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1.  Prion Folding Sends a Death Signal in Fungus 
PLoS Biology  2015;13(2):e1002058.
doi:10.1371/journal.pbio.1002058
PMCID: PMC4324830  PMID: 25671460
2.  An Innovative Lab-Based Training Program to Help Patient Groups Understand Their Disease and the Research Process 
PLoS Biology  2015;13(2):e1002067.
Genuine partnership between patient groups and medical experts is important but challenging. Our training program meets this challenge by organizing hands-on, lab-based training sessions for members of patient groups. These sessions allow “trainees” to better understand their disease and the biomedical research process, and strengthen links between patients and local researchers. Over the past decade, we and our partner institutes have received more than 900 French patients, with the participation of over 60 researchers and clinicians.
Lab-based mini-research projects allow members of patient groups to understand the scientific method and how research works in practice, thereby fostering genuine partnership between patient groups and medical experts.
doi:10.1371/journal.pbio.1002067
PMCID: PMC4323103  PMID: 25668201
3.  Ancient and Novel Small RNA Pathways Compensate for the Loss of piRNAs in Multiple Independent Nematode Lineages 
PLoS Biology  2015;13(2):e1002061.
Small RNA pathways act at the front line of defence against transposable elements across the Eukaryota. In animals, Piwi interacting small RNAs (piRNAs) are a crucial arm of this defence. However, the evolutionary relationships among piRNAs and other small RNA pathways targeting transposable elements are poorly resolved. To address this question we sequenced small RNAs from multiple, diverse nematode species, producing the first phylum-wide analysis of how small RNA pathways evolve. Surprisingly, despite their prominence in Caenorhabditis elegans and closely related nematodes, piRNAs are absent in all other nematode lineages. We found that there are at least two evolutionarily distinct mechanisms that compensate for the absence of piRNAs, both involving RNA-dependent RNA polymerases (RdRPs). Whilst one pathway is unique to nematodes, the second involves Dicer-dependent RNA-directed DNA methylation, hitherto unknown in animals, and bears striking similarity to transposon-control mechanisms in fungi and plants. Our results highlight the rapid, context-dependent evolution of small RNA pathways and suggest piRNAs in animals may have replaced an ancient eukaryotic RNA-dependent RNA polymerase pathway to control transposable elements.
A survey of the nematode phylum reveals loss of the Piwi/piRNA pathway in several lineages, but RNA-dependent RNA polymerases control transposable elements in its absence.
Author Summary
Transposable elements are segments of DNA that have the ability to copy themselves independently of the host genome and thus pose a severe threat to the integrity of the genome. Organisms have evolved mechanisms to restrict the spread of transposable elements, with small RNA molecules being one of the most important defense mechanisms. In animals, the predominant small RNA transposon-silencing mechanism is the piRNA pathway, which appears to be widely conserved. However, little is known about how small RNA pathways that target transposons evolve. In order to study this question we investigated small RNA pathways across the nematode phylum, using a well-studied model organism—the nematode Caenorhabditis elegans—as the starting point. Surprisingly we found that the piRNA pathway has been completely lost in all groups of nematodes bar those most closely related to C. elegans. This finding raises the intriguing question of how these nematodes are able to control transposable element mobilization without piRNAs. We discovered that there are other small RNA pathways that target transposable elements in these nematodes, employing RNA-dependent RNA polymerases in order to make small RNAs antisense to transposable elements. Intriguingly, the most ancient of these mechanisms, found in the most basal nematodes, is a Dicer-dependent RNA-directed DNA methylation pathway. This pathway shares strong similarity to transposon-silencing mechanisms in plants and fungi, suggesting that it might have been present in an ancient common ancestor of all eukaryotes. Our results highlight the rapid evolution of small RNA pathways and demonstrate the importance of examining molecular pathways in detail across a range of evolutionary distances.
doi:10.1371/journal.pbio.1002061
PMCID: PMC4323106  PMID: 25668728
4.  Mutualism Breakdown by Amplification of Wolbachia Genes 
PLoS Biology  2015;13(2):e1002065.
Most insect species are associated with vertically transmitted endosymbionts. Because of the mode of transmission, the fitness of these symbionts is dependent on the fitness of the hosts. Therefore, these endosymbionts need to control their proliferation in order to minimize their cost for the host. The genetic bases and mechanisms of this regulation remain largely undetermined. The maternally inherited bacteria of the genus Wolbachia are the most common endosymbionts of insects, providing some of them with fitness benefits. In Drosophila melanogaster, Wolbachia wMelPop is a unique virulent variant that proliferates massively in the hosts and shortens their lifespan. The genetic bases of wMelPop virulence are unknown, and their identification would allow a better understanding of how Wolbachia levels are regulated. Here we show that amplification of a region containing eight Wolbachia genes, called Octomom, is responsible for wMelPop virulence. Using Drosophila lines selected for carrying Wolbachia with different Octomom copy numbers, we demonstrate that the number of Octomom copies determines Wolbachia titers and the strength of the lethal phenotype. Octomom amplification is unstable, and reversion of copy number to one reverts all the phenotypes. Our results provide a link between genotype and phenotype in Wolbachia and identify a genomic region regulating Wolbachia proliferation. We also prove that these bacteria can evolve rapidly. Rapid evolution by changes in gene copy number may be common in endosymbionts with a high number of mobile elements and other repeated regions. Understanding wMelPop pathogenicity and variability also allows researchers to better control and predict the outcome of releasing mosquitoes transinfected with this variant to block human vector-borne diseases. Our results show that transition from a mutualist to a pathogen may occur because of a single genomic change in the endosymbiont. This implies that there must be constant selection on endosymbionts to control their densities.
