Hormone-induced calcium oscillations in liver cells can be explained by a simple one pool model

Hormone-induced oscillations of the free intracellular calcium concentration are thought to be relevant for frequency encoding of hormone signals. In liver cells, such Ca2+ oscillations occur in response to stimulation by hormones acting via phosphoinositide breakdown. This observation may be explained by cooperative, positive feedback of Ca2+ on its own release from one inositol 1,4,5-trisphosphate-sensitive pool, obviating oscillations of inositol 1,4,5-trisphosphate. The kinetic rate laws of the associated model have a mathematical structure reminiscent of the Brusselator, a hypothetical chemical model involving a rather improbable trimolecular reaction step, thus giving a realistic biological interpretation to this hallmark of dissipative structures. We propose that calmodulin is involved in mediating this cooperativity and positive feedback, as suggested by the presented experiments. For one, hormone-induced calcium oscillations can be inhibited by the (nonphenothiazine) calmodulin antagonists calmidazolium or CGS 9343 B. Alternatively, in cells overstimulated by hormone, as characterized by a non-oscillatory elevated Ca2+ concentration, these antagonists could again restore sustained calcium oscillations. The experimental observations, including modulation of the oscillations by extracellular calcium, were in qualitative agreement with the predictions of our mathematical model.     

Fluidity-dependence of membrane adhesiveness can be explained by thermotropic shifts in surface potential

It is demonstrated that the transition of both dimyristoylphosphatidylcholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC) from the gel to liquid-crystalline phase is paralleled by a pronounced increase in the negative surface potential of liposomes composed of either lipid. The Derjaguin-Landau-Verwey-Overbeek (DLVO) theory is applied to show that this phenomenon can serve as a simple explanation of diverse adhesive properties of solid and fluid lipid bilayers.     

Steady-state visual evoked potentials can be explained by temporal superposition of transient event-related responses

Background

One common criterion for classifying electrophysiological brain responses is based on the distinction between transient (i.e. event-related potentials, ERPs) and steady-state responses (SSRs). The generation of SSRs is usually attributed to the entrainment of a neural rhythm driven by the stimulus train. However, a more parsimonious account suggests that SSRs might result from the linear addition of the transient responses elicited by each stimulus. This study aimed to investigate this possibility.

Methodology/Principal Findings

We recorded brain potentials elicited by a checkerboard stimulus reversing at different rates. We modeled SSRs by sequentially shifting and linearly adding rate-specific ERPs. Our results show a strong resemblance between recorded and synthetic SSRs, supporting the superposition hypothesis. Furthermore, we did not find evidence of entrainment of a neural oscillation at the stimulation frequency.

Conclusions/Significance

This study provides evidence that visual SSRs can be explained as a superposition of transient ERPs. These findings have critical implications in our current understanding of brain oscillations. Contrary to the idea that neural networks can be tuned to a wide range of frequencies, our findings rather suggest that the oscillatory response of a given neural network is constrained within its natural frequency range.     

The physiological role of RNase T can be explained by its unusual substrate specificity

Escherichia coli RNase T, the enzyme responsible for the end-turnover of tRNA and for the 3' maturation of 5 S and 23 S rRNAs and many other small, stable RNAs, was examined in detail with respect to its substrate specificity. The enzyme was found to be a single-strand-specific exoribonuclease that acts in the 3' to 5' direction in a non-processive manner. However, although other Escherichia coli exoribonucleases stop several nucleotides downstream of an RNA duplex, RNase T can digest RNA up to the first base pair. The presence of a free 3'-hydroxyl group is required for the enzyme to initiate digestion. Studies with RNA homopolymers and a variety of oligoribonucleotides revealed that RNase T displays an unusual base specificity, discriminating against pyrimidine and, particularly, C residues. Although RNase T appears to bind up to 10 nucleotides in its active site, its specificity is defined largely by the last 4 residues. A single 3'-terminal C residue can reduce RNase T action by >100-fold, and 2-terminal C residues essentially stop the enzyme. In vivo, the substrates of RNase T are similar in that they all contain a double-stranded stem followed by a single-stranded 3' overhang; yet, the action of RNase T on these substrates differs. The substrate specificity described here helps to explain why the different substrates yield different products, and why certain RNA molecules are not substrates at all.     

Residual charge interactions in unfolded staphylococcal nuclease can be explained by the Gaussian-chain model

The discrepancy of the pH dependence of the unfolding free energy for staphylococcal nuclease from what is expected from an idealized model for the unfolded state is accounted for by the recently developed Gaussian-chain model. Residual electrostatic effects in the unfolded state are attributed to nonspecific interactions dominated by charges close along the sequence. The dominance of nonspecific local interactions appears to be supported by some experimental evidence.     

