Structural Insight into Chromatin Recognition by Multiple Domains of the Tumor Suppressor RBBP1

Retinoblastoma-binding protein 1 (RBBP1) is involved in gene regulation, epigenetic regulation, and disease processes. RBBP1 contains five domains with DNA-binding or histone-binding activities, but how RBBP1 specifically recognizes chromatin is still unknown. An AT-rich interaction domain (ARID) in RBBP1 was proposed to be the key region for DNA-binding and gene suppression. Here, we first determined the solution structure of a tandem PWWP-ARID domain mutant of RBBP1 after deletion of a long flexible acidic loop L12 in the ARID domain. NMR titration results indicated that the ARID domain interacts with DNA with no GC- or AT-rich preference. Surprisingly, we found that the loop L12 binds to the DNA-binding region of the ARID domain as a DNA mimic and inhibits DNA binding. The loop L12 can also bind weakly to the Tudor and chromobarrel domains of RBBP1, but binds more strongly to the DNA-binding region of the histone H2A-H2B heterodimer. Furthermore, both the loop L12 and DNA can enhance the binding of the chromobarrel domain to H3K4me3 and H4K20me3. Based on these results, we propose a model of chromatin recognition by RBBP1, which highlights the unexpected multiple key roles of the disordered acidic loop L12 in the specific binding of RBBP1 to chromatin.     

The coupling of biogeochemical cycles of nutrients

For any element which is incorporated into biomass, the biogeochemical cycle of that element in a given ecosystem will be coupled to that of any other element similarly incorporated. The mutual interaction of two such cycles is examined using a simple model in which each cycle is constrained into four compartments. In each cycle the assimilation rate (primary productivity) is related in a non-linear fashion to the two nutrients and to biomass. The interactions are represented by combining a hyperbolic dependence for each nutrient (involving a "Michaelis constant") with a logistic equation governing the dependence of rate on biomass (involving a "carrying capacity"). The response of the model to perturbation (e.g. mobilization of an abiotic reserve) is strongly governed by the values assigned to these constants. The coupled cycles can exhibit positive feed-back with anomalous responses of the steady state and time-dependent solutions may exhibit complex oscillatory behaviour. Both the steady-state sensitivity and the kinetic behaviour of such coupled systems are simplified if the range of atomic ratios permitted by the assimilation process is restricted. It will therefore be of importance to determine under what conditions the assimilation rates for different elements are governed by mass-action effects (Liebig's Law) or by stoichiometric constraints (Redfield ratios).     

The singularly perturbed Hodgkin-Huxley equations as a tool for the analysis of repetitive nerve activity

A qualitative analysis of the Hodgkin-Huxley model (Hodgkin and Huxley 1952), which closely mimics the ionic processes at a real nerve membrane, is performed by means of a singular perturbation theory. This was achieved by introducing a perturbation parameter that, if decreased, speeds up the fast variables of the Hodgkin-Huxley equations (membrane potential and sodium activation), whereas it does not affect the slow variables (sodium inactivation and potassium activation). In the most extreme case, if the perturbation parameter is set to zero, the original four-dimensional system degenerates to a system with only two differential equations. This degenerate system is easier to analyze and much more intuitive than the original Hodgkin-Huxley equations. It shows, like the original model, an infinite train of action potentials if stimulated by an input current in a suitable range. Additionally, explanations for the increased sensitivity to depolarizing current steps that precedes an action potential can be found by analysis of the degenerate system. Using the theory of Mishchenko and Rozov (1980) it is shown that the degenerate system does not only represent a simplification of the original Hodgkin-Huxley equations but also gives a valid approximation of the original model at least for stimulating currents that are constant within a suitable range.     

Increased straying by adult steelhead trout,Salmo gairdneri,following the 1980 eruption of Mount St. Helens

Synopsis This paper describes the magnitude and geographic dispersion of adult steelhead trout, Salmo gairdneri, diverted from Columbia River tributaries which were impacted by the 1980 volcanic eruption of Mount St. Helens. Compelling circumstantial evidence suggests that for 1–3 yr after the eruption, large numbers of adult steelhead migrating toward affected tributaries entered two non-affected tributaries flowing into the Columbia River upstream of natal streams. Streams downstream of affected tributaries did not appear to receive substantial numbers of displaced fish. I estimated that the percentage of non-natal steelhead migrating into the lower portions of the nearest upstream river increased from 16% pre-eruption to 45% post-eruption. Winter-run steelhead strays probably originated from both the Cowlitz and Toutle rivers, whereas summer-run strays originated predominantly from the Toutle River. Increased natural production in tributaries resulting from the infusion of large numbers of strays was of insufficient magnitude to be detected by the methods of this study.     

