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Biomedical subjects

Vic Norris

Publications and source records attributed to Vic Norris.

At least 19 recordsLinked to original sources
PubMed2006

Steady-state kinetic behaviour of two- or n-enzyme systems made of free sequential enzymes involved in a metabolic pathway.

The overall rate of functioning of a set of free sequential enzymes of the Michaelis-Menten type involved in a metabolic pathway has been computed as a function of the concentration of the initial substrate under steady-state conditions. Curves monotonically increasing up to a saturation plateau have been obtained in all cases. The shape of these curves is sometimes, but not usually, close to that of a hyperbola. Cases exist in which the overall rate of reaction becomes quasi proportional to the concentration of initial substrate almost up to the saturation plateau, which never occurs with individual enzymes. Increasing the number of enzymes sequentially involved in a metabolic pathway does not seem to generate any particularly original behaviour compared with that of two-enzyme systems.

Enzymes↗
PubMed2006

Compositional complementarity and prebiotic ecology in the origin of life.

We hypothesize that life began not with the first self-reproducing molecule or metabolic network, but as a prebiotic ecology of co-evolving populations of macromolecular aggregates (composomes). Each composome species had a particular molecular composition resulting from molecular complementarity among environmentally available prebiotic compounds. Natural selection acted on composomal species that varied in properties and functions such as stability, catalysis, fission, fusion and selective accumulation of molecules from solution. Fission permitted molecular replication based on composition rather than linear structure, while fusion created composomal variability. Catalytic functions provided additional chemical novelty resulting eventually in autocatalytic and mutually catalytic networks within composomal species. Composomal autocatalysis and interdependence allowed the Darwinian co-evolution of content and control (metabolism). The existence of chemical interfaces within complex composomes created linear templates upon which self-reproducing molecules (such as RNA) could be synthesized, permitting the evolution of informational replication by molecular templating. Mathematical and experimental tests are proposed.

Biological Evolution↗
PubMed2006

Steady-state kinetic behaviour of functioning-dependent structures.

A fundamental problem in biochemistry is that of the nature of the coordination between and within metabolic and signalling pathways. It is conceivable that this coordination might be assured by what we term functioning-dependent structures (FDSs), namely those assemblies of proteins that associate with one another when performing tasks and that disassociate when no longer performing them. To investigate a role in coordination for FDSs, we have studied numerically the steady-state kinetics of a model system of two sequential monomeric enzymes, E(1) and E(2). Our calculations show that such FDSs can display kinetic properties that the individual enzymes cannot. These include the full range of basic input/output characteristics found in electronic circuits such as linearity, invariance, pulsing and switching. Hence, FDSs can generate kinetics that might regulate and coordinate metabolism and signalling. Finally, we suggest that the occurrence of terms representative of the assembly and disassembly of FDSs in the classical expression of the density of entropy production are characteristic of living systems.

Dimerization↗
PubMed2005

Hypercomplexity.

What is biological complexity? How many sorts exist? Are there levels of complexity? How are they related to one another? How is complexity related to the emergence of new phenotypes? To try to get to grips with these questions, we consider the archetype of a complex biological system, Escherichia coli. We take the position that E. coli has been selected to survive adverse conditions and to grow in favourable ones and that many other complex systems undergo similar selection. We invoke the concept of hyperstructures which constitute a level of organisation intermediate between macromolecules and cells. We also invoke a new concept, competitive coherence, to describe how phenotypes are created by a competition between maintaining a consistent story over time and creating a response that is coherent with respect to both internal and external conditions. We suggest how these concepts lead to parameters suitable for describing the rich form of complexity termed hypercomplexity and we propose a relationship between competitive coherence and emergence.

Escherichia coli↗
PubMed2005

Hypothesis: chemotaxis in Escherichia coli results from hyper-structure dynamics.