Apparent cathepsin B deficiency in neuronal ceroid lipofuscinosis can be explained by peroxide inhibition

Fibroblasts from patients with various forms of neuronal ceroid lipofuscinosis (NCL or Batten's disease) showed decreasing cathepsin B activity with increasing passage number and time in culture. In contrast, other lysosomal hydrolase activities were largely unaffected. Cathepsin B activity, was found to be associated with the lysosome-enriched fraction following cell disruption and Percoll gradient fractionation. Exposure of fibroblasts to low concentrations (less than 0.1 mM) of hydrogen peroxide either in vivo or in vitro resulted in a dose-dependent loss of cathepsin B activity with no concomitant loss in cathepsin H activity or lysosomal hydrolase activity. These results suggest that a primary defect resulting in accumulation of abnormal peroxides could produce a secondary cathepsin B inhibition in lysosomes and lead to observed peptide and dolichol accumulation in NCL.     

The observed range for temporal mean-variance scaling exponents can be explained by reproductive correlation

The mean-variance scaling relationship known as Taylor's power law has been well documented empirically over the past four decades but a general theoretical explanation for the phenomenon does not exist. Here we provide an explanation that relates empirical patterns of temporal mean-variance scaling to individual level reproductive behavior. Initially, we review the scaling behavior of population growth models to establish theoretical limits for the scaling exponent b that is in agreement with the empirically observed range (1≤b≤2). We go on to show that the degree of reproductive covariance among individuals determines the scaling exponent b. Independent reproduction results in an exponent of one, while completely correlated reproduction results in the upper limit of two. Intermediate exponents, which are common empirically, can be generated through the decay of reproductive covariance with increasing population size. Finally, we describe how the link between reproductive correlation and the scaling exponent provides a way to infer properties of individual-level reproductive behavior, such as the relative influence of demographic stochasticity, from a macroecological pattern.     

Bayesian restoration of a hidden Markov chain with applications to DNA sequencing.

Hidden Markov models (HMMs) are a class of stochastic models that have proven to be powerful tools for the analysis of molecular sequence data. A hidden Markov model can be viewed as a black box that generates sequences of observations. The unobservable internal state of the box is stochastic and is determined by a finite state Markov chain. The observable output is stochastic with distribution determined by the state of the hidden Markov chain. We present a Bayesian solution to the problem of restoring the sequence of states visited by the hidden Markov chain from a given sequence of observed outputs. Our approach is based on a Monte Carlo Markov chain algorithm that allows us to draw samples from the full posterior distribution of the hidden Markov chain paths. The problem of estimating the probability of individual paths and the associated Monte Carlo error of these estimates is addressed. The method is illustrated by considering a problem of DNA sequence multiple alignment. The special structure for the hidden Markov model used in the sequence alignment problem is considered in detail. In conclusion, we discuss certain interesting aspects of biological sequence alignments that become accessible through the Bayesian approach to HMM restoration.     

Light-dependent orientation responses in animals can be explained by a model of compass cue integration

The magnetic compass sense of animals is currently thought to be based on light-dependent processes like the proposed radical pair mechanism. In accordance, many animals show orientation responses that depend on light. However, the orientation responses depend on the wavelength and irradiance of monochromatic light in rather complex ways that cannot be explained directly by the radical pair mechanism. Here, a radically different model is presented that can explain a vast majority of the complex observed light-dependent responses. The model put forward an integration process consisting of simple lateral inhibition between a normal functioning, light-independent magnetic compass (e.g. magnetite based) and a vision based skylight color gradient compass that misperceives compass cues in monochromatic light. Integration of the misperceived color compass cue and the normal magnetic compass not only explains most of the categorically different light-dependent orientation responses, but also shows a surprisingly good fit to how well the animals are oriented (r-values) under light of different wavelength and irradiance. The model parsimoniously suggests the existence of a single magnetic sense in birds (probably based on magnetic crystals).     

Lichen responses to nitrogen and phosphorus additions can be explained by the different symbiont responses

? Responses to simulated nitrogen (N) deposition with or without added phosphorus (P) were investigated for three contrasting lichen species - the N-sensitive Alectoria sarmentosa, the more N-tolerant Platismatia glauca and the N(2) -fixing Lobaria pulmonaria- in a field experiment. ? To examine whether nutrient limitation differed between the photobiont and the mycobiont within the lichen, the biomass responses of the respective bionts were estimated. ? The lichenized algal cells were generally N-limited, because N-stimulated algal growth in all three species. The mycobiont was P-limited in one species (A. sarmentosa), but the growth response of the mycobionts was complex, as fungal growth is also dependent on a reliable carbon export from the photobiont, which may have been the reason for the decrease of the mycobiont with N addition in P. glauca. ? Our findings showed that P availability was an important factor when studying effects of N deposition, as P supply can both mitigate and intensify the negative effects of N on epiphytic lichens.     

