Predictions of patterns of response to artificial selection in lines derived from natural populations

The pattern of response to artificial selection on quantitative traits in laboratory populations can tell us something of the genetic architecture in the natural population from which they were derived. We modeled artificial selection in samples drawn from natural populations in which variation had been maintained by recurrent mutation, with genes having an effect on the trait, which was subject to real stabilizing selection, and a pleitropic effect on fitness (the joint-effect model). Natural selection leads to an inverse correlation between effects and frequencies of genes, such that the frequency distribution of genes increasing the trait has an extreme U-shape. In contrast to the classical infinitesimal model, an early accelerated response and a larger variance of response among replicates were predicted. However, these are reduced if the base population has been maintained in the laboratory for some generations by random sampling prior to artificial selection. When multiple loci and linkage are also taken into account, the gametic disequilibria generated by the Bulmer and Hill-Robertson effects are such that little or no increase in variance and acceleration of response in early generations of artificial selection are predicted; further, the patterns of predicted responses for the joint-effect model now become close to those of the infinitesimal model. Comparison with data from laboratory selection experiments shows that, overall, the analysis did not provide clear support for the joint-effect model or a clear case for rejection.     

Sequence learning and the role of the hippocampus in rodent navigation

The hippocampus has long been associated with navigation and spatial representations, but it has been difficult to link directly the neurophysiological correlates of hippocampal place cells with navigational planning and action. In recent years, large-scale population recordings of place cells have revealed that spatial sequences are stored and activated in ways that may support navigational strategies. Plasticity mechanisms allow the hippocampus to store learned sequences of locations that may allow predictions of future locations based on past experience. These sequences can also be activated during navigational behavior in ways that may allow the animal to learn trajectories toward goals. Task-dependent alterations in place cell firing patterns may reflect the operation of the hippocampus in associating locations with navigationally relevant decision variables.     

Spatial modelling of the barn owl Tyto alba habitat using landscape characteristics derived from SPOT data

Landscape parameters extracted from classified SPOT satellite imagery are used as independent variables for predicting potential habitat areas of the barn owl Tyto alba in a landscape north-east of Brussels, Belgium Field data on the nest sites, recorded during 9 yr, are used as the dependent variable A canonical correlation analysis of the landscape characteristics of 'successful breeding and non-breeding sites' selects a set of most significant parameters contributing to the distinction between suitable and unsuitable breeding habitat parameters measuring the spatial configuration and fragmentation of landscape elements, such as deciduous woods and grasslands, in combination with some visual characteristics of the open spaces in the landscape The selected set of parameters formed the basis for the calculation of a habitat model, whereby potential breeding sites could be located throughout the complete study area, at specific levels of confidence The results showed the relevance of this method for landscape ecological research and nature conservation planning     

Bioactive N-terminal undecapeptides derived from parathyroid hormone: the role of alpha-helicity.

