Randomness and multilevel interactions in biology

The dynamic instability of living systems and the “superposition” of different forms of randomness are viewed, in this paper, as components of the contingently changing, or even increasing, organization of life through ontogenesis or evolution. To this purpose, we first survey how classical and quantum physics define randomness differently. We then discuss why this requires, in our view, an enriched understanding of the effects of their concurrent presence in biological systems’ dynamics. Biological randomness is then presented not only as an essential component of the heterogeneous determination and intrinsic unpredictability proper to life phenomena, due to the nesting of, and interaction between many levels of organization, but also as a key component of its structural stability. We will note as well that increasing organization, while increasing “order”, induces growing disorder, not only by energy dispersal effects, but also by increasing variability and differentiation. Finally, we discuss the cooperation between diverse components in biological networks; this cooperation implies the presence of constraints due to the particular nature of bio-entanglement and bio-resonance, two notions to be reviewed and defined in the paper.     

Mission impossible or mission accomplished: Do zoo organizational missions influence conservation practices?

Conservation is an important organizational focus for zoos and aquariums. Organizational identity theory predicts a relationship between what is central to organizations, such as their mission statements, and their strategic activities. Based on this theory, we tested how organizational missions relate to their conservation strategies and practices. Tax forms and websites provided data from 173 zoos and 38 aquariums in the Association of Zoos and Aquariums in North America. We analyzed conservation mission strength, organizational characteristics, and project features with dependent variables representing the depth of organizational conservation commitments: amount of grants zoos funded, number of partner organizations, and number of projects per zoo. On tax forms, the average amount of total conservation grants donated to partner organizations per zoo was over $650,000, while the average number of partners reported on the tax forms was two. The content analysis of websites revealed an average of 14 conservation partners and 10 projects per zoo. Negative binomial regression models were significant. The financial analysis revealed that only the number of zoo personnel, as a surrogate for organization size, significantly predicted the amount of zoos’ conservation grants. Website analyses found increasing budgets, organizational involvement, and geographic reach of the projects predicted increasing numbers of conservation projects and partnerships. However, our findings did not support the hypothesized relationship—strength of organizational mission did not predict strategy and activities. Zoos could do more to strategically activate their organizational identities and conservation missions to achieve their conservation goals.     

Coemergence of regularity and complexity during neural network development

With the growing recognition that rhythmic and oscillatory patterns are widespread in the brain and play important roles in all aspects of the function of our nervous system, there has been a resurgence of interest in neuronal synchronized bursting activity. Here, we were interested in understanding the development of synchronized bursts as information-bearing neuronal activity patterns. For that, we have monitored the morphological organization and spontaneous activity of neuronal networks cultured on multielectrode-arrays during their self-executed evolvement from a mixture of dissociated cells into an active network. Complex collective network electrical activity evolved from sporadic firing patterns of the single neurons. On the system (network) level, the activity was marked by bursting events with interneuronal synchronization and nonarbitrary temporal ordering. We quantified these individual-to-collective activity transitions using newly-developed system level quantitative measures of time series regularity and complexity. We found that individual neuronal activity before synchronization was characterized by high regularity and low complexity. During neuronal wiring, there was a transient period of reorganization marked by low regularity, which then leads to coemergence of elevated regularity and functional (nonstochastic) complexity. We further investigated the morphology-activity interplay by modeling artificial neuronal networks with different topological organizations and connectivity schemes. The simulations support our experimental results by showing increased levels of complexity of neuronal activity patterns when neurons are wired up and organized in clusters (similar to mature real networks), as well as network-level activity regulation once collective activity forms.     