Conflicting molecular phylogenies of European long-eared bats (Plecotus) can be explained by cryptic diversity

Conflicting phylogenetic signals of two data sets that analyse different portions of the same molecule are unexpected and require an explanation. In the present paper we test whether (i) differential evolution of two mitochondrial genes or (ii) cryptic diversity can better explain conflicting results of two recently published molecular phylogenies on the same set of species of long-eared bats (genus Plecotus). We sequenced 1714bp of three mitochondrial regions (16S, ND1, and D-loop) of 35 Plecotus populations from 10 European countries. A likelihood ratio test revealed congruent phylogenetic signals of the three data partitions. Our phylogenetic analyses demonstrated that the existence of a previously undetected Plecotus lineage caused the incongruities of previous studies. This lineage is differentiated on the species level and lives in sympatry with its sister lineage, Plecotus auritus, in Switzerland and Northern Italy. A molecular clock indicates that all European Plecotus species are of mid or late Pliocene origin. Plecotus indet. was previously described as an intergrade between P. auritus and Plecotus austriacus since it shares morphological characters with both. It is currently known from elevations above 800 m a.s.l. in the Alps, the Dinarian Alps and the Pindos mountains in Greece. Since we could demonstrate that incongruities of two molecular analyses simply arose from the mis-identification of one lineage, we conclude that molecular phylogenetic analyses do not free systematists from a thorough inclusion of morphological and ecological data.     

Preferences for coloured bower decorations can be explained in a nonsexual context

The sensory bias model of sexual selection suggests that elaborate male secondary sexual traits evolved to exploit biases in the female's sensory system. Such biases may have evolved in a nonsexual context. Male bowerbirds build and decorate elaborate structures, bowers, which function as targets of female choice. The colour of decorations used on bowers appears to be important in determining a male's mating success. We tested two predictions made by the sensory bias model, using cache presentation experiments of artificially coloured grapes made to captive bowerbirds of five species. We first searched for evidence of ancestral biases for certain colours that could explain current colour preferences across species. We found no single parsimonious explanation for ancestral patterns of colour preference across the family. We next tested whether female preference patterns could be explained in a nonsexual, foraging, context. For both of the species where sufficient data could be collected, female foraging preferences for grapes were significantly related to male preferences for grapes used as bower decorations. Our results suggest that choice of bower decoration colour may have evolved to exploit a bias in the female's sensory system, originally shaped by selection on foraging practices. Copyright 2003 Published by Elsevier Ltd on behalf of The Association for the Study of Animal Behaviour.      

Variability observed in mechano-regulated in vivo tissue differentiation can be explained by variation in cell mechano-sensitivity

Computational simulations of tissue differentiation have been able to capture the main aspects of tissue formation/regeneration observed in animal experiments-except for the considerable degree of variability reported. Understanding and modelling the source of this variability is crucial if computational tools are to be developed for clinical applications. The objective of this study was to test the hypothesis that differences in cell mechano-sensitivity between individuals can explain the variability of tissue differentiation patterns observed experimentally. Simulations of an experiment of tissue differentiation in a mechanically loaded bone chamber were performed. Finite element analysis was used to determine the biophysical environment, and a lattice-modelling approach was used to simulate cell activity. Differences in cell mechano-sensitivity among individuals were modelled as differences in cell activity rates, with the activation of cell activities regulated by the mechanical environment. Predictions of the tissue distribution in the chambers produced the two different classes of results found experimentally: (i) chambers with a layer of bone across the chamber covered by a layer of cartilage on top and (ii) chambers with almost no bone, mainly fibrous tissue and small islands of cartilage. This indicates that the differing cellular response to the mechanical environment (i.e., subject-specific mechano-sensitivity) could be a reason for the different outcomes found when implants (or tissue engineered constructs) are used in a population.     

Variations of colour vision in a New World primate can be explained by polymorphism of retinal photopigments