Large assemblies of different molecules and macromolecules,termed hyper structures, have been proposed to be the units of an intermediate level of organisation in bacteria. Here we propose a model for chemotaxis in Escherichia coli in which (1) the size and functioning of the chemo-signalling hyper-structure depends not only on the protein constituents but also on cardiolipin and calcium,(2) the coupled transcription, translation and insertion of nascent proteins (transertion) is a potentially powerful influence in determining the size of the chemo-signalling hyper-structure and therefore in affecting its function, and (3) a single transertional hyper-structure is jointly responsible for the synthesis of chemo-signalling and flagellar proteins so as to divorce the size of the chemo-signalling hyper-structure from the transertion of its constituents.

Cardiolipins↗
PubMed2004

A hypothesis to explain division site selection in Escherichia coli by combining nucleoid occlusion and Min.

The positioning of the site of cell division in Escherichia coli results, it is generally believed, from the operation of nucleoid occlusion in combination with the Min system. Nucleoid occlusion prevents division over the nucleoids and directs it by default to the mid-cell region between segregating nucleoids or to polar regions while the Min system prevents division in polar regions. Unresolved questions include how these systems interact to control the earliest known event in division, the assembly at the membrane of the tubulin-like protein, FtsZ, and, more importantly, what exactly constitutes a division site. Evidence exists that (1) the coupled transcription, translation and insertion of proteins into membrane (transertion), can structure the cytoplasmic membrane into phospholipid domains, (2) the MinD protein can convert vesicles into tubes and (3) a variety of membranous structures can be observed at mid-cell. These data support a model in which transertion from the segregating daughter chromosomes leads to the formation of a distinct proteolipid domain between them at mid-cell; the composition of this domain allows phospholipid tubes to extend like fingers into the cytoplasm; these tubes then become the substrate for the dynamic assembly and disassembly of FtsZ which converts them into the invaginating fold responsible for division; the Min system inhibits division at unwanted sites and times by removing these tubes especially at the cell poles.

Adenosine Triphosphatases↗
PubMed2004

Plant sensitivity to low intensity 105 GHz electromagnetic radiation.

Exposing seedlings of the flax, Linum usitatissimum L., to a variety of weak environmental stresses followed by a 2 day calcium deprivation, triggers the common response of production of epidermal meristems (actively dividing groups of cells) in the hypocotyl, which is the part of the stem between the root and the cotyledons (the pre-existing leaves in the embryo). This production reaches a plateau of 10-20 meristems after a month in the case of mechanical stimulation and cold shock. Recently, we have shown that radiation from a global system for mobile communication (GSM) telephone also triggers production of meristems with a plateau of around six meristems. Here, we show that a single 2 h exposure to radiation emitted at 105 GHz at non-thermal levels by a Gunn oscillator induces meristem production with kinetics similar to that induced by weak environmental stimuli and radiation from GSM telephone.

Calcium↗
PubMed2004

Ion condensation and signal transduction.

Many abiotic and other signals are transduced in eukaryotic cells by changes in the level of free calcium via pumps, channels and stores. We suggest here that ion condensation should also be taken into account. Calcium, like other counterions, is condensed onto linear polymers at a critical value of the charge density. Such condensation resembles a phase transition and has a topological basis in that it is promoted by linear as opposed to spherical assemblies of charges. Condensed counterions are delocalised and can diffuse in the so-called near region along the polymers. It is generally admitted that cytoskeletal filaments, proteins colocalised with these filaments, protein filaments distinct from cytoskeletal filaments, and filamentous assemblies of other macromolecules, constitute an intracellular macromolecular network. Here we draw attention to the fact that this network has physicochemical characteristics that enable counterion condensation. We then propose a model in which the feedback relationships between the condensation/decondensation of calcium and the activation of calcium-dependent kinases and phosphatases control the charge density of the filaments of the intracellular macromolecular network. We show how condensation might help mediate free levels of calcium both locally and globally. In this model, calcium condensation/decondensation on the macromolecular network creates coherent patterns of protein phosphorylation that integrate signals. This leads us to hypothesize that the process of ion condensation operates in signal transduction, that it can have an integrative role and that the macromolecular network serves as an integrative receptor.

