Distinct Levels Of Organization Research Articles

Assessment of diphenhydramine toxicity - Is its mode of action conserved between human and zebrafish?

The main aim of the study is to evaluate the effects of the pharmaceutical diphenhydramine (DPH) on embryo-larvae Danio rerio across distinct levels of organization - individual and subcellular - and correlate those effects with the DPH mode of action (MoA) assessed by in silico analysis. An embryos heartbeat rate reduction was observed at 10mg/L DPH, but 0.001 to 10mg/L did not significantly affect the zebrafish survival, hatching and morphology. Larvae swimming distance decreased (hypoactivity) at 1 and 10mg/L DPH. Moreover, the straightforward movements decrease and the increase in the zigzag movements or movements with direction changes, shown an erratic swimming behavior. Energy budgets decreased for lipid (0.01mg/L DPH) and carbohydrate (10mg/L DPH) contents. Cholinesterase (neural function) and glutathione S-transferase (Phase II biotransformation/antioxidant processes) increased their activities at 10mg/L DPH, where a decrease in the total glutathione content (antioxidant system) was observed. DNA damage was found at 0.01 and 10mg/L DPH. However, a DNA repair occurred after subsequent 72h in clean media. The in silico study revealed a relevant conservation between human and zebrafish DPH target molecules. These data provide a valuable ecotoxicological information about the DPH effects and MoA to non-target organisms.

The Unity of Nature in Schelling’s World Soul

The Unity of Nature in Schelling’s World Soul Naomi Fisher I Written in the middle of Schelling’s early period in the philosophy of nature, his 1798 On the World Soul offers an account of nature that is both a response to Kant’s Critique of Teleological Judgment as well as an example of the emphasis on natural and philosophical unity that dominates the post-Kantian philosophy of the late eighteenth and early nineteenth centuries. This 1798 work impressed Goethe and was one reason for Schelling’s appointment to a professorship at Jena.1 It has not, however, been a focus of interpretive work on Schelling. 2 That Schelling attempts to offer an organically [End Page 527] unified conception of nature in his early philosophy of nature is well known, but the manner in which he does this is underexplored. Some have maintained that Schelling construes all organization organically, including mechanical systems; 3 others consider such unity to be posited [End Page 528] as a requirement of subjectivity, that is, established primarily through transcendental arguments.4 Rather, Schelling’s assertion of the organic [End Page 529] unity of nature as a whole—indicated by the term “world soul” (Weltseele)—must be understood in the context of the main claim of this work: There is an organizing principle of nature, operating at various levels and in various ways, that grounds every kind of organization in nature; the world soul is one manifestation of this principle. It is primarily this organizing principle that grants nature its unity. It is not obvious how to characterize organizational unity or how organic unities in nature relate to mechanical laws. In what follows I offer an account of the unity of nature as presented in Schelling’s World Soul. I will show that the unity of nature in this work is characterized by a principle of organization that operates in a reflexive and iterative way: The results of the principle at one level are operated on by that principle iteratively at a higher level to produce different levels of organization. The lowest such level is matter-as-such, and the laws governing matter-as-such are universal; the highest level in nature is nature as a whole, and is singular and all-encompassing. Crucially, for Schelling, the very same principle is productive both of the overarching unity of an object and the elements that comprise this unity. This implies that the principle that guarantees unity does not unite originally disparate or independent elements but is always, even in the case of mechanical laws, productive of those elements. Far from being an ad hoc metaphysical principle that constitutes a mere assertion of unity, the organizational principle not only unifies various elements or features of nature into a cooperative organic system but also provides a metaphysical ground and explanation of those various features. What emerges from this picture is a conception of natural organization that can be summed up in the following way: The distinct iterative operations of the principle of organization give rise to distinct levels of organization. Such levels increase in particularity with each iteration, from the most general mechanical laws to the singular unity of the world-whole. All organization in nature is grounded in the principle of organization, including both organic and mechanical organization. The principle of organization can be articulated as follows: It is characterized as the opposition of positive and negative forces or principles, the unity of which—both in the sense of that which brings them together and in the sense of that which grants them the status of a singular principle—can be given only in the undifferentiated Absolute, which cannot be [End Page 530] accessed discursively.5 In other words, one must keep distinct the unity conferred by the principle within nature, to mechanism and organism, and to the universal organism, on the one hand, and the unity of the principle of nature, which cannot be grasped discursively, on the other. I will explain this last point in the final section of the paper. I will first lay out the structure and explanatory framework of the World Soul (section 2), showing how the positive and negative...

