New and Exciting in PLoS this week

There are new articles in four PLoS journals today. As always, you should rate the articles, post notes and comments and send trackbacks when you blog about the papers. You can now also easily place articles on various social services (CiteULike, Mendeley, Connotea, Stumbleupon, Facebook and Digg) with just one click. Here are my own picks for the week - you go and look for your own favourites:

Variable Mutation Rates as an Adaptive Strategy in Replicator Populations:

For evolving populations of replicators, there is much evidence that the effect of mutations on fitness depends on the degree of adaptation to the selective pressures at play. In optimized populations, most mutations have deleterious effects, such that low mutation rates are favoured. In contrast to this, in populations thriving in changing environments a larger fraction of mutations have beneficial effects, providing the diversity necessary to adapt to new conditions. What is more, non-adapted populations occasionally benefit from an increase in the mutation rate. Therefore, there is no optimal universal value of the mutation rate and species attempt to adjust it to their momentary adaptive needs. In this work we have used stationary populations of RNA molecules evolving in silico to investigate the relationship between the degree of adaptation of an optimized population and the value of the mutation rate promoting maximal adaptation in a short time to a new selective pressure. Our results show that this value can significantly differ from the optimal value at mutation-selection equilibrium, being strongly influenced by the structure of the population when the adaptive process begins. In the short-term, highly optimized populations containing little variability respond better to environmental changes upon an increase of the mutation rate, whereas populations with a lower degree of optimization but higher variability benefit from reducing the mutation rate to adapt rapidly. These findings show a good agreement with the behaviour exhibited by actual organisms that replicate their genomes under broadly different mutation rates.

Diagnostic Accuracy and Optimal Use of Three Tests for Tuberculosis in Live Badgers:

Accurate diagnosis of tuberculosis (TB) due to infection with Mycobacterium bovis is notoriously difficult in live animals, yet important if we are to understand the epidemiology of TB and devise effective strategies to limit its spread. Currently available tests for diagnosing TB in live Eurasian badgers (Meles meles) remain unvalidated against a reliable gold standard. The aim of the present study was to evaluate the diagnostic accuracy and optimal use of three tests for TB in badgers in the absence of a gold standard. A Bayesian approach was used to evaluate the diagnostic accuracy and optimal use of mycobacterial culture, gamma-interferon assay and a commercially available serological test using multiple samples collected from 305 live wild badgers. Although no single test was judged to be sufficiently sensitive and specific to be used as a sole diagnostic method, selective combined use of the three tests allowed guidelines to be formulated that allow a diagnosis to be made for individual animals with an estimated overall accuracy of 93% (range: 75% to 97%). Employing this approach in the study population of badgers resulted in approximately 13 out of 14 animals having their true infection status correctly classified from samples collected on a single capture. This method of interpretation represents a marked improvement on the current procedure for diagnosing M. bovis infection in live badgers. The results should be of use to inform future test and intervention strategies with the aim of reducing the incidence of TB in free-living wild badger populations.

Sheep Movement Networks and the Transmission of Infectious Diseases:

Various approaches have been used to investigate how properties of farm contact networks impact on the transmission of infectious diseases. The potential for transmission of an infection through a contact network can be evaluated in terms of the basic reproduction number, R0. The magnitude of R0 is related to the mean contact rate of a host, in this case a farm, and is further influenced by heterogeneities in contact rates of individual hosts. The latter can be evaluated as the second order moments of the contact matrix (variances in contact rates, and co-variance between contacts to and from individual hosts). Here we calculate these quantities for the farms in a country-wide livestock network: >15,000 Scottish sheep farms in each of 4 years from July 2003 to June 2007. The analysis is relevant to endemic and chronic infections with prolonged periods of infectivity of affected animals, and uses different weightings of contacts to address disease scenarios of low, intermediate and high animal-level prevalence. Analysis of networks of Scottish farms via sheep movements from July 2003 to June 2007 suggests that heterogeneities in movement patterns (variances and covariances of rates of movement on and off the farms) make a substantial contribution to the potential for the transmission of infectious diseases, quantified as R0, within the farm population. A small percentage of farms (80%) and these farms could be efficiently targeted by interventions aimed at reducing spread of diseases via animal movement.

Vocal Accuracy and Neural Plasticity Following Micromelody-Discrimination Training:

Recent behavioral studies report correlational evidence to suggest that non-musicians with good pitch discrimination sing more accurately than those with poorer auditory skills. However, other studies have reported a dissociation between perceptual and vocal production skills. In order to elucidate the relationship between auditory discrimination skills and vocal accuracy, we administered an auditory-discrimination training paradigm to a group of non-musicians to determine whether training-enhanced auditory discrimination would specifically result in improved vocal accuracy. We utilized micromelodies (i.e., melodies with seven different interval scales, each smaller than a semitone) as the main stimuli for auditory discrimination training and testing, and we used single-note and melodic singing tasks to assess vocal accuracy in two groups of non-musicians (experimental and control). To determine if any training-induced improvements in vocal accuracy would be accompanied by related modulations in cortical activity during singing, the experimental group of non-musicians also performed the singing tasks while undergoing functional magnetic resonance imaging (fMRI). Following training, the experimental group exhibited significant enhancements in micromelody discrimination compared to controls. However, we did not observe a correlated improvement in vocal accuracy during single-note or melodic singing, nor did we detect any training-induced changes in activity within brain regions associated with singing. Given the observations from our auditory training regimen, we therefore conclude that perceptual discrimination training alone is not sufficient to improve vocal accuracy in non-musicians, supporting the suggested dissociation between auditory perception and vocal production.