Altered dynamics upon oligomerization corresponds to key functional sites

It is known that over half of the proteins encoded by most organisms function as oligomeric complexes. Oligomerization confers structural stability and dynamics changes in proteins. We investigate the effects of oligomerization on protein dynamics and its functional significance for a set of 145 multimeric proteins. Using coarse‐grained elastic network models, we inspect the changes in residue fluctuations upon oligomerization and then compare with residue conservation scores to identify the functional significance of these changes. Our study reveals conservation of about ½ of the fluctuations, with ¼ of the residues increasing in their mobilities and ¼ having reduced fluctuations. The residues with dampened fluctuations are evolutionarily more conserved and can serve as orthosteric binding sites, indicating their importance. We also use triosephosphate isomerase as a test case to understand why certain enzymes function only in their oligomeric forms despite the monomer including all required catalytic residues. To this end, we compare the residue communities (groups of residues which are highly correlated in their fluctuations) in the monomeric and dimeric forms of the enzyme. We observe significant changes to the dynamical community architecture of the catalytic core of this enzyme. This relates to its functional mechanism and is seen only in the oligomeric form of the protein, answering why proteins are oligomeric structures. Proteins 2017; 85:1422–1434. © 2017 Wiley Periodicals, Inc.     

Strategy and software for the statistical spatial analysis of 3D intracellular distributions

The localization of proteins in specific domains or compartments in the 3D cellular space is essential for many fundamental processes in eukaryotic cells. Deciphering spatial organization principles within cells is a challenging task, in particular because of the large morphological variations between individual cells. We present here an approach for normalizing variations in cell morphology and for statistically analyzing spatial distributions of intracellular compartments from collections of 3D images. The method relies on the processing and analysis of 3D geometrical models that are generated from image stacks and that are used to build representations at progressively increasing levels of integration, ultimately revealing statistical significant traits of spatial distributions. To make this methodology widely available to end‐users, we implemented our algorithmic pipeline into a user‐friendly, multi‐platform, and freely available software. To validate our approach, we generated 3D statistical maps of endomembrane compartments at subcellular resolution within an average epidermal root cell from collections of image stacks. This revealed unsuspected polar distribution patterns of organelles that were not detectable in individual images. By reversing the classical ‘measure‐then‐average’ paradigm, one major benefit of the proposed strategy is the production and display of statistical 3D representations of spatial organizations, thus fully preserving the spatial dimension of image data and at the same time allowing their integration over individual observations. The approach and software are generic and should be of general interest for experimental and modeling studies of spatial organizations at multiple scales (subcellular, cellular, tissular) in biological systems.     

Extracellular matrix and embryonal morphogenesis: role of fibronectin in cell migration

The neural crest provides a useful paradigm for cell migration and modulations in cell adhesion during morphogenesis. In the present review, we describe the major findings on the role of the extracellular matrix glycoprotein fibronectin and its corresponding integrin receptor in the locomotory behavior of neural crest cells. In vivo, fibronectin is associated with the migratory routes of neural crest cells and, in some cases, it disappears from the environment of the cells as they stop migrating. In vitro, neural crest cells show a great preference for fibronectin substrates as compared to other matrix molecules. Both in vivo and in vitro, neural crest cell migration can be specifically inhibited by antibodies or peptides that interfere with the binding of fibronectin to its integrin receptor. However, the migratory behavior of neural crest cells cannot result solely from the interaction with fibronectin. Thus, neural crest cells exhibit a particular organization of integrin receptors on their surface and develop a cytoskeletal network which differs from that of non-motile cells. These properties are supposed to permit rapid changes in the shape of cells and to favor a transient adhesion to the substratum. Recent findings have established that different forms of fibronectin may occur, which differ by short sequences along the molecule. The functions of most of these sequences are not known, except for 1 of them which carries a binding site for integrin receptors. We have demonstrated that this site is recognized by neural crest cells and plays a crucial role in their displacement. It is therefore possible that the forms of fibronectin carrying this sequence are not evenly distributed in the embryo, thus allowing migrating neural crest cells to orientate in the embryo. Fibronectin would then not only play a permissive role in embryonic cell motility, but have an instructive function in cell behavior.     