An elegant experimental evolution approach reveals that a strain of the symbiotic bacterium Wolbachia that over-replicates and shortens the life of its fruit fly host owes this property to the amplification of a small region of its genome. Read the accompanying Primer.
Author Summary
Insects frequently carry intracellular bacteria that are passed from generation to generation through their eggs. These intracellular symbionts can be beneficial or parasitic, but because of their mode of transmission, they are always dependent on the reproduction of their carriers. They therefore have to control their own growth in order to minimize deleterious effects on the host. Bacteria of the genus Wolbachia are the most common maternally transmitted intracellular bacteria in insects. Most Wolbachia variants that are naturally associated with the fruit fly Drosophila melanogaster are benign to their hosts and provide them with protection against viruses. However, wMelPop is a virulent Wolbachia variant that over-replicates massively and shortens the lifespan of its fruit fly host. Here we show that amplification of a Wolbachia genomic region containing eight genes—called Octomom—is responsible for the pathogenic effects of wMelPop. Our results provide a link between genotype and phenotype in Wolbachia and show that virulence in symbionts can be simply caused by increases in gene copy number. These results also indicate that gene copy number variation may be a common mechanism underlying rapid evolution of intracellular symbionts.
doi:10.1371/journal.pbio.1002065
PMCID: PMC4323108  PMID: 25668031
5.  A Novel TGFβ Modulator that Uncouples R-Smad/I-Smad-Mediated Negative Feedback from R-Smad/Ligand-Driven Positive Feedback 
PLoS Biology  2015;13(2):e1002051.
As some of the most widely utilised intercellular signalling molecules, transforming growth factor β (TGFβ) superfamily members play critical roles in normal development and become disrupted in human disease. Establishing appropriate levels of TGFβ signalling involves positive and negative feedback, which are coupled and driven by the same signal transduction components (R-Smad transcription factor complexes), but whether and how the regulation of the two can be distinguished are unknown. Genome-wide comparison of published ChIP-seq datasets suggests that LIM domain binding proteins (Ldbs) co-localise with R-Smads at a substantial subset of R-Smad target genes including the locus of inhibitory Smad7 (I-Smad7), which mediates negative feedback for TGFβ signalling. We present evidence suggesting that zebrafish Ldb2a binds and directly activates the I-Smad7 gene, whereas it binds and represses the ligand gene, Squint (Sqt), which drives positive feedback. Thus, the fine tuning of TGFβ signalling derives from positive and negative control by Ldb2a. Expression of ldb2a is itself activated by TGFβ signals, suggesting potential feed-forward loops that might delay the negative input of Ldb2a to the positive feedback, as well as the positive input of Ldb2a to the negative feedback. In this way, precise gene expression control by Ldb2a enables an initial build-up of signalling via a fully active positive feedback in the absence of buffering by the negative feedback. In Ldb2a-deficient zebrafish embryos, homeostasis of TGFβ signalling is perturbed and signalling is stably enhanced, giving rise to excess mesoderm and endoderm, an effect that can be rescued by reducing signalling by the TGFβ family members, Nodal and BMP. Thus, Ldb2a is critical to the homeostatic control of TGFβ signalling and thereby embryonic patterning.
A LIM domain binding protein mediates both positive and negative feedback to fine-tune the regulation of transcription in response to transforming growth factor β signalling during embryonic development.
Author Summary
Cells depend on signals from their microenvironment to carry out their normal functions and coordinate responses. Once initiated, such signals often self-amplify via positive feedback to reach a sufficient level, when negative feedback can then be employed to dampen excess signalling. These feedback loops dynamically add or remove signalling components to maintain homeostasis. Their activation is often driven by the same signal transduction components, making it difficult to understand how signalling builds up in the first place. Here we find that the transcription co-factor Ldb2a enables differential response dynamics of negative and positive feedback upon the induction of TGFβ signalling. We show that Ldb2a directly activates expression of a TGFβ inhibitor that mediates negative feedback, while also repressing expression of TGFβ ligands that drive positive feedback. Moreover, expression of Ldb2a is itself activated by TGFβ signals. Thus, when Ldb2a levels are initially low, TGFβ signalling can self-amply and build up signal via positive feedback without being countered by negative feedback. We show that this regulatory mechanism is active in developing zebrafish embryos, where a loss of Ldb2a results in the over production of mesodermal and endodermal tissue types as a consequence of elevated TGFβ family signalling.
doi:10.1371/journal.pbio.1002051
PMCID: PMC4321984  PMID: 25665164
6.  Conformational Changes during Pore Formation by the Perforin-Related Protein Pleurotolysin 
PLoS Biology  2015;13(2):e1002049.
Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis. Soluble monomers assemble into large transmembrane pores via conformational transitions that remain to be structurally and mechanistically characterised. Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure of the two-part, fungal toxin Pleurotolysin (Ply), together with crystal structures of both components (the lipid binding PlyA protein and the pore-forming MACPF component PlyB). These data reveal a 13-fold pore 80 Å in diameter and 100 Å in height, with each subunit comprised of a PlyB molecule atop a membrane bound dimer of PlyA. The resolution of the EM map, together with biophysical and computational experiments, allowed confident assignment of subdomains in a MACPF pore assembly. The major conformational changes in PlyB are a ∼70° opening of the bent and distorted central β-sheet of the MACPF domain, accompanied by extrusion and refolding of two α-helical regions into transmembrane β-hairpins (TMH1 and TMH2). We determined the structures of three different disulphide bond-trapped prepore intermediates. Analysis of these data by molecular modelling and flexible fitting allows us to generate a potential trajectory of β-sheet unbending. The results suggest that MACPF conformational change is triggered through disruption of the interface between a conserved helix-turn-helix motif and the top of TMH2. Following their release we propose that the transmembrane regions assemble into β-hairpins via top down zippering of backbone hydrogen bonds to form the membrane-inserted β-barrel. The intermediate structures of the MACPF domain during refolding into the β-barrel pore establish a structural paradigm for the transition from soluble monomer to pore, which may be conserved across the whole superfamily. The TMH2 region is critical for the release of both TMH clusters, suggesting why this region is targeted by endogenous inhibitors of MACPF function.
Author Summary
Animals, plants, fungi, and bacteria all use pore-forming proteins of the membrane attack complex-perforin (MACPF) family as lethal, cell-killing weapons. These proteins are able to insert into the plasma membranes of target cells, creating large pores that short circuit the natural separation between the intracellular and extracellular milieu, with catastrophic results. However, the pore-forming proteins must undergo a substantial transformation from soluble precursors to a large barrel-shaped transmembrane complex as they punch their way into cells. Using a combination of X-ray crystallography and cryo electron microscopy, we have visualized, for the first time, the mechanism of action of one of these pore-forming proteins—pleurotolysin, a MACPF protein from the edible oyster mushroom. This enabled us to propose a model of the pleurotolysin pore by fitting the crystallographic structures of the pore proteins into a three-dimensional map of the pore obtained by cryo electron microscopy. We then designed a set of double mutants that allowed us to chemically trap intermediate states along the trajectory of the pore formation process, and to determine their structures too. By combining these data we proposed a detailed molecular mechanism for pore formation. The pleurotolysin first assembles into rings of 13 subunits, each of which then opens up by about 70° during pore formation. This process is accompanied by refolding and extrusion of two compact regions from each subunit into long hairpins that then zipper together to form an 80-Å wide barrel-shaped channel through the membrane.
A combination of structural methods reveals the complex process by which the perforin-like fungal toxin Pleurotolysin rearranges its structure to form a pore that punches a hole in target cell membranes.
doi:10.1371/journal.pbio.1002049
PMCID: PMC4318580  PMID: 25654333
7.  Flagging the Fatty Acid Ferryman 
PLoS Biology  2015;13(2):e1002054.
Fatty acids made in chloroplasts must be exported into the rest of the cell to be converted into commercially important plant oils. A new study identifies FAX1 as a protein that mediates this crucial transport step. Read the Research Article.
doi:10.1371/journal.pbio.1002054
PMCID: PMC4315455  PMID: 25646782
8.  Use and Misuse of Material Transfer Agreements: Lessons in Proportionality from Research, Repositories, and Litigation 
PLoS Biology  2015;13(2):e1002060.
Material transfer agreements exist to facilitate the exchange of materials and associated data between researchers as well as to protect the interests of the researchers and their institutions. But this dual mandate can be a source of frustration for researchers, creating administrative burdens and slowing down collaborations. We argue here that in most cases in pre-competitive research, a simple agreement would suffice; the more complex agreements and mechanisms for their negotiation should be reserved for cases where the risks posed to the institution and the potential commercial value of the research reagents is high.
The material transfer agreements designed to facilitate the exchange of materials between researchers are unnecessarily burdensome and obstructive and in most cases could be replaced by simpler tools.
doi:10.1371/journal.pbio.1002060
PMCID: PMC4315468  PMID: 25646804
9.  Calorie Restriction-Mediated Replicative Lifespan Extension in Yeast Is Non-Cell Autonomous 
PLoS Biology  2015;13(1):e1002048.
Calorie-restriction extends lifespan in many multicellular organisms; here substances secreted by calorie-restricted yeast are found to induce longer life in other yeast cells, suggesting that cellular communication is a component of this phenomenon even in a single-celled organism.
In laboratory yeast strains with Sir2 and Fob1 function, wild-type NAD+ salvage is required for calorie restriction (CR) to extend replicative lifespan. CR does not significantly alter steady state levels of intracellular NAD+ metabolites. However, levels of Sir2 and Pnc1, two enzymes that sequentially convert NAD+ to nicotinic acid (NA), are up-regulated during CR. To test whether factors such as NA might be exported by glucose-restricted mother cells to survive later generations, we developed a replicative longevity paradigm in which mother cells are moved after 15 generations on defined media. The experiment reveals that CR mother cells lose the longevity benefit of CR when evacuated from their local environment to fresh CR media. Addition of NA or nicotinamide riboside (NR) allows a moved mother to maintain replicative longevity despite the move. Moreover, conditioned medium from CR-treated cells transmits the longevity benefit of CR to moved mother cells. Evidence suggests the existence of a longevity factor that is dialyzable but is neither NA nor NR, and indicates that Sir2 is not required for the longevity factor to be produced or to act. Data indicate that the benefit of glucose-restriction is transmitted from cell to cell in budding yeast, suggesting that glucose restriction may benefit neighboring cells and not only an individual cell.
