly; theorists like Morris Cohen, John Salmond, and Oliver Wendell Holmes, Jr. thought this tactic made no sense. This chapter examines their dispute to argue that Gertrude Stein’s conceptualizing of groups of artists proposed representational solutions both similar to and ultimately divergent from these conceptions of corporate minds. A radical reading of Stein’s revolutionary prose poem, G.M.P. (1912), is offered, supported by archival manuscript evidence. That text ponders the difference between a publicly traded corporation, with its repetitive daily “life” exposed to anyone with a ticker-tape machine, and the creations of a group of painters and poets. Abstracting the art collectivity and giving the movement a name (“G.M.P.”) more typical of publicly traded companies on a stock exchange, Stein registers its divergence from a crowd, a corporate collective, or an individual. Like business entities, aesthetic movements possess emergent properties that are more than the sum of their artist parts; yet art’s immortality differs from a corporation’s life in perpetuity. Offering context for the period’s corporate ideas from various disciplines—political science, jurisprudence, philosophy, psychology—this chapter catches writers thinking through how a corporate group imagines and creates.

scholarly journals Toxicity Reduction of Euphorbia kansui Stir-Fried with Vinegar Based on Conversion of 3-O-(2′E,4′Z-Decadi-enoyl)-20-O-acetylingenol

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3806 ◽  
Author(s):  
Qiao Zhang ◽  
Yi Zhang ◽  
Shi-Kang Zhou ◽  
Kan Wang ◽  
Min Zhang ◽  
...  
Keyword(s):  
High Performance ◽  
Developmental Toxicity ◽  
Underlying Mechanism ◽  
Severe Toxicity ◽  
Sod Activity ◽  
Mechanisms Of Toxicity ◽  
Toxicity Reduction ◽  
Euphorbia Kansui ◽  
The Difference ◽  
Underlying Mechanisms

The dried roots of Euphorbia kansui S.L.Liou ex S.B.Ho have long been used to treat edema in China. However, the severe toxicity caused by Euphorbia kansui (EK) has seriously restricted its clinical application. Although EK was processed with vinegar to reduce its toxicity, the detailed mechanisms of attenuation in toxicity of EK stir-fried with vinegar (VEK) have not been well delineated. Diterpenoids are the main toxic ingredients of EK, and changes in these after processing may be the underlying mechanism of toxicity attenuation of VEK. 3-O-(2′E,4′Z-decadienoyl)-20-O-acetylingenol (3-O-EZ) is one of the diterpenoids derived from EK, and the content of 3-O-EZ was significantly reduced after processing. This study aims to explore the underlying mechanisms of toxicity reduction of VEK based on the change of 3-O-EZ after processing with vinegar. Based on the chemical structure of 3-O-EZ and the method of processing with vinegar, simulation experiments were carried out to confirm the presence of the product both in EK and VEK and to enrich the product. Then, the difference of peak area of 3-O-EZ and its hydrolysate in EK and VEK were detected by ultra-high-performance liquid chromatography (UPLC). Furthermore, the toxicity effect of 3-O-EZ and its hydrolysate, as well as the underlying mechanism, on zebrafish embryos were investigated. The findings showed that the diterpenoids (3-O-EZ) in EK can convert into less toxic ingenol in VEK after processing with vinegar; meanwhile, the content of ingenol in VEK was higher than that of EK. More interestingly, the ingenol exhibited less toxicity (acute toxicity, developmental toxicity and organic toxicity) than that of 3-O-EZ, and 3-O-EZ could increase malondialdehyde (MDA) content and reduce glutathione (GSH) content; cause embryo oxidative damage by inhibition of the succinate dehydrogenase (SDH) and superoxide dismutase (SOD) activity; and induce inflammation and apoptosis by elevation of IL-2 and IL-8 contents and activation of the caspase-3 and caspase-9 activity. Thus, this study contributes to our understanding of the mechanism of attenuation in toxicity of VEK, and provides the possibility of safe and rational use of EK in clinics.

scholarly journals Rational time investment during collective decision making in Temnothorax ants

2019 ◽  
Vol 15 (10) ◽  
pp. 20190542 ◽  
Author(s):  
Takao Sasaki ◽  
Benjamin Stott ◽  
Stephen C. Pratt
Keyword(s):  
Decision Making ◽  
Collective Decision ◽  
Collective Decision Making ◽  
Ant Colonies ◽  
Temnothorax Albipennis ◽  
Time Investment ◽  
Decision Outcomes ◽  
Nest Site Choice ◽  
The Difference ◽  
Underlying Mechanisms

The study of rational choice in humans and other animals typically focuses on decision outcomes, but rationality also applies to decision latencies, especially when time is scarce and valuable. For example, the smaller the difference in quality between two options, the faster a rational actor should decide between them. This is because the consequences of choosing the inferior option are less severe if the options are similar. Experiments have shown, however, that humans irrationally spend more time choosing between similar options. In this study, we assessed the rationality of time investment during nest-site choice by the rock ant, Temnothorax albipennis . Previous studies have shown that collective decision-making allows ant colonies to avoid certain irrational errors. Here we show that the same is true for time investment. Individual ants, like humans, irrationally took more time to complete an emigration when choosing between two similar nests than when choosing between two less similar nests. Whole colonies, by contrast, rationally made faster decisions when the options were more similar. We discuss the underlying mechanisms of decision-making in individuals and colonies and how they lead to irrational and rational time investment, respectively.