The role of individual variation in flowering and pollination in the reproductive success of a crepuscular buzz-pollinated plant.

Plant individuals within a population differ in their phenology and interactions with pollinators. However, it is still unknown how individual differences affect the reproductive success of plants that have functionally specialized pollination systems. Here, we evaluated whether plant individual specialization in phenology (temporal specialization) and in pollination (pollinator specialization) affect the reproductive success of the crepuscular-bee-pollinated plant Trembleya laniflora (Melastomataceae). We quantified flowering activity (amplitude, duration and overlap), plant-pollinator interactions (number of flowers visited by pollinators) and reproductive success (fruit set) of T. laniflora individuals from three distinct locations in rupestrian grasslands of southeastern Brazil. We estimated the degree of individual temporal specialization in flowering phenology and of individual specialization in plant-pollinator interactions, and tested their relationship with plant reproductive success. Trembleya laniflora presented overlapping flowering, a temporal generalization and specialized pollinator interactions. Flowering overlap among individuals and populations was higher than expected by chance but did not affect the individual interactions with pollinators and nor their reproductive success. In contrast, higher individual generalization in the interactions with pollinators was related to higher individual reproductive success. Our findings suggest that individual generalization in plant-pollinator interaction reduces the potential costs of specialization at the species level, ensuring reproductive success. Altogether, our results highlight the complexity of specialization/generalization of plant-pollinator interactions at distinct levels of organization, from individuals to populations, to species.

Environmental Oxygen is a Key Modulator of Development and Evolution: From Molecules to Ecology

Oxygen is a key regulator of both development and homeostasis and a promising candidate to bridge the influence of the environment and the evolution of new traits. To clarify the various ways in which oxygen may modulate embryogenesis, its effects are reviewed at distinct organizational levels. First, the role of pathways that sense dioxygen levels and reactive oxygen species are reviewed. Then, the effects of microenvironmental oxygen on metabolism, stemness, and differentiation throughout embryogenesis are discussed. Last, the interplay between ecology and development are reexamined with a focus on the evolution of tetrapods, including during the emergence of a novel mechanism that shapes amniote limbs-interdigital cell death. Both genetic and environmental components work together during the formation of organisms, highlighting the importance of a multidisciplinary approach for understanding the evolution of new traits.

How Does the Regulatory Genome Work?

The regulatory genome controls genome activity throughout the life of an organism. This requires that complex information processing functions are encoded in, and operated by, the regulatory genome. Although much remains to be learned about how the regulatory genome works, we here discuss two cases where regulatory functions have been experimentally dissected in great detail and at the systems level, and formalized by computational logic models. Both examples derive from the sea urchin embryo, but assess two distinct organizational levels of genomic information processing. The first example shows how the regulatory system of a single gene, endo16, executes logic operations through individual transcription factor binding sites and cis-regulatory modules that control the expression of this gene. The second example shows information processing at the gene regulatory network (GRN) level. The GRN controlling development of the sea urchin endomesoderm has been experimentally explored at an almost complete level. A Boolean logic model of this GRN suggests that the modular logic functions encoded at the single-gene level show compositionality and suffice to account for integrated function at the network level. We discuss these examples both from a biological-experimental point of view and from a computer science-informational point of view, as both illuminate principles of how the regulatory genome works.

Acute and chronic effects of paracetamol exposure on Daphnia magna: how oxidative effects may modulate responses at distinct levels of organization in a model species.