Complex ecological models with simple dynamics: From individuals to populations

The aim of this work is to study complex ecological models exhibiting simple dynamics. We consider large scale systems which can be decomposed into weakly coupled subsystems. Perturbation Theory is used in order to get a reduced set of differential equations governing slow time varying global variables. As examples, we study the influence of the individual behaviour of animals in competition and predator-prey models. The animals are assumed to do many activities all day long such as searching for food of different types. The degree of competition as well as the predation pressure are dependent upon these activities. Preys are more vulnerable when doing some activities during which they are very exposed to predators attacks rather than for others during which they are hidden. We study the effect of a change in the average individual behaviour of the animals on interspecific relationships. Computer simulations of the whole sets of equations are compared to simulations of the reduced sets of equations.     

Perturbation of gene frequencies in a natural population of Drosophila melanogaster: evidence for selection at the Adh locus

The cellar population of Drosophila melanogaster at the Chateau Tahbilk Winery (Victoria, Australia) was perturbed for alcohol dehydrogenase (Adh) gene frequencies. Phenol oxidase (Phox) frequencies were also perturbed and monitored as a control. Subsequent gene frequency changes, together with information on population structure, indicated that selection acted on the chromosome regions of both loci. Adh gene frequencies returned to preperturbation levels in a predictable manner. A model in which the relative fitness of Adh phenotypes was determined by temperature-dependent specific activities of enzymes of Adh genotypes adequately accounts for the rate of gene frequency change at this locus. Thus temperature behaves as a selective agent in modulating Adh gene frequencies in this cellar environment.     

Molecular Parameterisation and the Theoretical Calculation of Electrode Potentials

The difference in reduction potentials between ortho and para-benzoquinones has been calculated. The employs gas phase ab initio and semi-empirical computations in combination with free energy perturbation theory applied to gas and solution phase Monte Carlo simulations. The effects on calculated results of altering solute electrostatic parameterisation in solution phase simulations is examined. Atom centred charges derived from the molecular electrostatic potentials, MEPs, from optimised ab initio wavefunctions and charges generated by consideration of hydrogen bonded complexes are considered. Parameterisation of hydroxyl torsions in hydroquinone molecules is treated in a physically realistic manner. The coupled torsional system of the ortho-hydrobenzoquinone molecule is described by a potential energy surface calculated using gas phase AM1 semi-empirical computations rather than the simple torsional energy functions frequently employed in such calculations. Calculated differences in electrode potentials show that the electrostatic interactions of quinone and hydroquinone molecules in aqueous solution are not well described by atom centred charges derived from ab initio calculated MEPs. Moreover, results in good agreement with the experimental reduction potential difference can be obtained by employing high level ab initio calculations and solution phase electrostatic parameters developed by consideration of hydrogen bonded complexes.     

Bifurcation, Bursting, and Spike Frequency Adaptation

Many neural systems display adaptive properties that occur on timescales that are slower than the time scales associated withrepetitive firing of action potentials or bursting oscillations. Spike frequency adaptation is the name givento processes thatreduce the frequency of rhythmic tonic firing of action potentials,sometimes leading to the termination of spiking and the cell becomingquiescent. This article examines these processes mathematically,within the context of singularly perturbed dynamical systems.We place emphasis on the lengths of successive interspikeintervals during adaptation. Two different bifurcation mechanisms insingularly perturbed systems that correspond to the termination offiring are distinguished by the rate at which interspike intervalsslow near the termination of firing. We compare theoreticalpredictions to measurement of spike frequency adaptation in a modelof the LP cell of the lobster stomatogastric ganglion.     

Perturbation analysis of a two-locus model with directional selection and recombination

A population genetic two-locus model with additive, directional selection and recombination is considered. It is assumed that recombination is weaker than selection; i.e., the recombination parameter r is smaller than the selection coefficients. This assumption is appropriate for describing the effects of two-locus selection at the molecular level. The model is formulated in terms of ordinary differential equations (ODES) for the gamete frequencies x = (x ₁, x ₂, x ₃, x ₄), defined on the simplex S ₄. The ODEs are analyzed using first a regular pertubation technique. However, this approach yields satisfactory results only if r is very small relative to the selection coefficients and if the initial values x(0) are in the interior part of S ₄. To cope with this problem, a novel two-scale perturbation method is proposed which rests on the theory of averaging of vectorfields. It is demonstrated that the zeroth-order solution of this two-scale approach approximates the numerical solution of the model well, even if recombination rate is on the order of the selection coefficients.     

Regulation of growth in larvae of the crab : The effect of cyclic temperatures

Experiments were designed to demonstrate that growth is precisely regulated in crustacean larvae and that cyclic temperatures act as a perturbation on growth regulation. Newly hatched larvae were exposed to either the specific a cyclic temperature, cumulative growth was significantly inhibited. Also, the specific growth rate ( ) of larvae in the cyclic temperature regime was found to oscillate with decreasing amplitude around the of the larvae exposed to constant temperature. This oscillatory pattern has been observed in a wide variety of self-regulating systems. Evidence is presented to demonstrate that this regulatory mechanism also adapts to long-term exposure to cyclic temperatures. These findings increase our understanding of how larvae cope with and adapt to changing environmental temperatures. More significantly, the mechanism could provide a sensitive tool for estimating the effects of specific environmental disturbances on fitness.