Survival probability is predicted to underlie the evolution of life histories along a slow–fast continuum. Hibernation allows a diverse range of small mammals to exhibit seasonal dormancy, which might increase survival and consequently be associated with relatively slow life histories. We used phylogenetically informed GLS models to test for an effect of hibernation on seasonal and annual survival, and on key attributes of life histories among mammals. Monthly survival was in most cases higher during hibernation compared with the active season, probably because inactivity minimizes predation. Hibernators also have approximately 15 per cent higher annual survival than similar sized non-hibernating species. As predicted, we found an effect of hibernation on the relationships between life history attributes and body mass: small hibernating mammals generally have longer maximum life spans (50% greater for a 50 g species), reproduce at slower rates, mature at older ages and have longer generation times compared with similar-sized non-hibernators. In accordance with evolutionary theories, however, hibernating species do not have longer life spans than non-hibernators with similar survival rates, nor do they have lower reproductive rates than non-hibernators with similar maximum life spans. Thus, our combined results suggest that (i) hibernation is associated with high rates of overwinter and annual survival, and (ii) an increase in survival in hibernating species is linked with the coevolution of traits indicative of relatively slow life histories. With Glis glis). In this case, hibernation clearly is unrelated to energetic constraints, but probably functions to increase survival by eliminating predation from owls during years when most individuals skip reproduction ) and, in the same environments, other small mammals can be active throughout the winter. We suggest that a past focus on the remarkable metabolic and thermal physiology of hibernation has partly obscured its broader ecological significance. Hibernation is a prerequisite for small mammals to employ seasonal dormancy, which greatly increases the probability of surviving while environmental conditions are sub-optimal for reproduction. An ability to forego activity for up to nine months of the year, even when food is available, could in itself be an important purpose of hibernation. In other words, we suggest that predator avoidance, rather than energy savings, may have been the primary selective force for the evolution of hibernation.annual survival than predicted for their body mass. This effect is robust because we could detect it despite the inherent variability in estimates of survival for wild populations. We expected hibernation could particularly benefit the survival of the smallest species, which probably are more vulnerable to predation and starvation during winter than larger species, but we did not find a significant effect of hibernation on the slope of the relationship between survival and body mass. Nevertheless, there is an apparent trend in the data for hibernation to have a greater positive effect on survival in smaller species.We found that hibernating mammals generally also have higher (b)Hibernation has a significant influence on each of the key life history traits included in our analyses and these effects become more pronounced in smaller species. Mammals capable of hibernation generally have longer maximum recorded lifespans than predicted for their body mass. Our model predicts a 50 g hibernator, for example, has a potential maximum life span that is approximately 50 per cent or 2.8 years greater than its non-hibernating counterpart. A positive effect of hibernation on maximum life span was shown previously among bat species . Our resOur analyses also suggested an effect of hibernation on other key life history traits. Small hibernators generally have lower reproductive rates than predicted for their body mass. Whereas, when annual reproductive output is plotted against maximum life span, hibernating species are indistinguishable from other mammals. We also found a positive effect of hibernation on age of sexual maturity, which is strongly correlated with the pace of life histories ,70–73. SOur combined analyses suggest a link between the positive effect of hibernation on survival and the evolution of a relatively slow life history in hibernating mammals. This interpretation is in agreement with evolutionary theories of ageing, which predict survival rates of adult individuals to determine the optimal level of an apparent trade-off between somatic maintenance (i.e. senescence) and reproduction ,67,73,74Our study suggests a link in the direction of hibernation → survival → life history, but we cannot be certain of the direction of cause and effect among these traits. Hibernation clearly is an energetic requirement for many small mammals, such as insectivorous bats, to reside year-round at temperate latitudes. The need to fatten prior to hibernation, for example, could restrict investment in reproduction and hence lead to demographic changes that drive the evolution of correlated traits such as survival and rate of senescence. Nevertheless, many resident passerine birds and small mammals do not hibernate over the temperate winter season. Hibernators also can remain dormant well into the season when food is available , and hib