Author Summary
Though calorie restriction extends lifespan and healthspan in multiple model organisms, the intrinsic mechanisms remain unclear. In budding yeast Saccharomyces cerevisiae, manipulation of nicotinamide adenine dinucleotide (NAD+)—a central metabolic cofactor—can restrict or extend replicative lifespan, suggesting that NAD+-dependent targets might be mediators of extended longevity. However, although treating cells with the NAD+ precursor nicotinamide riboside extends lifespan, intracellular NAD+ metabolites levels are not altered by glucose restriction. This suggests the potential involvement of extracellular factors in replicative lifespan extension. Here we show that though yeast cells display a longevity benefit upon glucose restriction, these cells surprisingly lose the longevity benefit if moved from their local environment to fresh glucose-restricted media. They are, however, able to regain the longevity benefit, despite the change in environment, if the new environment is supplemented with conditioned medium from glucose restricted cells. Our results suggest that calorie restriction-induced longevity is not cell autonomous and, instead, appears to be transmitted from cell to cell in S. cerevisiae via a dialyzable extracellular factor.
doi:10.1371/journal.pbio.1002048
PMCID: PMC4310591  PMID: 25633578
10.  A Sensory-Motor Control Model of Animal Flight Explains Why Bats Fly Differently in Light Versus Dark 
PLoS Biology  2015;13(1):e1002046.
Animal flight requires fine motor control. However, it is unknown how flying animals rapidly transform noisy sensory information into adequate motor commands. Here we developed a sensorimotor control model that explains vertebrate flight guidance with high fidelity. This simple model accurately reconstructed complex trajectories of bats flying in the dark. The model implies that in order to apply appropriate motor commands, bats have to estimate not only the angle-to-target, as was previously assumed, but also the angular velocity (“proportional-derivative” controller). Next, we conducted experiments in which bats flew in light conditions. When using vision, bats altered their movements, reducing the flight curvature. This change was explained by the model via reduction in sensory noise under vision versus pure echolocation. These results imply a surprising link between sensory noise and movement dynamics. We propose that this sensory-motor link is fundamental to motion control in rapidly moving animals under different sensory conditions, on land, sea, or air.
Author Summary
Bats are extremely skillful aviators: they are able to capture prey and land on targets under challenging flight conditions, as well as maneuver accurately using either echolocation or vision. It remains a mystery, however, how bats—or other flying animals—rapidly translate the noisy incoming sensory information into correct motor commands in order to converge onto a target. To address this question, we developed a sensorimotor control model that explains animal flight guidance and tested it in bats with experiments conducted under dark and light conditions. The model reproduced the bats’ flight trajectory with very high accuracy, suggesting that bats have to estimate not only the angle to target but also changes in the angle over time (angular velocity). Additionally, we demonstrate that the bat must suppress its sensory noise by integrating sensory information over several sonar pulses in order to successfully guide its flight. Comparisons of flight trajectories in light and dark suggest that the surprisingly curved flights exhibited by bats in the dark are due to sensory noise, not motor limitations. We hypothesize that rapidly moving animals must adaptively change their motor control strategy to optimally match the sensory conditions.
A model of animal flight guidance suggests that bats use estimates of angular velocity and time-integrated sensory information to find their targets, and explains why bats fly straighter in the light than in the dark.
doi:10.1371/journal.pbio.1002046
PMCID: PMC4309566  PMID: 25629809
11.  Illegal Drugs Laws: Clearing a 50-Year-Old Obstacle to Research 
PLoS Biology  2015;13(1):e1002047.
For over 50 years, many medical drugs have been effectively banned from research and clinical treatment in the vain hope that this will stop recreational use. The scientific community should now challenge this pointless ban and get governments to improve their regulations so science can flourish.
The United Nations drug control conventions of 1960 and 1971 and later additions have inadvertently resulted in perhaps the greatest restrictions of medical and life sciences research. These conventions now need to be revised to allow neuroscience to progress unimpeded and to assist in the innovation of treatments for brain disorders. In the meantime, local changes, such as the United Kingdom moving cannabis from Schedule 1 to Schedule 2, should be implemented to allow medical research to develop appropriately.
doi:10.1371/journal.pbio.1002047
PMCID: PMC4307971  PMID: 25625189
12.  Population Diversification in a Yeast Metabolic Program Promotes Anticipation of Environmental Shifts 
PLoS Biology  2015;13(1):e1002042.
Detailed study of the dynamic response of yeast to combinations of sugars reveals an anticipatory population diversification strategy that allows rapid adaptation to shifts in environmental carbon source availability.
Author Summary
To survive in resource-limited and dynamic environments, microbial populations implement a diverse repertoire of regulatory strategies. These strategies often rely on anticipating impending environmental shifts, enabling the population to be prepared for a future change in conditions. It has long been known that cells optimize nutritional value from mixtures of carbon sources, for example glucose and galactose, by sequential activation of regulatory programs that allow for metabolizing the preferred carbon source first before metabolizing the secondary carbon source. Using automated flow-cytometry, we mapped the dynamical behavior of populations simultaneously presented with a large panel of different glucose and galactose concentrations. We show that, counter to expectations, in populations presented with glucose and galactose simultaneously, the galactose regulatory pathway is activated in a fraction of the cell population hours before glucose is fully consumed. We demonstrate that the size of this fraction of cells is tuned by the concentration of the two sugars. This population diversification may constitute a tradeoff between the benefit of rapid galactose consumption once glucose is depleted and the cost of expressing the galactose pathway.