The modern usage of pharmaceutical drugs has led to a progressive increase in their presence and environment concentrations, particularly in the aquatic compartment which is the most common final dumping location for this specific class of chemicals. These substances, due to their chemical and biological properties, can exert mostly uncharacterized toxic effects to non-target aquatic species, given the diverse pathways they activate, and the large number of putative targets in the wild. Among drugs in the environment, paracetamol assumes a leading role, considering its widespread therapeutic use and consequently, environmental presence. The present study aimed to assess the acute and chronic effects of paracetamol, in ecologically relevant levels, in the freshwater cladoceran Daphnia magna, namely focusing on biochemical and reproductive parameters. Considering the pro-oxidant effects of paracetamol, already described for a large set of aquatic organisms, specific enzymes involved in the anti-oxidant and metabolic responses were quantified, namely catalase (CAT) and glutathione S-transferases (GSTs) activities. Cholinesterases (ChEs) activity was quantified to evaluate the capacity of paracetamol to induce neurotoxicity, an indirect outcome of oxidative effects by paracetamol, that may affect feeding behavior and reproductive outcomes of this crustacean. Paracetamol in the tested levels showed no effect on reproductive traits of D. magna. Results obtained for organisms acutely exposed included significant increases in the activities of both GSTs and CAT, demonstrating a short-term pro-oxidative effect by paracetamol. On the contrary, ChEs activity was significantly decreased in organisms exposed to this drug, showing a possible interference with neurotransmission. On the contrary, no noteworthy effects were reported for organisms chronically exposed to ecologically realistic concentrations, evidencing the transient nature of the obtained biological response. These results demonstrate the responsiveness of D. magna to paracetamol, especially for high levels of exposure that, despite not being environmentally relevant, are able to trigger significant antioxidant responses. No population effects were likely to be caused by realistic levels of paracetamol, and the absence of biochemical changes after chronic exposure suggests that this specific organism may not be deleteriously affected by low levels of paracetamol, under real scenarios of contamination.

Fragility Assessment of Bovine Cortical Bone Using Scratch Tests.

Bone is a complex hierarchical material with five distinct levels of organization. Factors like aging and diseases like osteoporosis increase the fragility of bone, making it fracture-prone. Owing to the large socio-economic impact of bone fracture in our society, there is a need for novel ways to assess the mechanical performance of each hierarchical level of bone. Although stiffness and strength can be probed at all scales - nano-, micro-, meso-, and macroscopic - fracture assessment has so far been confined to macroscopic testing. This limitation restricts our understanding of bone fracture and constrains the scope of laboratory and clinical studies. In this research, we investigate the fracture resistance of bone from the microscopic to the mesoscopic length scales using micro scratch tests combined with nonlinear fracture mechanics. The tests are performed in the short longitudinal orientation on bovine cortical bone specimens. A meticulous experimental protocol is developed and a large number (102) of tests are conducted to assess the fracture toughness of cortical bone specimens while accounting for the heterogeneity associated with bone microstructure.

Evolution of acuteness in pathogen metapopulations: conflicts between "classical" and invasion-persistence trade-offs.

Classical life-history theory predicts that acute, immunizing pathogens should maximize between-host transmission. When such pathogens induce violent epidemic outbreaks, however, a pathogen's short-term advantage at invasion may come at the expense of its ability to persist in the population over the long term. Here, we seek to understand how the classical and invasion-persistence trade-offs interact to shape pathogen life-history evolution as a function of the size and structure of the host population. We develop an individual-based infection model at three distinct levels of organization: within an individual host, among hosts within a local population, and among local populations within a metapopulation. We find a continuum of evolutionarily stable pathogen strategies. At one end of the spectrum-in large well-mixed populations-pathogens evolve to greater acuteness to maximize between-host transmission: the classical trade-off theory applies in this regime. At the other end of the spectrum-when the host population is broken into many small patches-selection favors less acute pathogens, which persist longer within a patch and thereby achieve enhanced between-patch transmission: the invasion-persistence tradeoff dominates in this regime. Between these extremes, we explore the effects of the size and structure of the host population in determining pathogen strategy. In general, pathogen strategies respond to evolutionary pressures arising at both scales.

Profile-Statistical Periodicity of DNA Coding Regions

Novel methods for identifying a new type of DNA latent periodicity, called latent profile periodicity or latent profility, are used to search for periodic structures in genes. These methods reveal two distinct levels of organization of genetic information encoding. It is shown that latent profility in genes may correlate with specific structural features of their encoded proteins.