Adult speech perception reflects the long-term regularities of the native language, but it is also flexible such that it accommodates and adapts to adverse listening conditions and short-term deviations from native-language norms. The purpose of this article is to examine how the broader neuroscience literature can inform and advance research efforts in understanding the neural basis of flexibility and adaptive plasticity in speech perception. Specifically, we highlight the potential role of learning algorithms that rely on prediction error signals and discuss specific neural structures that are likely to contribute to such learning. To this end, we review behavioral studies, computational accounts, and neuroimaging findings related to adaptive plasticity in speech perception. Already, a few studies have alluded to a potential role of these mechanisms in adaptive plasticity in speech perception. Furthermore, we consider research topics in neuroscience that offer insight into how perception can be adaptively tuned to short-term deviations while balancing the need to maintain stability in the perception of learned long-term regularities. Consideration of the application and limitations of these algorithms in characterizing flexible speech perception under adverse conditions promises to inform theoretical models of speech. Spoken language is conveyed by transient acoustic signals with complex and variable structure. Ultimately, the challenge of speech perception is to map these signals to representations  of an individual's native language community. In real-world environments, this challenge is frequently exacerbated under adverse listening conditions arising from noisy listening environments, hearing impairment, or speech that deviates from long-term speech regularities due to talkers' accents, dialects or speech disorders. In circumstances where adverse conditions lead to systematic short-term deviations from the long-term regularities of a language, a listener can rapidly adjust the mappings from acoustic input to long-term knowledge. However, little is known about the mechanisms underlying adaptive plasticity in speech perception. Understanding such rapid adaptive plasticity may provide insight into how the perceptual system deals with adverse listening situations. Although there has been recent interest in investigating adaptive plasticity in speech perception, these studies have used different tasks and methodologies and remain mostly unconnected. It is one of the goals of this paper to review these findings and integrate the results within a potentially common framework.To this end, we examine a number of factors that influence adaptive plasticity in speech perception and review behavioral, computational, and functional neuroimaging studies that have contributed to our current understanding of adaptive processes. In reviewing these mostly separate strands of research, we take the view that examining candidate neural systems that may underlie the behavioral changes could reveal a unifying framework for understanding how adaptive plasticity is achieved. We draw from domains outside of speech perception to consider supervised learning relying on sensory prediction error signals as a potential mechanism for uniting seemingly distinct behavioral speech perception phenomena. From this perspective, we propose that understanding the neural basis of adaptive plasticity in speech perception will require integrating subcortical structures into current frameworks of speech processing, which until now have largely focused on the cerebral cortex. Specifically, we examine the possibility that subcortical-cortical interactions may form functional networks for driving plasticity.spoken word recognition following experience with distorted signals. The other examines changes in acoustic phonetic perception following experience with distorted input in disambiguating contexts. Both sets of studies show changes at early stages of speech processing, which are facilitated by disambiguating contextual sources of information . Across different studies and tasks, perceptual effects showing adaptive changes in speech perception have been variously termed “perceptual learning,” “adaptation,” “recalibration,” and “retuning,” with the choice of descriptor driven mostly by the associated task. Here, we use “adaptive plasticity” as a broader term to be inclusive of distinct literatures and different tasks that may tap into some of the same processes in adjusting speech perception to accommodate short-term deviations in speech acoustics.We first examine two distinct behavioral literatures, each demonstrating adaptive changes in speech perception in response to signal distortions. One set of studies investigates improvements in Adults rapidly and effortlessly extract words from fluent speech. However, adverse listening conditions can affect the quality and reliability of the acoustic speech signal and negatively impact word recognition, reducing intelligibility . This adaptive plasticity is facilitated by the availability of disambiguating external information (such as explicit feedback or corresponding clear and undistorted