Delineating the strategies by which cells contend with combinatorial changing environments is crucial for understanding cellular regulatory organization. When presented with two carbon sources, microorganisms first consume the carbon substrate that supports the highest growth rate (e.g., glucose) and then switch to the secondary carbon source (e.g., galactose), a paradigm known as the Monod model. Sequential sugar utilization has been attributed to transcriptional repression of the secondary metabolic pathway, followed by activation of this pathway upon depletion of the preferred carbon source. In this work, we demonstrate that although Saccharomyces cerevisiae cells consume glucose before galactose, the galactose regulatory pathway is activated in a fraction of the cell population hours before glucose is fully consumed. This early activation reduces the time required for the population to transition between the two metabolic programs and provides a fitness advantage that might be crucial in competitive environments.
doi:10.1371/journal.pbio.1002042
PMCID: PMC4307983  PMID: 25626086
13.  Optimal Conservation Outcomes Require Both Restoration and Protection 
PLoS Biology  2015;13(1):e1002052.
Conservation outcomes are principally achieved through the protection of intact habitat or the restoration of degraded habitat. Restoration is generally considered a lower priority action than protection because protection is thought to provide superior outcomes, at lower costs, without the time delay required for restoration. Yet while it is broadly accepted that protected intact habitat safeguards more biodiversity and generates greater ecosystem services per unit area than restored habitat, conservation lacks a theory that can coherently compare the relative outcomes of the two actions. We use a dynamic landscape model to integrate these two actions into a unified conservation theory of protection and restoration. Using nonlinear benefit functions, we show that both actions are crucial components of a conservation strategy that seeks to optimise either biodiversity conservation or ecosystem services provision. In contrast to conservation orthodoxy, in some circumstances, restoration should be strongly preferred to protection. The relative priority of protection and restoration depends on their costs and also on the different time lags that are inherent to both protection and restoration. We derive a simple and easy-to-interpret heuristic that integrates these factors into a single equation that applies equally to biodiversity conservation and ecosystem service objectives. We use two examples to illustrate the theory: bird conservation in tropical rainforests and coastal defence provided by mangrove forests.
In conservation, prevention is not always better than cure, either for protecting biodiversity or ecosystem services. It can be better to start habitat restoration before all available intact habitat has been protected.
Author Summary
Most species go extinct because humans have cleared their habitat. Habitat loss can also cause people to lose some of the services provided by ecosystems, such as the removal of carbon dioxide from the atmosphere or the protection of coastal communities from storm damage. There are two broad strategies for stopping and reversing habitat loss: we can either protect habitat that is currently intact, or we can restore habitat that has already been cleared. Superficially, we might imagine that, as with human health, “prevention is better than cure,” and that therefore habitat protection should be given priority over habitat restoration. However, there is currently no scientific theory to justify this belief. Here, we used an ecosystem model and dynamic optimization tools from mathematics to show that habitat restoration (such as tree planting) can, surprisingly, be more cost-effective than habitat protection (such as designating a national park) for two case studies. We discovered that the best decision depends on the relative costs of the two actions, the rate at which habitat is being lost, and the time lag between restored habitat being as useful as intact habitat for securing species and ecosystem services.
doi:10.1371/journal.pbio.1002052
PMCID: PMC4308106  PMID: 25625277
14.  Natural Variation in Preparation for Nutrient Depletion Reveals a Cost–Benefit Tradeoff 
PLoS Biology  2015;13(1):e1002041.
Yeast can anticipate the depletion of a preferred nutrient by preemptively activating genes for alternative nutrients; the degree of this preparation varies across natural strains and is subject to a fitness tradeoff.
Maximizing growth and survival in the face of a complex, time-varying environment is a common problem for single-celled organisms in the wild. When offered two different sugars as carbon sources, microorganisms first consume the preferred sugar, then undergo a transient growth delay, the “diauxic lag,” while inducing genes to metabolize the less preferred sugar. This delay is commonly assumed to be an inevitable consequence of selection to maximize use of the preferred sugar. Contrary to this view, we found that many natural isolates of Saccharomyces cerevisiae display short or nonexistent diauxic lags when grown in mixtures of glucose (preferred) and galactose. These strains induce galactose utilization (GAL) genes hours before glucose exhaustion, thereby “preparing” for the transition from glucose to galactose metabolism. The extent of preparation varies across strains, and seems to be determined by the steady-state response of GAL genes to mixtures of glucose and galactose rather than by induction kinetics. Although early GAL gene induction gives strains a competitive advantage once glucose runs out, it comes at a cost while glucose is still present. Costs and benefits correlate with the degree of preparation: strains with higher expression of GAL genes prior to glucose exhaustion experience a larger upfront growth cost but also a shorter diauxic lag. Our results show that classical diauxic growth is only one extreme on a continuum of growth strategies constrained by a cost–benefit tradeoff. This type of continuum is likely to be common in nature, as similar tradeoffs can arise whenever cells evolve to use mixtures of nutrients.
