Metals on the move: zinc ions in cellular regulation and in the coordination dynamics of zinc proteins

Homeostatic control maintains essential transition metal ions at characteristic cellular concentrations to support their physiological functions and to avoid adverse effects. Zinc is especially widely used as a catalytic or structural cofactor in about 3000 human zinc proteins. In addition, the homeostatic control of zinc in eukaryotic cells permits functions of zinc(II) ions in regulation and in paracrine and intracrine signaling. Zinc ions are released from proteins through ligand-centered reactions in zinc/thiolate coordination environments, and from stores in cellular organelles, where zinc transporters participate in zinc loading and release. Muffling reactions allow zinc ions to serve as signaling ions (second messengers) in the cytosol that is buffered to picomolar zinc ion concentrations at steady-state. Muffling includes zinc ion binding to metallothioneins, cellular translocations of metallothioneins, delivery of zinc ions to transporter proteins, and zinc ion fluxes through cellular membranes with the result of removing the additional zinc ions from the cytosol and restoring the steady-state. Targets of regulatory zinc ions are proteins with sites for transient zinc binding, such as membrane receptors, enzymes, protein–protein interactions, and sensor proteins that control gene expression. The generation, transmission, targets, and termination of zinc ion signals involve proteins that use coordination dynamics in the inner and outer ligand spheres to control metal ion association and dissociation. These new findings establish critically important functions of zinc ions and zinc metalloproteins in cellular control.     

Cellular zinc and redox buffering capacity of metallothionein/thionein in health and disease

Zinc is involved in virtually all aspects of cellular and molecular biology as a catalytic, structural, and regulatory cofactor in over 1000 proteins. Zinc binding to proteins requires an adequate supply of zinc and intact molecular mechanisms for redistributing zinc ions to make them available at the right time and location. Several dozen gene products participate in this process, in which interactions between zinc and sulfur donors determine the mobility of zinc and establish coupling between cellular redox state and zinc availability. Specifically, the redox properties of metallothionein and its apoprotein thionein are critical for buffering zinc ions and for controlling fluctuations in the range of picomolar concentrations of "free" zinc ions in cellular signaling. Metallothionein and other proteins with sulfur coordination environments are sensitive to redox perturbations and can render cells susceptible to injury when oxidative stress compromises the cellular redox and zinc buffering capacity in chronic diseases. The implications of these fundamental principles for zinc metabolism in type 2 diabetes are briefly discussed.     

Prediction of the doubly charged ion pattern by modelling the high- and low-resolution mass spectra of isotopomeric forms

The presence of doubly charged ions in mass spectra is detected only occasionally because their clusters are observed more rarely than singly charged ones. The patterns connected with doubly charged ions are located in the spectrum below M/2. The narrow shapes of such patterns as well as overlapping with other bands generate significant problems in their interpretation. The method described here is based on modelling of the isotopomeric form of single- and double-charged mass ion clusters. The present work attempts to explain the generation of the double charge disotopomeric patterns of high- as well as low-resolution spectra. Predicting the high-resolution mass cluster is simpler than calculations of the low-resolution cluster. The high-resolution cluster may represent the initial form of low-resolution pattern formation.

The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling

Free zinc ions are potent effectors of proteins. Their tightly controlled fluctuations ("zinc signals") in the picomolar range of concentrations modulate cellular signaling pathways. Sulfur (cysteine) donors generate redox-active coordination environments in proteins for the redox-inert zinc ion and make it possible for redox signals to induce zinc signals. Amplitudes of zinc signals are determined by the cellular zinc buffering capacity, which itself is redox-sensitive. In part by interfering with zinc and redox buffering, reactive species, drugs, toxins, and metal ions can elicit zinc signals that initiate physiological and pathobiochemical changes or lead to cellular injury when free zinc ions are sustained at higher concentrations. These interactions establish redox-inert zinc as an important factor in redox signaling. At the center of zinc/redox signaling are the zinc/thiolate clusters of metallothionein. They can transduce zinc and redox signals and thereby attenuate or amplify these signals.     