The Cybersemiotics and Info-Computationalist Research Programmes as Platforms for Knowledge Production in Organisms and Machines

Both Cybersemiotics and Info-computationalist research programmes represent attempts to unify understanding of information, knowledge and communication. The first one takes into account phenomenological aspects of signification which are insisting on the human experience "from within". The second adopts solely the view "from the outside" based on scientific practice, with an observing agent generating inter-subjective knowledge in a research community. The process of knowledge production, embodied into networks of cognizing agents interacting with the environment and developing through evolution is studied on different levels of abstraction in both frames of reference. In order to develop scientifically tractable models of evolution of intelligence in informational structures from pre-biotic/chemical to living networked intelligent organisms, including the implementation of those models in artificial agents, a basic level language of Info-Computationalism has shown to be suitable. There are however contexts in which we deal with complex informational structures essentially dependent on human first person knowledge where high level language such as Cybersemiotics is the appropriate tool for conceptualization and communication. Two research projects are presented in order to exemplify the interplay of info-computational and higher-order approaches: The Blue Brain Project where the brain is modeled as info-computational system, a simulation in silico of a biological brain function, and Biosemiotics research on genes, information, and semiosis in which the process of semiosis is understood in info-computational terms. The article analyzes differences and convergences of Cybersemiotics and Info-computationalist approaches which by placing focus on distinct levels of organization, help elucidate processes of knowledge production in intelligent agents.

Trust at Different Organizational Levels

The authors explore the effects of trust at three distinct organizational levels in a marketing collaboration: interorganizational trust between collaborating firms, each firm's agency trust in its own representatives assigned to a collaborative entity (coentity), and intraentity trust among the representatives assigned to the coentity. Dyadic survey and longitudinal objective performance data from 114 international joint ventures indicate that trust at each level has unique effects but similarly influences the collaborating firms' resource investments or the coentity's use of those resources. Interorganizational and agency trust motivate resource investments in the coentity, particularly in the context of a differentiation strategy, whereas intraentity trust promotes coordination within the coentity, and interorganizational trust and a differentiation strategy magnify that effect. Intraentity trust can also undermine coentity responsiveness to environmental change, especially when joined by interorganizational trust between collaborating firms and formalized decision making within the coentity. These findings demonstrate that managing and building trust at multiple levels is critical to the success of interorganizational marketing collaborations.

Multi‐scale regulated plant community dynamics: mechanisms and implications

Plant competition is not a direct interaction, but operates via environmental feedback loops, which interconnect population densities and environmental regulating variables. It is suggested that due to scale dependent elements of these feedback loops, competition may occur eventually on very different scales, necessitating a cross‐scale extension of plant competition theory. After introducing the concept of cross‐scale competition, we incorporate its elements into a metacommunity model and study its implications on community organization. It is found that both the equilibrium community composition, regarding coexisting functional types, and its stability depend on scale dependent attributes of environmental feedback loops and disturbance regimes. We argue that plant communities are likely to exhibit properties, which are in line with the hierarchical ecosystem concept. Environmental feedback loops on different scales act as distinct organizational levels, what can be affected by disturbances of corresponding spatial extent.

Third culture: cybersemiotic’s inclusion of a biosemiotic theory of mind

The necessity of a third culture to find new cultural synergy between the two incompatible cultures of science and technology on one hand and humanities and social sciences on the other hand is stronger than ever in the globalized world. Today, complexity science with cybernetic, cognitive information science informed by general systems theory on one hand and one the other biosemiotics, informed by Peirce’s pragmaticistic philosophy on the other seem to be the two most obvious candidates to make the new transdisciplinary framework. The informational paradigm cannot make its philosophical framework encompass signification and first person experience and many researchers are instead trying to eliminate these aspects as having no causal influence on reality. A way out seem to use the still more advanced interpretations of C. S. Peirce’s semiotic philosophy in the form of biosemiotics as a foundation and adding the theories of complexity, self-organization, systems evolution, emergence, down ward causation, information, closure, agency and autopoiesis on this new foundation. I call this new framework Cybersemiotics and explore the ontological aspects of it here suggesting five distinct levels of organization making a synergy of scientific, semiotic, evolutionary, system theoretical and cybernetic concepts.