Author Summary
When microorganisms encounter multiple sugars, they often consume a preferred sugar (such as glucose) before consuming alternative sugars (such as galactose). In experiments on laboratory strains of yeast, cells typically stop growing when the preferred sugar runs out, and start growing again only after taking time to turn on genes for alternative sugar utilization. This pause in growth, the “diauxic lag,” is a classic example of the ability of cells to make decisions based on environmental signals. Here we find, however, that when different natural yeast strains are grown in a mix of glucose and galactose, some strains do not exhibit a diauxic lag, or have a very short one. These “short lag” strains are able to turn on galactose utilization—or GAL—genes up to four hours before the glucose runs out, in effect preparing for the transition to galactose consumption. Although such preparation helps strains avoid the diauxic lag, it causes them to grow slower before glucose runs out, presumably because of the metabolic burden of expressing GAL genes. These observations suggest that microbes in nature may commonly face a tradeoff between growing efficiently on their preferred nutrient and being ready to consume alternative nutrients should the preferred nutrient run out.
doi:10.1371/journal.pbio.1002041
PMCID: PMC4308108  PMID: 25626068
15.  Adult Neurogenesis in Humans- Common and Unique Traits in Mammals 
PLoS Biology  2015;13(1):e1002045.
New neurons generated in the adult brain have been shown in rodents to mediate specific functions, including neural plasticity. This Essay discusses recent work on human adult neurogenesis, examining how it compares to that in other mammals.
New neurons are continuously generated in specific regions in the adult brain. Studies in rodents have demonstrated that adult-born neurons have specific functional features and mediate neural plasticity. Data on the extent and dynamics of adult neurogenesis in adult humans are starting to emerge, and there are clear similarities and differences compared to other mammals. Why do these differences arise? And what do they mean?
doi:10.1371/journal.pbio.1002045
PMCID: PMC4306487  PMID: 25621867
16.  Characterizing the Transmission Dynamics and Control of Ebola Virus Disease 
PLoS Biology  2015;13(1):e1002057.
Carefully calibrated transmission models have the potential to guide public health officials on the nature and scale of the interventions required to control the ongoing Ebola virus disease epidemic in West Africa.
Carefully calibrated transmission models have the potential to guide public health officials on the nature and scale of the interventions required to control epidemics. In the context of the ongoing Ebola virus disease (EVD) epidemic in Liberia, Drake and colleagues, in this issue of PLOS Biology, employed an elegant modeling approach to capture the distributions of the number of secondary cases that arise in the community and health care settings in the context of changing population behaviors and increasing hospital capacity. Their findings underscore the role of increasing the rate of safe burials and the fractions of infectious individuals who seek hospitalization together with hospital capacity to achieve epidemic control. However, further modeling efforts of EVD transmission and control in West Africa should utilize the spatial-temporal patterns of spread in the region by incorporating spatial heterogeneity in the transmission process. Detailed datasets are urgently needed to characterize temporal changes in population behaviors, contact networks at different spatial scales, population mobility patterns, adherence to infection control measures in hospital settings, and hospitalization and reporting rates.
doi:10.1371/journal.pbio.1002057
PMCID: PMC4301953  PMID: 25607595
17.  Where Next for Microbiome Research? 
PLoS Biology  2015;13(1):e1002050.
The last decade has seen a staggering transformation in our knowledge of microbial communities. Here, seven short pieces speculate as to what the next ten years might hold in store.
The development of high-throughput sequencing technologies has transformed our capacity to investigate the composition and dynamics of the microbial communities that populate diverse habitats. Over the past decade, these advances have yielded an avalanche of metagenomic data. The current stage of “van Leeuwenhoek”–like cataloguing, as well as functional analyses, will likely accelerate as DNA and RNA sequencing, plus protein and metabolic profiling capacities and computational tools, continue to improve. However, it is time to consider: what’s next for microbiome research? The short pieces included here briefly consider the challenges and opportunities awaiting microbiome research.
doi:10.1371/journal.pbio.1002050
PMCID: PMC4300079  PMID: 25602283
18.  A Low-Cost, Hands-on Module to Characterize Antimicrobial Compounds Using an Interdisciplinary, Biophysical Approach 
PLoS Biology  2015;13(1):e1002044.
A cost-effective and resource-efficient hands-on educational module that uses an interdisciplinary approach to characterize antimicrobial compounds, combining microbiology experiments and a physics-based analytical model.
We have developed a hands-on experimental module that combines biology experiments with a physics-based analytical model in order to characterize antimicrobial compounds. To understand antibiotic resistance, participants perform a disc diffusion assay to test the antimicrobial activity of different compounds and then apply a diffusion-based analytical model to gain insights into the behavior of the active antimicrobial component. In our experience, this module was robust, reproducible, and cost-effective, suggesting that it could be implemented in diverse settings such as undergraduate research, STEM (science, technology, engineering, and math) camps, school programs, and laboratory training workshops. By providing valuable interdisciplinary research experience in science outreach and education initiatives, this module addresses the paucity of structured training or education programs that integrate diverse scientific fields. Its low-cost requirements make it especially suitable for use in resource-limited settings.
doi:10.1371/journal.pbio.1002044
PMCID: PMC4300086  PMID: 25602254
19.  Structure-Guided Design of Selective Epac1 and Epac2 Agonists 
PLoS Biology  2015;13(1):e1002038.