哺乳动物卵母细胞成熟和受精中细胞骨架重组和作用

卵母细胞成熟和受精是动物生殖过程的核心环节。细胞骨架是遍布于卵母细胞胞质中的一种复杂的蛋白质纤维网络,研究表明,卵母细胞成熟和受精过程中伴随着广泛的胞质骨架重组。哺乳动物卵母细胞和早期胚胎中细胞骨架具有其独特的分布和功能,使卵母细胞和胚胎呈现出不同的变化特点。微丝、微管的分布变化与卵母细胞成熟和受精中遗传物质的重组密切相关。近年来,对哺乳动物不同物种间卵母细胞和胚胎中细胞骨架成分的研究取得了很大的进展,结合这些研究成果,对哺乳动物卵母细胞成熟和受精过程中细胞骨架的重组、分布和作用进行了介绍。同时,对多种信号转导途径参与卵母细胞成熟和受精中细胞骨架系统的调控也作了探讨。     

The skin barrier in healthy and diseased state

The primary function of the skin is to protect the body for unwanted influences from the environment. The main barrier of the skin is located in the outermost layer of the skin, the stratum corneum. The stratum corneum consists of corneocytes surrounded by lipid regions. As most drugs applied onto the skin permeate along the lipid domains, the lipid organization is considered to be very important for the skin barrier function. It is for this reason that the lipid organization has been investigated quite extensively. Due to the exceptional stratum corneum lipid composition, with long chain ceramides, free fatty acids and cholesterol as main lipid classes, the lipid organization is different from that of other biological membranes. In stratum corneum, two lamellar phases are present with repeat distances of approximately 6 and 13 nm. Moreover the lipids in the lamellar phases form predominantly crystalline lateral phases, but most probably a subpopulation of lipids forms a liquid phase. Diseased skin is often characterized by a reduced barrier function and an altered lipid composition and organization. In order to understand the aberrant lipid organization in diseased skin, information on the relation between lipid composition and organization is crucial. However, due to its complexity and inter-individual variability, the use of native stratum corneum does not allow detailed systematic studies. To circumvent this problem, mixtures prepared with stratum corneum lipids can be used. In this paper first the lipid organization in stratum corneum of normal and diseased skin is described. Then the role the various lipid classes play in stratum corneum lipid organization and barrier function has been discussed. Finally, the information on the role various lipid classes play in lipid phase behavior has been used to interpret the changes in lipid organization and barrier properties of diseased skin.     

The Role of the Organization Structure in the Diffusion of Innovations

Diffusion and adoption of innovations is a topic of increasing interest in economics, market research, and sociology. In this paper we investigate, through an agent based model, the dynamics of adoption of innovative proposals in different kinds of structures. We show that community structure plays an important role on the innovation diffusion, so that proposals are more likely to be accepted in homogeneous organizations. In addition, we show that the learning process of innovative technologies enhances their diffusion, thus resulting in an important ingredient when heterogeneous networks are considered. We also show that social pressure blocks the adoption process whatever the structure of the organization. These results may help to understand how different factors influence the diffusion and acceptance of innovative proposals in different communities and organizations.     

A lack of response of the financial behaviors of biodiversity conservation nonprofits to changing economic conditions

The effectiveness of conservation organizations is determined in part by how they adapt to changing conditions. Over the previous decade, economic conditions in the United States (US) showed marked variation including a period of rapid growth followed by a major recession. We examine how biodiversity conservation nonprofits in the US responded to these changes through their financial behaviors, focusing on a sample of 90 biodiversity conservation nonprofits and the largest individual organization (The Nature Conservancy; TNC). For the 90 sampled organizations, an analysis of financial ratios derived from tax return data revealed little response to economic conditions. Similarly, more detailed examination of conservation expenditures and land acquisition practices of TNC revealed only one significant relationship with economic conditions: TNC accepted a greater proportion of conservation easements as donated in more difficult economic conditions. Our results suggest that the financial behaviors of US biodiversity conservation nonprofits are unresponsive to economic conditions.     