speech), and also by signals that are relatively less distorted and, therefore, more intelligible. Disambiguating information and baseline intelligibility may have their influence on adaptive plasticity through a common means: each may impact the relative accuracy with which the distorted acoustics are mapped to established long-term regularities of the native language.If both externally-provided and internally-generated information contribute to adaptive plasticity, the impact of external feedback on adaptive plasticity is likely to be greater for less intelligible signal distortions compared to more intelligible distortions. Indeed, when distortion intelligibility and the presence of external feedback are independently manipulated, the two factors interact to modulate the degree of adaptive plasticity observed . This mapping is complicated by the fact that even when measured in quiet, well-controlled laboratory conditions, the acoustics conveying a particular phoneme or word are highly variable  than /I/. The same listener might also encounter a native Pittsburgh talker chatting about the local football team, the Steelers, in the local dialect that produces English /i/ with acoustics more typical of /I/ (the Stillers). Listeners would have little difficulty in either case as the perceptual system flexibly adjusts to such signal distortions.Under adverse conditions more typical of natural listening environments, there are short-term deviations in speech acoustics introduced by sources like foreign accent, dialect, noise, different speakers, and speech disorder. These systematic deviations can distort the acoustic speech signal. A listener may encounter a native Spanish talker referring in English to a iss , but as /g/ in the context of __ift , lexical knowledge provides a means of disambiguating the sound . Two classes of hierarchical models—feedforward models  increases the activation of the congruent phoneme (/s/) through direct excitatory feedback, granting it an advantage over the partially-activated /∫/. To achieve adaptive plasticity, the mapping of lower-level perceptual information to phonetic categories is adjusted via Hebbian learning such that subsequent perception of these consonants is more likely to activate the consonant consistent with the previous lexical context, even in the absence of the biasing context. By this account, the same lexical feedback that influences online acoustic phonetic perception also guides learning of the mapping of distorted speech onto pre-lexical representations. A difficulty for this account is its time course. Whereas adaptive plasticity effects can require as few as 10–20 trials to evoke, Hebbian learning has a much slower time course for learning  that modulate activity in regions associated with perceptual processes  . That a predictive context may lead to either increased or decreased activity as a function of the intelligibility of the stimulus  , and analyses (focusing on specific changes and sometimes specific regions) across studies, many questions remain open. Furthermore, even though there is a great deal of evidence supporting the multiple stream view of speech processing, there is still debate regarding the role of specific regions in speech and language processes. Despite these caveats, the current evidence is consistent with a view that frontal  and temporal areas  are sensitive to context and stimulus properties. Frontal areas may provide the source of the predictive feedback, potentially involving different frontal areas for different sources of contextual information  model consists of several cerebral cortical areas that interact with the cerebellum, forming a network that guides sensorimotor adaptation in speech production. Through these interactions, internal models can be used to detect and correct errors under sensory input perturbations. Neuroimaging studies of sensorimotor adaptation in speech production have yielded results consistent with predictions from this model. In a study that investigated somatosensory perturbations by using a device to block jaw movement, increases in the BOLD signal were observed across left inferior frontal gyrus, ventral premotor cortices, supramarginal gyri, and the cerebellum, consistent with the model's predictions. These results provided support for the view that cerebro-cerebellar interactions are involved in sensorimotor adaptation in speech  productions, subsequent perception of another talker's /s/-/∫/ (as in sip to ship) sounds was also shifted. Thus, the consequences of sensorimotor adaptation (attributed to cerebellar supervised learning mechanisms) may have a perceptual component that is unrelated to changes in motor output.In light of known interactions between perception and production, a relationship between the mechanisms that underlie sensorimotor and sensory adaptation seems likely. In fact, even sensorimotor adaptation can evoke “purely” perceptual shifts that are unaccounted for by changes in motor output  can maintain multiple adaptive adjustments to internal models (Cunningham and Welch, Everyday speech communication largely takes place in suboptimal or even adverse listening conditions, at least relative to the pristine listening environments in which most research is