Evidence that Adaptation in Drosophila Is Not Limited by Mutation at Single Sites:

Adaptation in eukaryotes is often assumed to be limited by the waiting time for adaptive mutations. This is because effective population sizes are relatively small, typically on the order of only a few million reproducing individuals or less. It should therefore take hundreds or even thousands of generations until a particular new mutation emerges. However, several striking examples of rapid adaptation appear inconsistent with this view. Here we investigate a showpiece case for rapid adaptation, the evolution of pesticide resistance in the classical genetic organism Drosophila melanogaster. Our analysis reveals distinct population genetic signatures of this adaptation that can only be explained if the number of reproducing flies is, in fact, more than 100-fold larger than commonly believed. We argue that the old estimates, based on standing levels of neutral genetic variation, are misleading in the case of rapid adaptation because levels of standing variation are strongly affected by infrequent population crashes or adaptations taking place in the vicinity of neutral sites. Our results suggest that many standard assumptions about the adaptive process in eukaryotes need to be reconsidered.

A Cell-Based Model for Quorum Sensing in Heterogeneous Bacterial Colonies:

Unicellular organisms have the ability to communicate with each other via signaling molecules, leading to correlated behaviors resembling that of higher organisms. This process, called quorum sensing, allows the cells to monitor the population size or density in a decentralized fashion and perform a common task when these parameters exceed predefined threshold values. The quorum sensing mechanism has been implicated in diverse functions such as producing bioluminescence, virulence factors, and initiating biofilm formation. Complex emergent behaviors, such as quorum sensing, can be hard to analyze and understand without the assistance of mathematical and computational models. Here, we present a cell-based model of proliferating bacterial microcolonies and investigate how population-level responses can emerge from the signaling and mechanical properties of individual cells. We study both signaling variations within homogeneous (homotypic) bacterial populations as well as signaling and competition in mixed heterotypic populations. We investigate in particular how population size, local cell density, and spatial confinement affect colony growth and predict strategies for facilitating quorum sensing. We also show that the interplay between "honest" quorum sensing signal producing bacteria and non-producing "cheaters" can lead to emergent feedback regulation via differentiated growth that provides only a transient benefit for cheating cells.

Low-Level Vibrations Retain Bone Marrow's Osteogenic Potential and Augment Recovery of Trabecular Bone during Reambulation:

Mechanical disuse will bias bone marrow stromal cells towards adipogenesis, ultimately compromising the regenerative capacity of the stem cell pool and impeding the rapid and full recovery of bone morphology. Here, it was tested whether brief daily exposure to high-frequency, low-magnitude vibrations can preserve the marrow environment during disuse and enhance the initiation of tissue recovery upon reambulation. Male C57BL/6J mice were subjected to hindlimb unloading (HU, n = 24), HU interrupted by weight-bearing for 15 min/d (HU+SHAM, n = 24), HU interrupted by low-level whole body vibrations (0.2 g, 90 Hz) for 15 min/d (HU+VIB, n = 24), or served as age-matched controls (AC, n = 24). Following 3 w of disuse, half of the mice in each group were released for 3 w of reambulation (RA), while the others were sacrificed. RA+VIB mice continued to receive vibrations for 15 min/d while RA+SHAM continued to receive sham loading. After disuse, HU+VIB mice had a 30% greater osteogenic marrow stromal cell population, 30% smaller osteoclast surface, 76% greater osteoblast surface but similar trabecular bone volume fraction compared to HU. After 3 w of reambulation, trabecular bone of RA+VIB mice had a 30% greater bone volume fraction, 51% greater marrow osteoprogenitor population, 83% greater osteoblast surfaces, 59% greater bone formation rates, and a 235% greater ratio of bone lining osteoblasts to marrow adipocytes than RA mice. A subsequent experiment indicated that receiving the mechanical intervention only during disuse, rather than only during reambulation, was more effective in altering trabecular morphology. These data indicate that the osteogenic potential of bone marrow cells is retained by low-magnitude vibrations during disuse, an attribute which may have contributed to an enhanced recovery of bone morphology during reambulation.