Animals↗
PubMed2004

Introduction to the concept of functioning-dependent structures in living cells.

The assembly of proteins into larger structures may confer advantages such as increased resistance to hydrolytic enzymes. metabolite channelling, and reduction of the number of proteins or other active molecules required for cell functioning. We propose the term functioning-dependent structures (FDSs) for those associations of proteins that are created and maintained by their action in accomplishing a function, as reported in many experiments. Here we model the simplest possible cases of two-partner FDSs in which the associations either catalyse or inhibit reactions. We show that FDSs may display regulatory properties (e.g., a sigmoidal response or a linear kinetic behaviour over a large range of substrate concentrations) even when the individual proteins are enzymes of the Michaelis-Menten type. The possible involvement of more complicated FDSs or of FDS networks in real living systems is discussed. From the thermodynamic point of view, FDS formation and decay are responsible for an extra production of entropy, which may be considered characteristic of living systems.

Cell Physiological Phenomena↗
PubMed2004

Reticulated hyaluronan hydrogels: a model for examining cancer cell invasion in 3D.

The extracellular polysaccharide hyaluronan (HA) controls cell migration, differentiation and proliferation, and contributes to the invasiveness of human cancers. The roles of HA cell surface receptors and hyaluronidases (HAses) in this process are still controversial. In order to investigate their involvement in cancer pathogenesis, we developed a reticulated HA hydrogel, a three-dimensional matrix in which cells can invade and grow. We have studied thirteen cell lines, from primary tumors or metastases, that migrated into the HA hydrogel and proliferated giving rise to clusters and colonies. The number of colonies, which reflects tumor cell invasiveness, ranged from 7 to 193 after 5 days of culture. Invasion was dependent on the production of HAse as well as other factors. Optimal colonization occurred when cells released HAse, lacked HA-binding sites and did not secrete HA. Moreover, we describe for the first time a HAse activity at physiological pH that may be responding to the confinement of the enzyme in a three-dimensional structure. We show here that this reticulated matrix provides a three-dimensional model for investigating mechanisms involved in malignant invasion.

Binding Sites↗
PubMed2004

A hyperstructure approach to mitochondria.

Several questions in our understanding of mitochondria are unanswered. These include how the ratio of mitochondrial (mt)DNA to mitochondria is maintained, how the accumulation of defective, rapidly replicating mitochondrial DNA is avoided, how the ratio of mitochondria to cells is adjusted to fit cellular needs, and why any proteins are synthesized in mitochondria rather than simply imported. In bacteria, large hyperstructures or assemblies of proteins, mRNA, lipids and ions have been proposed to constitute a level of organization intermediate between macromolecules and whole cells. Here, we suggest how the concept of hyperstructures together with other concepts developed for bacteria such as transcriptional sensing and spontaneous segregation may provide answers to mitochondrial problems. In doing this, we show how the problem of the very existence of mtDNA brings its own solution.

DNA, Mitochondrial↗
PubMed2003

Networks as constrained thermodynamic systems.

We show how a network of interconnections between nodes can be constructed to have a specified distribution of nodal degrees. This is achieved by treating the network as a thermodynamic system subject to constraints and then rewiring the system to maintain the constraints while increasing the entropy. The general construction is given and illustrated by the simple example of an exponential network. By considering the constraints as a cost function analogous to an internal energy, we obtain a characterisation of the correspondence between the intensive and extensive variables of the network. Applied to networks in living organisms, this approach may lead to macroscopic variables useful in characterising living systems.

Entropy↗
PubMed2003

Modelling autocatalytic networks with artificial microbiology.