conducted. The acoustic speech signals most often conveying meaning to listeners in everyday conversation carry the influence of noisy environments, foreign accented talkers, reduced conversational speech, and dysfluency (see Mattys et al., Based on the synthesis of these literatures, we argued that the generation of predictions, prediction error signals, and supervised learning may be significant in driving adaptive plasticity. In particular, we highlighted the potential for a cerebellar-dependent supervised learning mechanism to play a role in adaptive plasticity in speech perception and described preliminary evidence that supports this possibility. This perspective suggests some directions for future research that will better develop neurobiological models of speech communication that capture the dynamic, online flexibility of the system.Although a great deal of evidence points to the importance of subcortical-cortical interactions in adaptive plasticity in other domains, the mainstream literature on speech perception has yet to make significant contact with the literature on subcortical contributions to adaptive plasticity. Neuroscience research relevant to adaptive plasticity in speech perception and, indeed to speech perception more generally, has tended to be be focused on the cerebrum. Although we know less about contributions of subcortical structures in speech perception, there have been a number of studies that have highlighted roles for the cerebellum, thalamus, caudate, and the brainstem that may be defined by specific functions, or interactions with specific regions in cerebral cortex Ravizza, .In the broader neuroscience literature, developing perspectives have suggested that different types of learning mechanisms may be subserved by different neural systems. At least three types of potentially distinct and interacting learning circuits have been proposed for unsupervised, reinforcement, and supervised learning (see Doya, In speech perception, both unsupervised and supervised learning mechanisms have been used to account for adaptive plasticity (Norris et al., In speech, there is behavioral evidence that listeners can achieve greater levels of adaptation that go beyond those reached with rapid adaptation training paradigms, if they are exposed to multiple sessions with consolidation (Banai and Lavner, In light of the parallels we have drawn between adaptive plasticity in speech perception and sensorimotor adaptation, it is interesting to note that research has demonstrated retention of sensorimotor adaptation effects over more than a year (Yamamoto et al., Beyond delineating the learning mechanisms available to guide adaptive plasticity in speech perception, there also are many open questions regarding the nature of putative prediction errors and how predictions may be derived from various information sources. The field has focused much attention on the role of lexical information in driving adaptive plasticity. Other sources of information, such as co-speech gestures from arm and hand movements associated with speech communication (Skipper et al., In conclusion, evidence for a flexible speech perception system that rapidly adapts to accommodate systematic distortions in acoustic speech input is abundant. A review of behavioral, computational, and neuroscience research related to rapid adaptive mechanisms suggests that it may be informative to consider phenomena in literatures outside of speech communication to identify common and unifying principles of how the brain balances stability and plasticity. Here, we examined cerebellar-dependent supervised learning that relies on sensory prediction error signals as a potential mechanism for supervising adaptive changes in speech perception. The predictions used to derive the error signals may be generated from multiple interacting sources of external sensory and internally-generated information. By incorporating cerebral-subcortical interactions established in other literatures into neuroanatomical theories of speech perception, the mechanisms that contribute to stability and plasticity may be better understood.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There has recently been a substantial decline in malaria incidence in much of Africa. While the decline can clearly be linked to increasing coverage of mosquito vector control interventions and effective drug treatment in most settings, the ubiquity of reduction raises the possibility that additional ecological and associated evolutionary changes may be reinforcing the effectiveness of current vector control strategies in previously unanticipated ways.Here it is hypothesized that the increasing coverage of insecticide-treated bed nets and other vector control methods may be driving selection for a shift in mosquito life history that reduces their ability to transmit malaria parasites. Specifically it is hypothesized that by substantially increasing the extrinsic rate of mortality experienced in vector populations, these interventions are creating a fitness incentive for mosquitoes to re-allocate their resources towards greater short-term reproduction at the expense of longer-term survival. As malaria transmission is fundamentally dependent on mosquito survival, a life history shift in this