The skin barrier in healthy and diseased state

The primary function of the skin is to protect the body for unwanted influences from the environment. The main barrier of the skin is located in the outermost layer of the skin, the stratum corneum. The stratum corneum consists of corneocytes surrounded by lipid regions. As most drugs applied onto the skin permeate along the lipid domains, the lipid organization is considered to be very important for the skin barrier function. It is for this reason that the lipid organization has been investigated quite extensively. Due to the exceptional stratum corneum lipid composition, with long chain ceramides, free fatty acids and cholesterol as main lipid classes, the lipid organization is different from that of other biological membranes. In stratum corneum, two lamellar phases are present with repeat distances of approximately 6 and 13 nm. Moreover the lipids in the lamellar phases form predominantly crystalline lateral phases, but most probably a subpopulation of lipids forms a liquid phase. Diseased skin is often characterized by a reduced barrier function and an altered lipid composition and organization. In order to understand the aberrant lipid organization in diseased skin, information on the relation between lipid composition and organization is crucial. However, due to its complexity and inter-individual variability, the use of native stratum corneum does not allow detailed systematic studies. To circumvent this problem, mixtures prepared with stratum corneum lipids can be used. In this paper first the lipid organization in stratum corneum of normal and diseased skin is described. Then the role the various lipid classes play in stratum corneum lipid organization and barrier function has been discussed. Finally, the information on the role various lipid classes play in lipid phase behavior has been used to interpret the changes in lipid organization and barrier properties of diseased skin.     

N-3 fatty acids and membrane microdomains: From model membranes to lymphocyte function

This article summarizes the author's research on fish oil derived n-3 fatty acids, plasma membrane organization and B cell function. We first cover basic model membrane studies that investigated how docosahexaenoic acid (DHA) targeted the organization of sphingolipid-cholesterol enriched lipid microdomains. A key finding here was that DHA had a relatively poor affinity for cholesterol. This work led to a model that predicted DHA acyl chains in cells would manipulate lipid-protein microdomain organization and thereby function. We then review how the predictions of the model were tested with B cells in vitro followed by experiments using mice fed fish oil. These studies reveal a highly complex picture on how n-3 fatty acids target lipid-protein organization and B cell function. Key findings are as follows: (1) n-3 fatty acids target not just the plasma membrane but also endomembrane organization; (2) DHA, but not eicosapentaenoic acid (EPA), disrupts microdomain spatial distribution (i.e. clustering), (3) DHA alters protein lateral organization and (4) changes in membrane organization are accompanied by functional effects on both innate and adaptive B cell function. Altogether, the research over the past 10 years has led to an evolution of the original model on how DHA reorganizes membrane microdomains. The work raises the intriguing possibility of testing the model at the human level to target health and disease.     

Cerebral blood flow regulation in REM sleep: a model for flow-metabolism coupling.

The pattern of metabolic and circulatory changes occurring during REM sleep in the whole brain is also observed at a regional level in different instances of functional activation. This pattern is characterized by an increase in metabolic rate, blood flow, glucose and oxygen uptake, the increase in glucose uptake generally exceeding oxygen uptake. A model of interpretation is presented, based on the assumption that substantial limitation to oxygen diffusion exists in the brain. According to the model, microregions lying at mid-distance between capillaries may become hypoxic, depending on metabolic rate and blood-cell PO2 difference. At increasing metabolic rates, O2 consumption in pericapillary microregions increases and the PO2 drop becomes steeper. As a consequence, in microregions far from capillaries a decrease in O2 availability occurs, in concomitance with the increase in metabolic rate, so that non-oxidative glucose metabolism develops locally. A similar spatial PO2 pattern forms in the case of arterial hypoxia, when capillary PO2, and then blood-cell PO2 difference, is reduced. The hypoxic microregions are the source of vasodilatatory messages, the consequent vasodilatation increasing average capillary PO2 and then favoring O2 diffusion to the tissue. Oxygen thus appears to be a better candidate than glucose as a mediator of blood flow-metabolism coupling. This is supported by its higher extraction fraction and by the fact that, in physiologic conditions, arterial hypoxia (and not hypoglycemia) acts on cerebral blood flow. Moreover, the diffusion capacity of glucose in the brain is higher than that of oxygen, so that diffusion limitation is more likely to occur for oxygen. The present model allows consistent organization of the stereotyped changes in cerebral blood flow and glucose and oxygen uptake occurring both in REM sleep and in other instances of brain activation.     