The second messenger cAMP is known to augment glucose-induced insulin secretion. However, its downstream targets in pancreatic β-cells have not been unequivocally determined. Therefore, we designed cAMP analogues by a structure-guided approach that act as Epac2-selective agonists both in vitro and in vivo. These analogues activate Epac2 about two orders of magnitude more potently than cAMP. The high potency arises from increased affinity as well as increased maximal activation. Crystallographic studies demonstrate that this is due to unique interactions. At least one of the Epac2-specific agonists, Sp-8-BnT-cAMPS (S-220), enhances glucose-induced insulin secretion in human pancreatic cells. Selective targeting of Epac2 is thus proven possible and may be an option in diabetes treatment.
Author Summary
cAMP is a small molecule produced by cells that activates proteins involved in a wide range of biological processes, including olfaction, pacemaker activity, regulation of gene expression, insulin secretion, and many others. In the case of insulin secretion, cAMP seems to impinge on different stages of the signalling cascade to regulate secretory activity in pancreatic β-cells. Here we have developed a chemically modified version of cAMP that specifically only activates Epac2, one of the cAMP-responsive proteins in this cascade. Furthermore, our cAMP analogue activates Epac2 more potently than cAMP itself does. We have determined several crystal structures of Epac2 in complex with cAMP analogues to help us explain the molecular basis of the observed selectivity and the strong activation potential. In addition, we were able to show that the analogue is able to potentiate glucose-induced secretion of insulin from human pancreatic islets. The principal challenge during this study was identifying and understanding small differences in the cAMP-binding domains of cAMP-regulated proteins and matching these differences with suitable modifications of the cAMP molecule.
A newly developed analogue of cAMP that selectively activates Epac2 can potentiate glucose-induced insulin secretion from human pancreatic β-cells.
doi:10.1371/journal.pbio.1002038
PMCID: PMC4300089  PMID: 25603503
20.  Correction: Evolution of Sexes from an Ancestral Mating-Type Specification Pathway 
PLoS Biology  2015;13(1):e1002055.
doi:10.1371/journal.pbio.1002055
PMCID: PMC4289062  PMID: 25575020
21.  Pain: A Distributed Brain Information Network? 
PLoS Biology  2015;13(1):e1002037.
How is pain processed in the brain? This Primer discusses evidence that the nociceptive input and cognitive modulation are processed independently as parts of an integrated brain network from which subjective pain emerges. See the Research Article.
Understanding how pain is processed in the brain has been an enduring puzzle, because there doesn't appear to be a single “pain cortex” that directly codes the subjective perception of pain. An emerging concept is that, instead, pain might emerge from the coordinated activity of an integrated brain network. In support of this view, Woo and colleagues present evidence that distinct brain networks support the subjective changes in pain that result from nociceptive input and self-directed cognitive modulation. This evidence for the sensitivity of distinct neural subsystems to different aspects of pain opens up the way to more formal computational network theories of pain.
doi:10.1371/journal.pbio.1002037
PMCID: PMC4285395  PMID: 25562782
22.  Computational Framework Explains How Animals Select Actions with Rewarding Outcomes 
PLoS Biology  2015;13(1):e1002035.
A new model of how the brain learns beneficial behavior from rewarding outcomes emphasizes the importance of the striatum, replicates experimental data, and raises new questions about neurological disorders. Read the Research Article.
doi:10.1371/journal.pbio.1002035
PMCID: PMC4285397  PMID: 25562602
23.  Finding Our Way through Phenotypes 
Deans, Andrew R. | Lewis, Suzanna E. | Huala, Eva | Anzaldo, Salvatore S. | Ashburner, Michael | Balhoff, James P. | Blackburn, David C. | Blake, Judith A. | Burleigh, J. Gordon | Chanet, Bruno | Cooper, Laurel D. | Courtot, Mélanie | Csösz, Sándor | Cui, Hong | Dahdul, Wasila | Das, Sandip | Dececchi, T. Alexander | Dettai, Agnes | Diogo, Rui | Druzinsky, Robert E. | Dumontier, Michel | Franz, Nico M. | Friedrich, Frank | Gkoutos, George V. | Haendel, Melissa | Harmon, Luke J. | Hayamizu, Terry F. | He, Yongqun | Hines, Heather M. | Ibrahim, Nizar | Jackson, Laura M. | Jaiswal, Pankaj | James-Zorn, Christina | Köhler, Sebastian | Lecointre, Guillaume | Lapp, Hilmar | Lawrence, Carolyn J. | Le Novère, Nicolas | Lundberg, John G. | Macklin, James | Mast, Austin R. | Midford, Peter E. | Mikó, István | Mungall, Christopher J. | Oellrich, Anika | Osumi-Sutherland, David | Parkinson, Helen | Ramírez, Martín J. | Richter, Stefan | Robinson, Peter N. | Ruttenberg, Alan | Schulz, Katja S. | Segerdell, Erik | Seltmann, Katja C. | Sharkey, Michael J. | Smith, Aaron D. | Smith, Barry | Specht, Chelsea D. | Squires, R. Burke | Thacker, Robert W. | Thessen, Anne | Fernandez-Triana, Jose | Vihinen, Mauno | Vize, Peter D. | Vogt, Lars | Wall, Christine E. | Walls, Ramona L. | Westerfeld, Monte | Wharton, Robert A. | Wirkner, Christian S. | Woolley, James B. | Yoder, Matthew J. | Zorn, Aaron M. | Mabee, Paula
PLoS Biology  2015;13(1):e1002033.