direction would greatly benefit control.Drosophila populations. Long-term selection experiments on these organisms suggest that increasing extrinsic mortality by a magnitude similar to that anticipated from the up-scaling of vector control measures generated an increase in their intrinsic mortality rate. Although this increase was small, a change of similar magnitude in Anopheles vector populations would be predicted to reduce malaria transmission by 80%.At present, direct evaluation of this hypothesis within natural vector populations presents several logistical and methodological challenges. In the meantime, many insights can be gained from research previously conducted on wild The hypothesis presented here provides a reminder that evolutionary processes induced by interventions against disease vectors may not always act to neutralize intervention effectiveness. In the search for new intervention strategies, consideration should be given to both the potential disadvantages and advantages of evolutionary processes resulting from their implementation, and attempts made to exploit those with greatest potential to enhance control. There has recently been a substantial decline in malaria incidence in Africa ,2. Some Scaling-up of interventions creates the risk that parasites will develop resistance to drugs ,6, or thAnopheles gambiae sensu latu and Anopheles funestus have adapted over many generations to feed on sleeping humans in mud-brick dwellings, and then rest indoors while digesting their blood meal. This behaviour is under threat from the massive scaling-up of ITNs and IRS . ThiEvolutionary theory ,25 and eDrosophila populations  may inculations ; dipteraDrosophila to different extrinsic mortality regimes over a period of five years (50-90 generations). Selection under high extrinsic mortality resulted in both an increase in fecundity, and a small increase in (intrinsic) mortality when assayed in the absence of selection . Any correlated change in these parameters prompted by intervention use could magnify or diminish the transmission effects proposed here. For example, the enhanced investment in short-term reproduction hypothesized here could be manifested as an increase in the number of eggs laid in one clutch. This could intensify competition during larval development, which through its connection with mosquito population growth  and adulThe possibility of the phenomena described here has important consequences. It provides a reminder that the evolutionary processes induced by interventions against disease vectors may not always act to neutralize intervention effectiveness. Secondly, it argues that large-scale distribution of highly effective interventions could have unpredictable effects. The selective pressures on life history traits depend on local ecology, for example, mosquitoes with high innate fecundity may have the greatest advantage in areas of abundant rainfall where larval habitat is not limiting, whereas in areas with long dry seasons selection may favour mosquito longevity over short-term reproduction . MosquitThe authors declare that they have no competing interests.All authors contributed to the development of this hypothesis, and provided comments on the manuscript. HMF and TAS drafted the manuscript. All authors read and approved the final manuscript.


Carcinus maenas on the foraging behavior of two common intertidal gastropod molluscs. Of the two model consumers studied, Littorina littorea is morphologically more vulnerable to crab predation than Gibbula umbilicalis, and it exhibited greater competitive ability in the absence of predation threat. However, Littorina demonstrated a greater anti-predator response when experimentally exposed to predation cues, resulting in a lower level of foraging. This reversed the competitive interaction, allowing Gibbula substantially increased access to shared resources. Our results demonstrate that the susceptibility of consumers to predation can influence species interactions, and suggest that inter-specific differences in trait-mediated indirect interactions are another mechanism through which non-consumptive predator effects may influence trophic interactions.Numerous studies indicate that the behavioral responses of prey to the presence of predators can have an important role in structuring assemblages through trait-mediated indirect interactions. Few studies, however, have addressed how relative susceptibility to predation influences such interactions. Here we examine the effect of chemical cues from the common shore crab  Predator-prey interactions are fundamental aspects of ecology, yet it is comparatively recently that non-lethal interactions and the indirect effects of predators have been considered in detail. Assemblages of interacting species have long been conceptualized as food webs, where species interact with one another via consumer–resource links. Chains of such direct interactions can also allow species to interact indirectly with one another through one or more intervening species Pisaster ochraceus had on populations of the mussel Mytilus californianus. Paine The trophic cascade concept has been widely accepted, and indirect interactions between organisms were originally thought to have been initiated through these