The influence of sodium and potassium dynamics on excitability,seizures, and the stability of persistent states: I. Single neuron dynamics

In these companion papers, we study how the interrelated dynamics of sodium and potassium affect the excitability of neurons, the occurrence of seizures, and the stability of persistent states of activity. In this first paper, we construct a mathematical model consisting of a single conductance-based neuron together with intra- and extracellular ion concentration dynamics. We formulate a reduction of this model that permits a detailed bifurcation analysis, and show that the reduced model is a reasonable approximation of the full model. We find that competition between intrinsic neuronal currents, sodium-potassium pumps, glia, and diffusion can produce very slow and large-amplitude oscillations in ion concentrations similar to what is seen physiologically in seizures. Using the reduced model, we identify the dynamical mechanisms that give rise to these phenomena. These models reveal several experimentally testable predictions. Our work emphasizes the critical role of ion concentration homeostasis in the proper functioning of neurons, and points to important fundamental processes that may underlie pathological states such as epilepsy.

Semi-automated, Membrane-Based Protocol for DNA Isolation from Plants

Many plant species are considered difficult for DNA isolation due to their high concentrations of secondary metabolites such as polysaccharides and polyphenols. Several protocols have been developed to overcome this problem, but they are typically time-consuming, not scalable for high throughput and not compatible with automation. Although a variety of commercial kits are available for plant DNA isolation, their cost is high and these kits usually have limited taxonomic applicability. In a previous study we developed an inexpensive automation-friendly protocol for DNA extraction from animal tissues. Here we demonstrate that a similar protocol allows DNA isolation from plants.

Formulations for delivery of therapeutic proteins

Advances in biotechnology have now created a capacity to produce therapeutically active proteins on a commercial scale, opening the potential for their application in an array of disease conditions. The process of translation of the variety of different therapeutic proteins into the medicines used in clinics is now occurring. To assist in this translation, new formulations to deliver proteins could play an important role. These new formulations need to more adequately address the pharmacological and therapeutic requirement for each particular protein/peptide and, in that way, either improve present therapies or extend with new entries the current list of protein based medicines used in clinic.

3D Multi-agent models for protein release from PLGA spherical particles with complex inner morphologies

In order to better understand and predict the release of proteins from bioerodible microspheres or nanospheres, it is important to know the influences of different initial factors on the release mechanisms, though often it is difficult to assess what exactly is at the origin of a certain dissolution profile. We propose here a new class of fine-grained multi-agent models built to incorporate increasing complexity, permitting the exploration of the role of different parameters, especially that of the internal morphology of the spheres, in the exhibited release profile. This approach, based on Monte Carlo (MC) and cellular automata (CA) techniques, has permitted the testing of various assumptions and hypotheses about several experimental systems of nanospheres encapsulating proteins. Results have confirmed that this modelling approach has increased the resolution over the complexity involved, opening promising perspectives for future developments, especially complementing in vitro experimentation.

Leitlinien zur molekulargenetischen Diagnostik: Fragiles-X und Fragiles-X assoziiertes Tremor/Ataxie Syndrom

Ohne Zusammenfassung

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Individual variability of behavioural responses by Wandering Albatrosses (Diomedea exulans) to human disturbance

Sub-Antarctic Marion Island has had a permanent research station for 50 years and the islands Wandering Albatrosses have been intensively studied for 20 years. The reactions of breeding birds to approaches by a human on foot were recorded. Three response variables were calculated: intensity of vocal reaction (IVR), intensity of non-vocal reaction (INR) and overall response index (ORI). At 5 m from the nest, twice as many birds stood and/or vocalised as at 15 m. Nearest neighbour distance, age and gender did not explain individual variability of responses. Study colony birds had higher IVR scores than non-study colony birds; birds at colonies closest to the station had the highest ORI scores. A better breeding record was associated with lower IVR and ORI scores, but a causative relationship remains to be demonstrated. A minimum viewing distance of 25 m is recommended for breeding Wandering Albatrosses.

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Strategies of abstraction

Abstraction is seen as an active process which both enlightens and obscures. Abstractions are not true or false but relatively enlightening or obscuring according to the problem under study; different abstractions may grasp different aspects of a problem. Abstractions may be useless if they can answer questions only about themselves. A theoretical enterprise explores reality through acluster of abstractions that use different perspectives, temporal and horizontal scales, and assumes different givens.