The squirrel monkey (Saimiri sciureus) exhibits a polymorphism of colour vision: some animals are dichromatic, some trichromatic, and within each of these classes there are subtypes that resemble the protan and deutan variants of human colour vision. For each of ten individual monkeys we have obtained (i) behavioural measurements of colour vision and (ii) microspectrophotometric measurements of retinal photopigments. The behavioural tests, carried out in Santa Barbara, included wavelength discrimination, Rayleigh matches, and increment sensitivity at 540 and 640 nm. The microspectrophotometric measurements were made in London, using samples of fresh retinal tissue and a modified Liebman microspectrophotometer: the absorbance spectra for single retinal cells were obtained by passing a monochromatic measuring beam through the outer segments of individual rods and cones. The two types of data, behavioural and microspectrophotometric, were obtained independently and were handed to a third party before being interchanged between experimenters. From all ten animals, a rod pigment was recorded with lambda max (wavelength of peak absorbance) close to 500 nm. In several animals, receptors were found that contained a short-wave pigment (mean lambda max = 433.5 nm): these violet-sensitive receptors were rare, as in man and other primate species. In the middle- to long-wave part of the spectrum, there appear to be at least three possible Saimiri photopigments (with lambda max values at about 537,550 and 565 nm) and individual animals draw either one or two pigments from this set, giving dichromatic or trichromatic colour vision. Thus, those animals that behaviourally resembled human protanopes exhibited only one pigment in the red-green range, with lambda max = 537 nm; other behaviourally dichromatic animals had single pigments lying at longer wavelengths and these were the animals that behaviourally had higher sensitivity to long wavelengths. Four of the monkeys were behaviourally judged to be trichromatic. None of the latter animals exhibited the two widely separated pigments (close to 535 and 567 nm) that are found in the middle- and long-wave cones of macaque monkeys.(ABSTRACT TRUNCATED AT 400 WORDS)     

Preference of wet dune species for waterlogged conditions can be explained by adaptations and specific recruitment requirements

The preference of wetland angiosperms for waterlogged soils has been explained by several hypotheses: (1) wetland species are adapted to waterlogging and sensitive to drought; (2) wetland species are tolerant to drought, but inferior competitors at drier conditions; (3) wetland species have narrow moisture optima for recruitment. We tested these hypotheses by the application of permanent and fluctuating water levels to experimental wet dune plant communities with four species that frequently occur in wet dune slacks (Carex flacca, Molinia caerulea, Samolus valerandi and Schoenus nigricans) and one competitive species of drier conditions (Calamagrostis epigejos). After 3 years, fluctuating water levels had led to lower total biomass production than permanent water levels, indicating that switching from aerated to anoxic soil conditions involved physiological costs. The collective biomass of wetland species was highest at permanently waterlogged conditions with interspecific variation in the biomass optima. At the nutrient-poor growth conditions of this long-term experiment, biomass of Calamagrostis was independent of water level treatment, thus the hypothesized competitive superiority of this species at drier conditions could not explain the biomass responses of the wetland species in this study. Instead, this is evidence for an ecological preference of adult wet dune plants for waterlogged to moist conditions. Recruitment of most wet dune slack species occurred in a narrower range of water levels than adult growth, indicating that recruitment requirements also pose a limitation to the distribution of these wet dune species. Incorporation of recruitment into nature management support models may improve their predictions.     

Genetic diversity patterns in the SR-BI/II locus can be explained by a recent selective sweep

The human scavenger receptor class B type I (SR-BI and splice variant SR-BII) plays a central role in HDL cholesterol metabolism and represents a candidate gene for a number of related diseases. We examined the genetic diversity of its coding and flanking regions in a sample of 178 chromosomes from individuals of European, African, East Asian (including Southeast Asian), Middle-Eastern as well as Amerindian descent. Nine of the 14 polymorphisms observed are new. Four of the five variants causing amino acid replacements, G2S, S229G, R484W, and G499R, are likely to affect protein structure and function. SR-BI/BII diversity is partitioned among 19 haplotypes; all but one interconnected by single mutation or a recombination event. Such tight haplotype network and the unusual geographic partitioning of this diversity, high not only in Africa but in East Asia as well, suggests its recent origin and possible effect of selection. Coalescent analysis infers a relatively short time to the most recent common ancestor and points to population expansion in Africa and East Asia. These two continents differ significantly in pairwise F(ST) values, differing as well from a single cluster formed by Europe, Middle East and America. In the context of findings for similarly analyzed other loci, we propose that a selective sweep at the origin of modern human populations could explain the low level of ancestral SR-BI/II diversity. The unusually deep split between Africa and Asia, well beyond the Upper Paleolithic when inferred under neutrality, is consistent with subsequent geographical and demographic expansion favoring the accumulation of new variants, especially in groups characterized by large effective population sizes, such as Asians and Africans. The relevance of such partitioning of SR-BI/II diversity remains to be investigated in genetic epidemiological studies which can be guided by the present findings.     

High dopamine transporter selectivity can be displayed by remarkably simple non-nitrogen containing inhibitors

A series of 2-(3,4-dichlorophenyl)-cyclopent-1-enyl carboxylic acid esters and amides were prepared and tested for binding to the DAT, SERT, and NET. The achiral compounds were easily attained and found to inhibit DAT binding with K(i)-values ranging from 0.095 to 0.00003 mM. Among the compounds tested 2-(3,4-dichlorophenyl)-cyclopent-1-enyl carboxylic acid 2-methylphenyl ester was found to be highly selective with SERT/DAT>7000; NET/DAT>1700, K(i)=60 nM.