The N-terminal 1-34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses in bone characteristic of the native intact PTH. Recent studies have demonstrated that N-terminal fragments presenting the principal activating domain such as PTH(1-11) and PTH(1-14) with helicity-enhancing substitutions yield potent analogues with PTH(1-34)-like activity. To further investigate the role of alpha-helicity on biological potency, we designed and synthesized by solid-phase methodology the following hPTH(1-11) analogues substituted at positions 1 and/or 3 by the sterically hindered and helix-promoting C(alpha)-tetrasubstituted alpha-amino acids alpha-amino isobutyric acid (Aib), 1-aminocyclopentane-1-carboxylic acid (Ac(5)c) and 1-aminocyclohexane-1-carboxylic acid (Ac(6)c): Ac(5)c-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (I); Aib-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (II); Ac(6)c-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (III); Aib-V-Ac(6)c-E-I-Q-L-M-H-Q-R-NH(2) (IV); Aib-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (V); S-V-Aib-E-I-Q-L-M-H-Q-R-NH(2) (VI), S-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (VII); Ac(5)c-V-S-E-I-Q-L-M-H-Q-R-NH(2) (VIII); Ac(6)c-V-S-E-I-Q-L-M-H-Q-R-NH(2) (IX); Ac(5)c-V-Ac(5)c-E-I-Q-L-M-H-Q-R-NH(2) (X); Ac(6)c-V-Ac(6)c-E-I-Q-L-M-H-Q-R-NH(2) (XI). All analogues were biologically evaluated and conformationally characterized in 2,2,2-trifluoroethanol (TFE) solution by circular dichroism (CD). Analogues I-V, which cover the full range of biological activity observed in the present study, were further conformationally characterized in detail by nuclear magnetic resonance (NMR) and computer simulations studies. The results of ligand-stimulated cAMP accumulation experiments indicated that analogues I and II are active, analogues III, VI and VII are very weakly active and analogues IV, V, VIII-XI are inactive. The most potent analogue, I exhibits biological activity 3500-fold higher than that of the native PTH(1-11) and only 15-fold weaker than that of the native sequence hPTH(1-34). Remarkably, the two most potent analogues, I and II, and the very weakly active analogues, VI and VII, exhibit similar helix contents. These results indicate that the presence of a stable N-terminal helical sequence is an important but not sufficient condition for biological activity.     

The role of iron in the bacterial degradation of organic matter derived from Phaeocystis antarctica

In high-nutrient low-chlorophyll areas, bacterial degradation of organic matter may be iron-limited. The response of heterotrophic bacteria to Fe addition may be directly controlled by Fe availability and/or indirectly controlled through the effect of enhanced phytoplankton productivity and the subsequent supply of organic matter suitable for bacteria. In the present study, the role of Fe on bacterial carbon degradation was investigated through regrowth experiments by monitoring bacterial response to organic substrates derived from Phaeocystis antarctica cultures set up in <1 nM Fe (LFe) and in Fe-amended (HFe) Antarctic seawater. Results showed an impact of Fe addition on the morphotype dominance (colonies vs. single cells) of P. antarctica and on the quality of Phaeocystis-derived organic matter. Fe addition leaded to a decrease of C/N ratio of Phaeocystis material. The bacterial community composition was modified as observed from denaturing gradient gel electrophoresis (DGGE) profiles in LFe as compared to HFe bioassays. The percentage of active bacteria as well as their specific metabolic activities (ectoenzymatic hydrolysis, growth rates and bacterial growth efficiency) were enhanced in HFe bioassays. As a consequence, the lability of Phaeocystis-derived organic matter was altered, i.e., after seven days more than 90% was degraded in HFe and only 9% (dissolved) and 55% (total) organic carbon were degraded in LFe bioassays. By inducing increased bacterial degradation and preventing the accumulation of dissolved organic carbon, the positive effect of Fe supply on the carbon biological pump may partly be counteracted.     

Leptin and its role in hippocampal synaptic plasticity

It is well documented that the hormone leptin plays a pivotal role in regulating food intake and body weight via its hypothalamic actions. However, leptin receptors are expressed throughout the brain with high levels found in the hippocampus. Evidence is accumulating that leptin has widespread actions on CNS function and in particular learning and memory. Recent studies have demonstrated that leptin-deficient or-insensitive rodents have impairments in hippocampal synaptic plasticity and in spatial memory tasks performed in the Morris water maze. Moreover, direct administration of leptin into the brain facilitates hippocampal long-term potentiation (LTP), and improves memory performance in mice. There is also evidence that, at the cellular level, leptin has the capacity to convert hippocampal short-term potentiation (STP) into LTP, via enhancing NMDA receptor function. Recent data indicates that leptin can also induce a novel form of NMDA receptor-dependent hippocampal long-term depression. Here, we review the evidence implicating a key role for the hormone leptin in modulating hippocampal synaptic plasticity and discuss the role of lipid signaling cascades in this process.     