Self‐organization in raised bog patterning: the origin of microtope zonation and mesotope diversity

Summary Raised bogs of the boreal and temperate zone typically show surface patterning on two distinct organizational levels. A conspicuous pattern of alternating dry strings and wet flarks aligned perpendicular to the slope occurs in combination with other microtopes, resulting in a mesotope pattern. Patterning on both these levels can be explained by a simple, spatially explicit model that assumes predominantly lateral water flow through an acrotelm that is draped over a dome‐shaped catotelm. The model distinguishes two types of surface elements: hummocks with low transmissivity growing under dry conditions and hollows with high transmissivity growing under wet conditions. Hummocks dam up water and stimulate the development of hollows upslope, whereas hollows effectively drain upslope areas, stimulating the development of hummocks. If the dome is steep and the recharge high enough, this leads to the development of a string–flark microtope. Four distinct types of microtopes are distinguished: (i) areas entirely covered by hummocks, (ii) randomly arranged hummocks and hollows, (iii) string–flark striping patterns and (iv) areas entirely covered by hollows. Different combinations of sharply delineated microtopes occur with different parameter settings, allowing for the classification of four types of raised bog mesotopes. In addition to such qualitative differences, the extent and composition of the microtopes vary with parameter settings, reflecting the variety observed in natural systems. Our simple simulation model shows how small‐scale, local processes can create a variety of large and complex landscape patterns. These patterns can be used to describe raised bogs in terms of biological entities of a higher organizational order (ecosystem biodiversity), typically recognizable in often species‐poor peatland ecosystems.

Organization of the musculature of schistosome cercariae.

Phalloidin-fluorescein isothiocyanate staining of filamentous actin was used to identify muscle systems within the cercariae of Schistosoma mansoni. Examination of labeled cercariae by confocal scanning laser microscopy revealed distinct organizational levels of myofiber arrangements within the body wall, anterior cone, acetabulum, and esophagus. The body wall throughout showed a typical latticelike arrangement of outer circular and inner longitudinal myofibers, with an additional innermost layer of diagonal fibers in the anterior portion of the body. Circular and longitudinal fibers were also evident in the anterior organ and esophagus and, to some extent, the ventral acetabulum. Most striking was the striation of the cercarial tail musculature.

The Structure of Organizational Incentives

0 The financial support of Peat Marwick Main & Co., Ernst & Young, David Hauck, and the Reginald H. Jones Center for Management Policy, Strategy, and Organization is gratefully acknowledged. We would like to thank Sherwin Rosen, Stanley Baiman, Marshall Meyer, three anonymous reviewers, and the workshop participants at the Wharton School, Harvard Business School, Washington University, Northwestern University, Odense University, Uppsala University, and the Shore Conference on Strategic Models for their helpful comments. To improve understanding and design of organizational incentives, we used confidential compensation data obtained for four distinct organizational levels (ranging from plant manager to corporate chief executive officer) to evaluate the ability of tournament, managerial power, and agency theories to explain these observed compensation data. Our results suggest that organizational incentives are most appropriately characterized by a combination of these models, rather than being completely described by a single theoretical description.'

Distribution and orientation of bone in the human lumbar vertebral centrum.

This article describes regional variations in cancellous bone morphology within the human lumbar spine of a 60-year-old woman. An automated imaging technique, based upon the method of directed secants, was used to quantify variations in bone porosity and trabecular size, distribution, and orientation within serial transverse histological sections of the L1 and L2 vertebral centrum. Several morphologically distinct levels of organization were observed along the axis of the centrum. The superior and inferior sections of the centrum were made up of an open-celled network of trabeculae, while the translational and middle sections consisted primarily of plate-like trabeculae forming a closed-cell structure. The densest and most oriented bone was found in the superior and inferior sections of the posterior-lateral centrum, whereas least dense and least oriented bone was found in the central third of the anterior centrum. Average trabecular thickness did not vary appreciably from level to level, but varied considerably within a given level, particularly in the inferior sections of the centrum. The number of trabeculae was lowest in the central sections of the centrum, where plate-like trabeculae were most prevalent. The topological architecture of different levels within the centrum exhibited a remarkable degree of organization, which suggests that the spine, like other skeletal structures, has adapted to functional stresses produced during daily activities. Detailed morphological data are tabulated and should be of use to investigators interested in modeling the three-dimensional structural and physical properties of the lumbar spine.

The SV40 enhancer contains two distinct levels of organization.

The SV40 transcriptional enhancer is composed of separate 15 to 20 base-pair-(bp)-long enhancer elements that cooperate with one another or duplicates of themselves to enhance transcription. These elements are bipartite, being composed of subunits, called enhansons, that can be duplicated or interchanged to create new enhancer elements. Enhansons differ from the enhancer elements because they are very sensitive to changes in spacing. This prototypic enhancer, therefore, contains two distinct levels of organization, each of which requires redundancy to be effective.