Developing an independent anti-racist model for asylum rights organizing in England

Since the mid-1990s third-sector professionals and organizations have come under increasing pressure to help enforce restrictive and punitive policies towards refugees and asylum seekers. This paper presents one response, using an empirical case study to develop an Independent Anti-Racist Model for asylum rights organizing. This combines data from a three-year study comparing four organizations in a major city in England and reflections on the author's experience as a member of the case study organization, contextualized in the literature. The paper identifies a related set of features distinguishing this model from other types of organization and the conditions making it possible, and concludes that it offers wider lessons for work with groups in a conflictual relationship with the state.     

Monitoring the organization and dynamics of bovine hippocampal membranes utilizing Laurdan generalized polarization

Organization and dynamics of cellular membranes in the nervous system are crucial for the function of neuronal membrane receptors. The lipid composition of neuronal cells is unique and has been correlated with the increased complexity in the organization of the nervous system during evolution. Previous work from our laboratory has established bovine hippocampal membranes as a convenient natural source for studying neuronal receptors such as the G-protein coupled serotonin_1A receptor. In this paper, we have explored the organization and dynamics of bovine hippocampal membranes using the amphiphilic environment-sensitive fluorescent probe Laurdan. Our results show that the emission spectra of Laurdan display an additional red shifted peak as a function of increasing temperature in native as well as cholesterol-depleted membranes and liposomes made from lipid extracts of the native membrane. Interestingly, wavelength dependence of Laurdan generalized polarization (GP) in native membranes indicates the presence of an ordered gel-like phase at low temperatures, whereas characteristics of the liquid-ordered phase are observed at high temperatures. Similar experiments performed using cholesterol-depleted membranes show fluidization of the membrane with increasing cholesterol depletion. In addition, results from fluorescence polarization of DPH indicate that the hippocampal membrane is fairly ordered even at physiological temperature. The temperature dependence of Laurdan excitation GP provides a measure of the apparent thermal transition temperature and extent of cooperativity in these membranes. Analysis of time-resolved fluorescence measurements of Laurdan shows reduction in mean fluorescence lifetime with increasing temperature due to change in environmental polarity. These results constitute novel information on the dynamics of hippocampal membranes and its modulation by cholesterol depletion monitored using Laurdan fluorescence.     

Sensitivity of the photosynthetic apparatus to UV-A radiation: role of light-harvesting complex II–photosystem II supercomplex organization

In this work we study the effect of UV-A radiation on the function of the photosynthetic apparatus in thylakoid membranes with different organization of the light-harvesting complex II–photosystem II (LHCII–PSII) supercomplex. Leaves and isolated thylakoid membranes from a number of previously characterized pea species with different LHCII size and organization were subjected to UV-A treatment. A relationship was found between the molecular organization of the LHCII (ratio of the oligomeric to monomeric forms of LHCII) and UV-A-induced changes both in the energy transfer from PSII to PSI and between the chlorophyll–protein complexes within the LHCII–PSII supercomplex. Dependence on the organization of the LHCII was also found with regard to the degree of inhibition of the photosynthetic oxygen evolution. The susceptibility of energy transfer and oxygen evolution to UV-A radiation decreased with increasing LHCII oligomerization when the UV-A treatment was performed on isolated thylakoid membranes, in contrast to the effect observed in thylakoid membranes isolated from pre-irradiated pea leaves. The data suggest that UV-A radiation leads mainly to damage of the PSIIα centers. Comparison of membranes with different organization of their LHCII–PSII supercomplex shows that the oligomeric forms of LHCII play a key role for sensitivity to UV-A radiation of the photosynthetic apparatus. S. G. Taneva is Associated member of the Institute of Biophysics, Bulgarian Academy of Sciences.     

Microfilament reorganization during apoptosis: the role of Gas2, a possible substrate for ICE-like proteases.