Detection of symmetrical decomposition of molecules—isotopomeric analysis of the M/2 clusters

The interpretation of mass spectra (ms) of molecules containing poly-isotopic elements (e.g. Ge, Se, W, Os, Sn, Te, Zn, Yb) can be difficult due to the occurrence of fragments resulting from isotopomeric composition. MS-clusters located in the range lower than or equal to M/2 are very difficult to interpret. In this area many perturbations may be observed. The coincidence of different fragmentation pathways, the existence of multiply charged ions, background levels, etc. can all contribute to this problem. The present paper reports the application of multi-isotopomeric analysis methods for low-resolution ms. We present a solution that may be useful for detection of the symmetrical decomposition of a molecule and for elucidation of cluster ion genesis. The complex character of the cluster does not perturb determination of the contents of the investigated pattern. In such cases the dominated component is applied in subsequent computations.

Membrane microdomains from early gastrula embryos of medaka, <Emphasis Type="Italic">Oryzias latipes</Emphasis>, are a platform of E-cadherin- and carbohydrate-mediated cell–cell interactions during epiboly

Formation of membrane microdomain is critical for cell migration (epiboly) during gastrulation of medaka fish [Adachi et al. (Biochem. Biophys. Res. Commun. 358:848–853, 2007)]. In this study, we characterized membrane microdomain from gastrula embryos to understand its roles in epiboly. A cell adhesion molecule (E-cadherin), its associated protein (β-catenin), transducer proteins (PLCγ, cSrc), and a cytoskeleton protein (β-actin) were enriched in the membrane microdomain. Le^X-containing glycolipids and glycoproteins (Le^X-gp) were exclusively enriched in the membrane microdomain. Interestingly, the isolated membrane microdomain had the ability to bind to each other in the presence of Ca²⁺. This membrane microdomain binding was achieved through the E-cadherin homophilic and the Le^X-glycan-mediated interactions. E-cadherin and Le^X-gp were co-localized on the same membrane microdomain, suggesting that these two interactions are operative at the same time. Thus, the membrane microdomain functions as a platform of the E-cadherin- and Le^X-glycan-mediated cell adhesion and signal transduction.

A self-managing wide-area data streaming service

Efficient and robust data streaming services are a critical requirement of emerging Grid applications, which are based on seamless interactions and coupling between geographically distributed application components. Furthermore the dynamism of Grid environments and applications requires that these services be able to continually manage and optimize their operation based on system state and application requirements. This paper presents a design and implementation of such a self-managing data-streaming service based on online control strategies. A Grid-based fusion workflow scenario is used to evaluate the service and demonstrate its feasibility and performance.

Consistency principle in biological dynamical systems

We propose a principle of consistency between different hierarchical levels of biological systems. Given a consistency between molecule replication and cell reproduction, universal statistical laws on cellular chemical abundances are derived and confirmed experimentally. They include a power law distribution of gene expressions, a lognormal distribution of cellular chemical abundances over cells, and embedding of the power law into the network connectivity distribution. Second, given a consistency between genotype and phenotype, a general relationship between phenotype fluctuations by genetic variation and isogenic phenotypic fluctuation by developmental noise is derived. Third, we discuss the chaos mechanism for stem cell differentiation with autonomous regulation, resulting from a consistency between cell reproduction and growth of the cell ensemble.

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Language processing with dynamic fields

We construct a mapping from complex recursive linguistic data structures to spherical wave functions using Smolensky’s filler/role bindings and tensor product representations. Syntactic language processing is then described by the transient evolution of these spherical patterns whose amplitudes are governed by nonlinear order parameter equations. Implications of the model in terms of brain wave dynamics are indicated. Electronic supplementary material  The online version of this article (doi: ) contains supplementary material, which is available to authorized users.

The nature of developmental constraints and the difference-maker argument for externalism

One current version of the internalism/externalism debate in evolutionary theory focuses on the relative importance of developmental constraints in evolutionary explanation. The received view of developmental constraints sees them as an internalist concept that tend to be shared across related species as opposed to selective pressures that are not. Thus, to the extent that constraints can explain anything, they can better explain similarity across species, while natural selection is better able to explain their differences. I challenge both of these aspects of the received view and propose a hierarchical view of constraints.