scholarly journals Biological Properties of 6-Gingerol: A Brief Review

2014 ◽  
Vol 9 (7) ◽  
pp. 1934578X1400900 ◽  
Author(s):  
Shaopeng Wang ◽  
Caihua Zhang ◽  
Guang Yang ◽  
Yanzong Yang
Keyword(s):  
Fruits And Vegetables ◽  
Biological Activities ◽  
Zingiber Officinale ◽  
Biological Properties ◽  
Anticancer Activities ◽  
Inhibition Of Angiogenesis ◽  
Underlying Mechanisms ◽  
Pharmacologically Active

Numerous studies have revealed that regular consumption of certain fruits and vegetables can reduce the risk of many diseases. The rhizome of Zingiber officinale (ginger) is consumed worldwide as a spice and herbal medicine. It contains pungent phenolic substances collectively known as gingerols. 6-Gingerol is the major pharmacologically-active component of ginger. It is known to exhibit a variety of biological activities including anticancer, anti-inflammation, and anti-oxidation. 6-Gingerol has been found to possess anticancer activities via its effect on a variety of biological pathways involved in apoptosis, cell cycle regulation, cytotoxic activity, and inhibition of angiogenesis. Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, 6-gingerol has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various diseases. Taken together, this review summarizes the various in vitro and in vivo pharmacological aspects of 6-gingerol and the underlying mechanisms.

Shape Homeostasis in Virtual Embryos

2009 ◽  
Vol 15 (2) ◽  
pp. 161-183 ◽  
Author(s):  
Tim Andersen ◽  
Richard Newman ◽  
Tim Otter
Keyword(s):  
Regulatory Networks ◽  
Developmental Process ◽  
Three Dimensional ◽  
High Capacity ◽  
Cellular Systems ◽  
Emergent Properties ◽  
Complex Interactions ◽  
Self Repair ◽  
Underlying Mechanisms ◽  
Cellular Components

We have constructed a computational platform suitable for examining emergence of shape homeostasis in simple three-dimensional cellular systems. An embryo phenotype results from a developmental process starting with a single cell and its genome. When coupled to an evolutionary search, this platform can evolve embryos with particular stable shapes and high capacity for self-repair, even though repair is not genetically encoded or part of the fitness criteria. With respect to the genome, embryo shape and self-repair are emergent properties that arise from complex interactions among cells and cellular components via signaling and gene regulatory networks, during development or during repair. This report analyzes these networks and the underlying mechanisms that control embryo growth, organization, stability, and robustness to injury.

scholarly journals Dynamic Allostery Highlights the Evolutionary Differences between the CoV-1 and CoV-2 Main Proteases

2021 ◽  
Author(s):  
P. Campitelli ◽  
J. Lu ◽  
S. B. Ozkan
Keyword(s):  
Comparative Analysis ◽  
Active Sites ◽  
Distal Region ◽  
Catalytic Site ◽  
Dynamic Coupling ◽  
Long Distance ◽  
Inhibitor Binding ◽  
Coupling Index ◽  
Two Systems ◽  
Biophysical Changes

ABSTRACTThe SARS-CoV-2 coronavirus has become one of the most immediate and widely-studied systems since its identification and subsequent global outbreak from 2019-2020. In an effort to understand the biophysical changes as a result of mutations, the mechanics of multiple different proteins within the SARS-CoV-2 virus have been studied and compared with SARS-CoV-1. Focusing on the main protease (mPro), we first explored the long range dynamic-relationship, particularly in cross-chain dynamics, using the Dynamic Coupling Index (DCI) to investigate the dynamic coupling between the catalytic site residues and the rest of the protein, both inter and intra chain for the CoV-1 and CoV-2 mPro. We found that there is significant cross-chain coupling between these active sites and distal residues in the CoV-2 mPro but it was missing in CoV-1. The enhanced long distance interactions, particularly between the two chains, suggest subsequently enhanced cooperativity for CoV-2. A further comparative analysis of the dynamic flexibility using the Dynamic Flexibility Index (DFI) between the CoV-1 and CoV-2 mPros shows that the inhibitor binding near active sites induces change in flexibility to a distal region of the protein, opposite in behavior between the two systems; this region becomes more flexible upon inhibitor binding in CoV-1 while it becomes less flexible in the CoV-2 mPro. Upon inspection, we show that, on average, the dynamic flexibility of the sites substituted from CoV-1 to CoV-2 changes significantly less than the average calculated across all residues within the structure, indicating that the differences in behaviors between the two systems is likely the result of allosteric influence, where the new substitutions in COV-2 induce flexibility and dynamical changes elsewhere in the structure.SIGNIFICANCEHere we have conducted a comparative analysis between the SARS-CoV-1 and SARS-CoV-2 mPro systems to shed mechanistic insight on the biophysical changes associated with the mutations between these two enzymes. Our work shows that the CoV-2 mPro system exhibits enhanced cross-chain communication between catalytic site residues and the rest of the structure. Further, both dynamic coupling and dynamic flexibility analyses indicates that, largely, the dynamic changes as evaluated by DCI and DFI occur at sites other than the mutation sites themselves, indicating that the functional differences between these two proteins are a result of dynamic allostery

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