Local Adaptation of Aboveground Herbivores towards Plant Phenotypes Induced by Soil Biota:

Soil biota may trigger strong physiological responses in plants and consequently induce distinct phenotypes. Plant phenotype, in turn, has a strong impact on herbivore performance. Here, we tested the hypothesis that aboveground herbivores are able to adapt to plant phenotypes induced by soil biota. We bred spider mites for 15 generations on snap beans with three different belowground biotic interactions: (i) no biota (to serve as control), (ii) arbuscular mycorrhizal fungi and (ii) root-feeding nematodes. Subsequently, we conducted a reciprocal selection experiment using these spider mites, which had been kept on the differently treated plants. Belowground treatments induced changes in plant biomass, nutrient composition and water content. No direct chemical defence through cyanogenesis was detected in any of the plant groups. Growth rates of spider mites were higher on the ecotypes on which they were bred for 15 generations, although the statistical significance disappeared for mites from the nematode treatment when corrected for all multiple comparisons. These results demonstrate that belowground biota may indeed impose selection on the aboveground insect herbivores mediated by the host plant. The observed adaptation was driven by variable quantitative changes of the different separately studied life history traits (i.e. fecundity, longevity, sex-ratio, time to maturity).

Heterogeneity of Glia in the Retina and Optic Nerve of Birds and Mammals:

We have recently described a novel type of glial cell that is scattered across the inner layers of the avian retina [1]. These cells are stimulated by insulin-like growth factor 1 (IGF1) to proliferate, migrate distally into the retina, and up-regulate the nestin-related intermediate filament transitin. These changes in glial activity correspond with increased susceptibility of neurons to excitotoxic damage. This novel cell-type has been termed the Non-astrocytic Inner Retinal Glia-like (NIRG) cells. The purpose of the study was to investigate whether the retinas of non-avian species contain cells that resemble NIRG cells. We assayed for NIRG cells by probing for the expression of Sox2, Sox9, Nkx2.2, vimentin and nestin. NIRG cells were distinguished from astrocytes by a lack of expression for Glial Fibrilliary Acidic Protein (GFAP). We examined the retinas of adult mice, guinea pigs, dogs and monkeys (Macaca fasicularis). In the mouse retina and optic nerve head, we identified numerous astrocytes that expressed GFAP, S100β, Sox2 and Sox9; however, we found no evidence for NIRG-like cells that were positive for Nkx2.2, nestin, and negative for GFAP. In the guinea pig retina, we did not find astrocytes or NIRG cells in the retina, whereas we identified astrocytes in the optic nerve. In the eyes of dogs and monkeys, we found astrocytes and NIRG-like cells scattered across inner layers of the retina and within the optic nerve. We conclude that NIRG-like cells are present in the retinas of canines and non-human primates, whereas the retinas of mice and guinea pigs do not contain NIRG cells.

Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses:

The global process of aging disturbs a broad range of cellular mechanisms in a complex fashion and is not well understood. One important goal of computational approaches in aging is to develop integrated models in terms of a unifying aging theory, predicting progression of aging phenotypes grounded on molecular mechanisms. However, current experimental data incoherently reflects many isolated processes from a large diversity of approaches, biological model systems, and species, which makes such integration a challenging task. In an attempt to close this gap, we iteratively develop a fuzzy-logic cell systems model considering the interplay of damage, metabolism, and signaling by positive and negative feedback-loop motifs using relationships drawn from literature data. Because cellular biodynamics may be considered a complex control system, this approach seems particularly suitable. Here, we demonstrate that rule-based fuzzy-logic models provide semi-quantitative predictions that enhance our understanding of complex and interlocked molecular mechanisms and their implications on the aging physiome.

Understanding Adaptation in Large Populations:

For the past half-century, population genetics has been dominated by studies of molecular evolution, interpreted under the neutral theory. This predicts that the rate of substitution equals the rate of neutral mutation and that the genetic diversity within populations depends on the product of population size and neutral mutation rate, 4Nμ. Yet, diversity clearly does not increase in direct proportion to population size [1], [2]. Bacterial populations are typically more diverse than insects, which in turn are more diverse than mammals, but these differences span only an order of magnitude, even though actual population sizes vary far more. We can see that the standard neutral theory makes no sense for very abundant species; it predicts that genes share common ancestry 2N generations back, which may often be older than the species, and, for microbes, older than the planet itself.

Fungal Cell Gigantism during Mammalian Infection:

In this article we describe the formation of giant cells by the human fungal pathogen Cryptococcus neoformans during infection, involving an approximately 900-fold increase in volume compared to that of yeast cells grown in vitro. This switch to gigantism is a dramatic transition that is posited to have important consequences during infection. The paper reports the phenotypic characterization of these cells and the relationship between giant cell formation and polyploidy which suggests that gigantism is achieved by continued cell growth and DNA replication without fission. During infection, we observed an inverse correlation between the proportion of giant cells in the lung of infected mice and the inflammatory response elicited by the animals. In conclusion, our results indicate that during infection, C. neoformans forms giant cells, which might be implicated in fungal survival in the host during long time periods, especially during chronic and asymptomatic infection. The capacity for gigantism is an important new facet in fungal pathogenesis that provides the pathogen with the ability to escape host defences. We propose that the transition to gigantism can have profound consequences for the host-pathogen interaction including promoting fungal persistence in the host that can translate into latency and disease relapses.


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