Honeybee navigation: critically examining the role of the polarization compass

Although it is widely accepted that honeybees use the polarized-light pattern of the sky as a compass for navigation, there is little direct evidence that this information is actually sensed during flight. Here, we ask whether flying bees can obtain compass cues derived purely from polarized light, and communicate this information to their nest-mates through the ‘waggle dance’. Bees, from an observation hive with vertically oriented honeycombs, were trained to fly to a food source at the end of a tunnel, which provided overhead illumination that was polarized either parallel to the axis of the tunnel, or perpendicular to it. When the illumination was transversely polarized, bees danced in a predominantly vertical direction with waggles occurring equally frequently in the upward or the downward direction. They were thus using the polarized-light information to signal the two possible directions in which they could have flown in natural outdoor flight: either directly towards the sun, or directly away from it. When the illumination was axially polarized, the bees danced in a predominantly horizontal direction with waggles directed either to the left or the right, indicating that they could have flown in an azimuthal direction that was 90° to the right or to the left of the sun, respectively. When the first half of the tunnel provided axial illumination and the second half transverse illumination, bees danced along all of the four principal diagonal directions, which represent four equally likely locations of the food source based on the polarized-light information that they had acquired during their journey. We conclude that flying bees are capable of obtaining and signalling compass information that is derived purely from polarized light. Furthermore, they deal with the directional ambiguity that is inherent in polarized light by signalling all of the possible locations of the food source in their dances, thus maximizing the chances of recruitment to it.     

The role of molecular modelling in biomedical research

The synergy between experimental and computational biology has greatly benefited both fields, providing invaluable information in many different areas of the life sciences. This minireview will focus on one specific aspect of computational biology, molecular modelling, and describe a few examples highlighting the effectiveness of protein structural analysis and modelling in providing relevant information about systems of biomedical interest.     

Neurite formation by neurons derived from adult rat hippocampal progenitor cells is susceptible to myelin inhibition

Myelin-associated inhibitors expressed following injury to the adult central nervous system (CNS) induce growth cone collapse and retraction of the axonal cytoskeleton. Myelin-associated glycoprotein (MAG) is a bi-functional molecule that promotes neuritogenesis in some immature neurons during development then becomes inhibitory to neurite outgrowth as neurons mature. Progress is being made towards the elucidation of the downstream events that regulate myelin inhibition of regeneration in neuronal populations. However it is not known how adult-derived neural stem cells or progenitors respond to myelin during neuronal differentiation and neuritogenesis. Here we examine the effect of MAG on neurons derived from an adult rat hippocampal progenitor cell line (AHPCs). We show that, unlike their developmental counterparts, AHPC-derived neurons are susceptible to MAG inhibition of neuritogenesis during differentiation and display a 57% reduction in neurite outgrowth when compared with controls. We demonstrate that this effect can be overcome (by up to 69%) by activation of the neurotrophin, cyclic AMP and protein kinase A pathways or by Rho-kinase suppression. We also demonstrate that combination of these factors enhanced neurite outgrowth from differentiating neurons in the presence of MAG. This work provides important information for the successful generation of new neurons from adult neural stem cell populations within compromised adult circuitry and is thus directly relevant to endogenous repair and regeneration of the adult CNS.     

Altered processes of vesicle recycling in hippocampal presynapses during modelling of glutamate neurotoxicity

Morphometric electron microscope research was conducted on hippocampal slices from zone CAl in 1-month-old rats after raising extracellular glutamate concentration to 500 µM for 0.5 h and in control animals. Distributions of principal spatial parameters of presynaptic terminals (PT) were obtained using an original statistical-stereological approach. An abrupt increase was demonstrated in numbers of membrane caveolae associated with phases of vesicle recycling (averaging 13 to a single PT), and an increase in mean area of axolemma, as well as minor changes in the volume of test PT. The findings obtained are examined from the aspect of equivalent changes in the physicochemical mechanisms of endo- and exocytosis. A discussion follows of the potential role of the discovered effects in long-term potentiation processes and in those of neurotoxicity in general.Dnepropetrovsk State University. A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 22, No. 6, pp. 819–826, November–December, 1990.     