Cells can usefully be equated to autocatalytic networks that increase in mass and then divide. To begin to model relationships between autocatalytic networks and cell division, we have written a program of artificial chemistry that simulates a cell fed by monomers. These monomers are symbols that can be assembled into linear (non-branched) polymers to give different lengths. A reaction is catalysed by a particular polymer or 'enzyme' that may itself be a reactant of that reaction (autocatalysis). These reactions are only studied within the confines of the 'cell' or 'reaction chamber'. There is a flux of material through the cell and eventually the mass of polymers reaches a threshold at which we analyse the cell. Our results indicate a similarity between the connectivity of the reaction network and that of real metabolic networks. Developing the model will entail attributing increased probabilities of reactions to polymers that are colocalised to evaluate the consequences of the dynamics of large assemblies of diverse molecules (hyperstructures) and of cell division.

Bacteria↗
PubMed2003

A strand-specific model for chromosome segregation in bacteria.

Chromosome separation and segregation must be executed within a bacterial cell in which the membrane and cytoplasm are highly structured. Here, we develop a strand-specific model based on each of the future daughter chromosomes being associated with a different set of structures or hyperstructures in an asymmetric cell. The essence of the segregation mechanism is that the genes on the same strand in the parental cell that are expressed together in a hyperstructure continue to be expressed together and segregate together in the daughter cell. The model therefore requires an asymmetric distribution of classes of genes and of binding sites and other structures on the strands of the parental chromosome. We show that the model is consistent with the asymmetric distribution of highly expressed genes and of stress response genes in Escherichia coli and Bacillus subtilis. The model offers a framework for interpreting data from genomics.

Bacillus subtilis↗
PubMed2002

Hypothesis: a phospholipid translocase couples lateral and transverse bilayer asymmetries in dividing bacteria.

Cell division in bacteria such as Escherichia coli entails changes in the radii of curvature of the invaginating cytoplasmic membrane which culminate in rearrangements of its monolayers. Division therefore risks perturbing transverse and lateral asymmetries and compromising membrane integrity. This leads us to propose that a strong selective pressure exists for a phospholipid translocator that would transfer phospholipids across the cytoplasmic membrane so as to both demarcate the division site and mediate lipid composition during division. This translocase has an affinity for phospholipids with small headgroups and unsaturated acyl chains which it translocates so as to (1) generate changes in the radius of curvature, (2) facilitate septum formation, (3) minimise bilayer disruption during fusion and (4) prevent septum formation at old or inappropriate division sites. We discuss briefly possible candidates for this translocase including ABC transporters and proteins localised to the division site.

Bacteria↗
PubMed2002

Hypothesis: hyperstructures regulate initiation in Escherichia coli and other bacteria.

Hyperstructures or modules have been proposed to constitute a level of organisation intermediate between macromolecules and whole cells. In this model of intracellular organisation, hyperstructures compete and collaborate for existence within the membrane and cytoplasm. Those directly involved in the cell cycle include initiation, replication and division hyperstructures based on DnaA, SeqA and the 2-minute cluster, respectively. During the run-up to initiation, the mass to DNA ratio increases and, we contend, differential gene expression leads to some hyperstructures becoming more active and stable than others. This results in a drop in the diversity of hyperstructures, some of which release DnaA as they dissociate, and a DnaA-initiation hyperstructure forms. Subsequent DNA replication and cell division generate different daughter cells containing different hyperstructures. This has the advantage of increasing the phenotypic diversity of the population. In developing this model, we also invoke hyperstructures in the partitioning of origins of replication.

Bacterial Proteins↗
PubMed2002

Quasi-periodic behaviour in a model for the lithium-induced, electrical oscillations of frog skin.

The fact that oscillations can be induced in studies of the maintenance of the electrical potential of frog skin by addition of lithium allowed evaluation of several parameters fundamental to the functioning of the system in vivo (e.g. relative volumes of internal compartments, characteristic times of ionic exchanges between compartments). A realistic model was thus proposed under the form of a set of ordinary differential equations. In the past, numerical simulations using such a model reproduced the periodic experimental oscillations and was able to provide an explanation for the global synchronised oscillations of the whole skin. In that paper, new numerical simulations reproduce the non-periodic oscillations which were observed two decades ago, but not reproduced by the model. Moreover, the dynamical process under which all the local oscillators are synchronised is explained in terms of a tangent bifurcation.

Adaptation, Physiological↗