Imagine if we could compute across phenotype data as easily as genomic data; this article calls for efforts to realize this vision and discusses the potential benefits.
Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.
doi:10.1371/journal.pbio.1002033
PMCID: PMC4285398  PMID: 25562316
24.  Distinct Brain Systems Mediate the Effects of Nociceptive Input and Self-Regulation on Pain 
PLoS Biology  2015;13(1):e1002036.
Two distinct parallel neural systems independently contribute to our overall experience of pain – separately modulated by noxious input and by cognitive self-regulation.
Cognitive self-regulation can strongly modulate pain and emotion. However, it is unclear whether self-regulation primarily influences primary nociceptive and affective processes or evaluative ones. In this study, participants engaged in self-regulation to increase or decrease pain while experiencing multiple levels of painful heat during functional magnetic resonance imaging (fMRI) imaging. Both heat intensity and self-regulation strongly influenced reported pain, but they did so via two distinct brain pathways. The effects of stimulus intensity were mediated by the neurologic pain signature (NPS), an a priori distributed brain network shown to predict physical pain with over 90% sensitivity and specificity across four studies. Self-regulation did not influence NPS responses; instead, its effects were mediated through functional connections between the nucleus accumbens and ventromedial prefrontal cortex. This pathway was unresponsive to noxious input, and has been broadly implicated in valuation, emotional appraisal, and functional outcomes in pain and other types of affective processes. These findings provide evidence that pain reports are associated with two dissociable functional systems: nociceptive/affective aspects mediated by the NPS, and evaluative/functional aspects mediated by a fronto-striatal system.
Author Summary
Does cognitive self-regulation influence pain experience by affecting the primary representations of painful (nociceptive) stimuli in the brain? Or does it regulate reported pain via a neural pathway that is distinct from the one that mediates nociceptive pain? The present study demonstrates that nociceptive and cognitive manipulations of pain influence two distinct, separable neural systems, which operate together to construct the pain experience. The neurologic pain signature (NPS) mediates the effects of noxious input, whereas a fronto-striatal pathway connecting nucleus accumbens and ventromedial prefrontal cortex mediates the effects of cognitive self-regulation of pain. These findings help move the field beyond the “one system” view of pain as a primarily nociceptive process, and provide a foundation for new approaches to multidimensional pain assessment and treatment.
doi:10.1371/journal.pbio.1002036
PMCID: PMC4285399  PMID: 25562688
25.  A New Framework for Cortico-Striatal Plasticity: Behavioural Theory Meets In Vitro Data at the Reinforcement-Action Interface 
PLoS Biology  2015;13(1):e1002034.
A computational model yields new insights into the bewildering complexity of cortico-striatal plasticity and its rationale for supporting operant learning.
Operant learning requires that reinforcement signals interact with action representations at a suitable neural interface. Much evidence suggests that this occurs when phasic dopamine, acting as a reinforcement prediction error, gates plasticity at cortico-striatal synapses, and thereby changes the future likelihood of selecting the action(s) coded by striatal neurons. But this hypothesis faces serious challenges. First, cortico-striatal plasticity is inexplicably complex, depending on spike timing, dopamine level, and dopamine receptor type. Second, there is a credit assignment problem—action selection signals occur long before the consequent dopamine reinforcement signal. Third, the two types of striatal output neuron have apparently opposite effects on action selection. Whether these factors rule out the interface hypothesis and how they interact to produce reinforcement learning is unknown. We present a computational framework that addresses these challenges. We first predict the expected activity changes over an operant task for both types of action-coding striatal neuron, and show they co-operate to promote action selection in learning and compete to promote action suppression in extinction. Separately, we derive a complete model of dopamine and spike-timing dependent cortico-striatal plasticity from in vitro data. We then show this model produces the predicted activity changes necessary for learning and extinction in an operant task, a remarkable convergence of a bottom-up data-driven plasticity model with the top-down behavioural requirements of learning theory. Moreover, we show the complex dependencies of cortico-striatal plasticity are not only sufficient but necessary for learning and extinction. Validating the model, we show it can account for behavioural data describing extinction, renewal, and reacquisition, and replicate in vitro experimental data on cortico-striatal plasticity. By bridging the levels between the single synapse and behaviour, our model shows how striatum acts as the action-reinforcement interface.
Author Summary
A key component of survival is the ability to learn which actions, in what contexts, yield useful and rewarding outcomes. Actions are encoded in the brain in the cortex but, as many actions are possible at any one time, there needs to be a mechanism to select which one is to be performed. This problem of action selection is mediated by a set of nuclei known as the basal ganglia, which receive convergent “action requests” from all over the cortex and select the one that is currently most important. Working out which is most important is determined by the strength of the input from each action request: the stronger the connection, the more important that action. Understanding learning thus requires understanding how that strength is changed by the outcome of each action. We built a computational model that demonstrates how the brain's internal signal for outcome (carried by the neurotransmitter dopamine) changes the strength of these cortical connections to learn the selection of rewarded actions, and the suppression of unrewarded ones. Our model shows how several known signals in the brain work together to shape the influence of cortical inputs to the basal ganglia at the interface between our actions and their outcomes.
doi:10.1371/journal.pbio.1002034
PMCID: PMC4285402  PMID: 25562526

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