Gas2, a component of the microfilament system, belongs to the class of gas genes whose expression is induced at growth arrest. After serum or growth factor addition to quiescent NIH 3T3 cells, Gas2 is hyperphosphorylated and relocalized at the membrane ruffles. By overexpressing gas2wt and a series of deletion mutants of the C-terminal region, we have analysed its role in the organization of the actin cytoskeleton in different cell lines. Overexpression of Gas2 deleted at its C-terminal region (delta 276-314 and delta 236-314), but not its wild-type form, induces dramatic changes in the actin cytoskeleton and cell morphology. These effects are not due to interference of the deleted forms with the endogenous Gas2wt function but could be ascribed to a gain of function. We demonstrate that during apoptosis the C-terminal domain of Gas2 is removed by proteolytic cleavage, resulting in a protein that is similar in size to the described delta 276-314. Moreover, by using in vitro mutagenesis, we also demonstrate that the proteolytic processing of Gas2 during apoptosis is dependent on an aspartic acid residue at position 279. The evidence accumulated here could thus represent a first example of a mechanism linking apoptosis with the co-ordinated microfilament-dependent cell shape changes, as possibly mediated by an interleukin-1 beta-converting enzyme (ICE)-like dependent proteolytic cleavage of the Gas2 protein.     

Pitfalls of the most commonly used models of context dependent substitution

Background  

Neighboring nucleotides exert a striking influence on mutation, with the hypermutability of CpG dinucleotides in many genomes being an exemplar. Among the approaches employed to measure the relative importance of sequence neighbors on molecular evolution have been continuous-time Markov process models for substitutions that treat sequences as a series of independent tuples. The most widely used examples are the codon substitution models. We evaluated the suitability of derivatives of the nucleotide frequency weighted (hereafter NF) and tuple frequency weighted (hereafter TF) models for measuring sequence context dependent substitution. Critical properties we address are their relationships to an independent nucleotide process and the robustness of parameter estimation to changes in sequence composition. We then consider the impact on inference concerning dinucleotide substitution processes from application of these two forms to intron sequence alignments from primates.     

Antisymmetry,directional asymmetry,and dynamic morphogenesis

Fluctuating asymmetry is the most commonly used measure of developmental instability. Some authors have claimed that antisymmetry and directional asymmetry may have a significant genetic basis, thereby rendering these forms of asymmetry useless for studies of developmental instability. Using a modified Rashevsky-Turing reaction-diffusion model of morphogenesis, we show that both antisymmetry and directional asymmetry can arise from symmetry-breaking phase transitions. Concentrations of morphogen on right and left sides can be induced to undergo transitions from phase-locked periodicity, to phase-lagged periodicity, to chaos, by simply changing the levels of feedback and inhibition in the model. The chaotic attractor has two basins of attraction-right sidedominance and left side dominance. With minor disturbance, a developmental trajectory settles into one basin or the other. With increasing disturbance, the trajectory can jump from basin to basin. The changes that lead to phase transitions and chaos are those expected to occur with either genetic change or stress. If we assume that the morphogen influences the behavior of cell populations, then a transition from phase-locked periodicity to chaos in the morphogen produces a corresponding transition from fluctuating asymmetry to antisymmetry in both morphogen concentrations and cell populations. Directional asymmetry is easily modeled by introducing a bias in the conditions of the simulation. We discuss the implications of this model for researchers using fluctuating asymmetry as an indicator of stress.     

Organizational capacity and ecological restoration

Organizations entrusted with responsibilities and resources to repair ecosystems have for many decades pursued their defining purpose against long odds created by a host of inherent challenges, notably the long time frames required for ecological recovery and landscape-level stressors. Global change compounds these challenges, increasing shocks to the operating environments of these organizations. Interest in assessing organizational capacity to respond to system shocks (i.e. resilience) productively has been strong in many fields, though not in the restoration arena. The objectives of this paper are to build awareness of the importance of organizations for achieving the aims of restoration and to spur organizational research to strengthen the restoration sector. I summarize research on organizations relevant to the restoration sector and with this foundation propose a framework for assessing the capacity of restoration organizations. The proposed framework is an adaptation of models used in other sectors, based on five critical capacities: situation awareness, governance and leadership, internal resources, external relations, and change readiness. We can assess the extent to which an organization possesses each capacity by eliciting feedback about functions linked to each capacity. Devising assessment tools from this framework requires attention to key realities of the restoration sector including prevalence of short-term funding, effect of externalities on restoration outcomes, dependence on partnerships of multiple organizations for complex and large restorations. Exploration into assessment approaches for restoration organizations highlights a major knowledge gap that, if addressed, could enhance the reliability of restoration as a global and local strategy for improving ecosystems services.