Microtubule cytoskeleton and morphogenesis in the amoebae of the myxomycete Physarum polycephalum.

The amoebae of the myxomycete Physarum polycephalum are of interest in order to analyze the morphogenesis of the microtubule and microfilament cytoskeleton during cell cycle and flagellation. The amoebal interphase microtubule cytoskeleton consists of 2 distinct levels of organization, which correspond to different physiological roles. The first level is composed of the 2 kinetosomes or centrioles and their associated structures. The anterior kinetosomes forming the anterior and posterior flagella are morphologically distinguishable. Each centriole plays a role in the morphogenesis of its associated satellites and specific microtubule arrays. The 2 distinct centrioles correspond to the 2 successive maturation stages of the pro-centrioles which are built during prophase. The second level of organization consists of a prominent microtubule organizing center (mtoc 1) to which the anterior centriole is attached at least during interphase. The mtoc plays a role in the formation of the mitotic pole. These observations based on ultrastructural and physiological analyses of the amoebal cytoskeleton are now being extended to the biochemical level. The complex formed by the 2 centrioles and the mtoc 1 has been purified without modifying the microtubule-nucleating activity of the mtoc 1. Several microtubule-associated proteins have been characterized by their ability to bind taxol-stabilized microtubules. Their functions (e.g., microtubule assembly, protection of microtubules against dilution or cold treatment, phosphorylating and ATPase activities) are under investigation. These biochemical approaches could allow in vitro analysis of the morphogenesis of the amoebal microtubule cytoskeleton.

Hierarchy of fibrillar organization levels in the polytene interphase chromosomes of Chironomus.

ABSTRACT The present study shows a hierarchy of fibrillar organization levels in polytene somatic interphase chromosomes. The chromosomes of several Chironomus species have been examined by electron microscopy in situ, i.e., in the physiological environment of intact salivary glands, and in vitro as spread preparations. In situ, the basic structural element of bands, interbands and constitutive heterochromatin is a DNP fibre (chromatid) which varies in thickness from 11 to 25 nm. The fibre displays a varying degree of coiling in bands and interbands. It runs more or less straight through the interbands but forms aggregates (chromomeres), which have a densely packed fibrillar texture, in the band regions. On the whole there is always an abrupt transition between the fibre and the chromomeres which it connects. Constitutive heterochromatin is also made up of a fibre of the same thickness as in bands and interbands. However, in the heterochromatin the fibre generally measures 20–25 nm. In telomeric heterochromatin the fibre is extremely densely arranged, whereas the centric heterochromatin (chromocentre) of C. melanotus is made up of very loosely bundled fibres. Neither type of heterochromatin exhibits any visible subdivision into chromomeres and interchromomeres. In spread preparations of native isolated polytene chromosomes of different Chironomus tissues seen in vitro the bands and interbands are also composed of a DNP fibre which varies in thickness from 11 to 25 nm. Fibres in spread preparations are at most 20–25 nm thick. The spreading of band regions enables one to recognize more or less tangled, sometimes transcribed 0 · 8–8 · 4 μm loops, which are regarded as unfolded chromomeres. The shape of the 20–25-nm fibre in band (loop) and interband regions is irregular and clearly reflects orderly packing of globular particles (superbeads) embedded in a diffuse matrix. The latter can be removed by spreading the fibres in low salt medium or distilled water, which also makes individual superbeads visible. Arranged in a row, 4 superbeads account for 0·1 μm. Superbeads are structures consisting of subunits which correspond in size (n 0± 10 nm) to nucleosomes. Tentatively, there are 7–12 nucleosomes in one superbead. A row of nucleosomes constitutes the 11–13-nm fibre. This is the basic fibre of polytene chromosomes. The 20–25-nm fibre appears to be a higher order of the basic fibre. Digestion of the 20–25-nm fibre by trypsin and DNase reveals that the fibre is unineme as far as its DNA is concerned. The fact that polytene interphase chromosomes analysed in situ and in vitro both show a 20-25-nm fibre, leads to the conclusion that this fibre represents the highest level of fibrillar organization of the DNP fibre. Presumably the distinct levels of organization revealed by the 20–25-nm fibre in vitro also exist in the chromosomes in situ, but are invisible because the fibres prepared at physiological ionic strength are densely packed.