Multi-scale modelling of amyloid formation from unfolded proteins using a set of theory derived rate constants

Traditional simulation and analysis of amyloid aggregation kinetics has involved the examination of a single lumped parameter taken to reflect the total mass of protein in amyloid form. However use of increasingly sophisticated multi-experimental strategies capable of providing information on the structure of the growing fibril at the mesoscopic and atomistic level, has put extra information within the experimenter's reach. Although such data can be presented empirically, its incorporation into a theoretical model is more problematic due to scaling issues associated with modern day approaches which fall into either the particle based or statistical based categories. Here we present a coarse grained multi-scale simulation of irreversible amyloid formation that straddles this simulation divide by using a set of theory derived size and conformation specific rate constants to simulate the kinetic evolution of the amyloid fibril population. This approach represents a potentially profitable simulation/analytical strategy that will help to probe more deeply into the underlying molecular driving forces behind the phenomenon of amyloid formation.     

Feedback control strategies for spatial navigation revealed by dynamic modelling of learning in the Morris water maze

The Morris water maze is an experimental procedure in which animals learn to escape swimming in a pool using environmental cues. Despite its success in neuroscience and psychology for studying spatial learning and memory, the exact mnemonic and navigational demands of the task are not well understood. Here, we provide a mathematical model of rat swimming dynamics on a behavioural level. The model consists of a random walk, a heading change and a feedback control component in which learning is reflected in parameter changes of the feedback mechanism. The simplicity of the model renders it accessible and useful for analysis of experiments in which swimming paths are recorded. Here, we used the model to analyse an experiment in which rats were trained to find the platform with either three or one extramaze cue. Results indicate that the 3-cues group employs stronger feedback relying only on the actual visual input, whereas the 1-cue group employs weaker feedback relying to some extent on memory. Because the model parameters are linked to neurological processes, identifying different parameter values suggests the activation of different neuronal pathways.     

Spatial cognition and neuro-mimetic navigation: a model of hippocampal place cell activity

 A computational model of hippocampal activity during spatial cognition and navigation tasks is presented. The spatial representation in our model of the rat hippocampus is built on-line during exploration via two processing streams. An allothetic vision-based representation is built by unsupervised Hebbian learning extracting spatio-temporal properties of the environment from visual input. An idiothetic representation is learned based on internal movement-related information provided by path integration. On the level of the hippocampus, allothetic and idiothetic representations are integrated to yield a stable representation of the environment by a population of localized overlapping CA3-CA1 place fields. The hippocampal spatial representation is used as a basis for goal-oriented spatial behavior. We focus on the neural pathway connecting the hippocampus to the nucleus accumbens. Place cells drive a population of locomotor action neurons in the nucleus accumbens. Reward-based learning is applied to map place cell activity into action cell activity. The ensemble action cell activity provides navigational maps to support spatial behavior. We present experimental results obtained with a mobile Khepera robot. Received: 02 July 1999 / Accepted in revised form: 20 March 2000     

Potent inhibitors of CDK5 derived from roscovitine: Synthesis,biological evaluation and molecular modelling

Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer’s or Parkinson’s diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC₅₀ = 350 nM; CDK5/p25, IC₅₀ = 200 nM). These new molecules were synthesized using an original Buchwald–Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC₅₀ values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC₅₀ values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC₅₀ values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer’s disease (3g, 3h, 4m; IC₅₀ values ranging from 300 to 400 nM).     

The role of modelling in the control of toxic blue-green algae

Blooms and scums of blue-green algae (cyanobacteria)have occurred throughout the world for many years andare only one of many problems associated withover-enrichment by nutrients of fresh and marinewaters. Although much studied and written about,eutrophication poses complex and difficult managementproblems. The role of modelling as an aid to thecontrol of blue green algae is discussed.