density-mediated routes alone. For example, classic studies by Paine Where prey undertake anti-predatory responses, they invariably incur some cost. For example, vulnerability to predators usually increases whilst prey forage, but avoiding predators often means decreasing food intake Whereas morphological plasticity and ontogenetic changes in body size differences may reduce the probability of predation during an encounter, behavioral avoidance serves to reduce encounter rates. Furthermore, behavioral avoidance can occur immediately on encountering a predator whilst undergoing morphological changes requires a considerably longer time period. Habitat shifts and reductions in feeding rate in response to a predator have been documented in a wide range of studies  would respond to predation cues less than Littorina  would be at a competitive disadvantage and, hence, graze relatively less algal resource, under predation cue conditions.Here we chose to use these two extremes of trait expression as a model system for examining how susceptibility to predation can influence non-consumptive effects. In the first experiment we tested the All animal work was carried out in accordance with the ASAB/ABS Ethical Guidelines. Approval was not necessary for this work as it involves gastropod molluscs and decapod crustaceans; invertebrates which require no research permits or approval in the UK. Likewise, we did not require permits to access the collection sites, nor to remove animals and algae for laboratory studies as the collection sites were on public land that was not National Park land or Government Protected; and there is no legislation restricting the collection of these organisms. Gastropods used in the production of predation cues were first humanely killed by freezing. To minimize the number of individuals used we kept sample sizes to the minimum suitable for effective statistical analysis. Furthermore, those individuals used in the trials were kept for a short time in optimal conditions before being returned to the shore.Littorina littorea (L.) and Gibbula umbilicalis (da Costa) from Hannafore Point, UK . The snails were standardized to a small size range for all experiments  and were maintained on sea lettuce (Ulva lactuca L.) collected from Plymouth Hoe, UK . There was no significant species difference in shell width , but Gibbula had a significantly lower aspect ratio than Littorina .We collected Carcinus maenas L.) were collected from the Plym Estuary, UK  and Heybrook Bay, UK  and were maintained on a diet of common mussels (Mytilus edulis L.). Overall, nine male crabs were used to prepare the predation cue water. All of the crabs were undamaged and relatively large . Throughout the experiment all study organisms were maintained in aerated seawater (35 PSU) at 15°C.Shore crabs  was positioned at the centre of the dish and 68 ml of control  or predation cue was added. Predation cue water was made separately for each gastropod species and was taken from two aquaria each containing 1700 ml of seawater in which one Carcinus had been maintained for 24 hours. Two snails conspecific to the test species were fed to each crab at the onset of the 24 hour period and an additional crushed conspecific snail was added to the tank immediately before the trials. This preparation exposed the snails to both chemical cues from natural predators, alarm cues from conspecifics, and effluent from crushed conspecifics. The mixture provided the prey with several olfactory cues (predator kairomones and prey death pheromones), a combination that was chosen in order to maximize anti-predator behavior as it indicates that predation is actually occurring This experiment followed a similar protocol to Cotton et al. Ulva grazed. After 24 hours, the Ulva disks were removed, placed between a sheet of clear acetate and graph paper, and then scanned into PhotoStudio 5. The area (mm2) of the remaining algae was then calculated.Behavioral data were collected by scan sampling at 15 minute intervals for the first 300 minutes. Behavior was scored as: Eating, Moving, Stationary, At waterline/Out of water. Fleeing to the waterline and exiting the water are well-documented anti-predatory behaviors performed by gastropods Littorina-Littorina, Gibbula-Gibbula) or heterospecific (Littorina-Gibbula) pairs. Pairs of gastropods were then placed in each dish before the addition of Ulva and the control or predation cue. Three different predation cues were prepared by feeding a single Carcinus with two snails , and adding two crushed snails of the same species immediately prior to the experiment.This experiment followed a protocol similar to Experiment 1. Sixty snails of each species were food deprived for 48 hours and were then assigned to one of two treatments (control or predation cue) in conspecific . In order to ensure that these disks were not entirely consumed, trials in Experiment 2 ran for 195 mins. Behavioral data in these trials can be quantified for each individual , but the amount of grazing could only be quantified per trial, not per individual snail.Behavioral and foraging data were collected as for Experiment 1, but because of limitations on the availability of unblemished sheets of Statistical analyses were performed using SPSS 15. Throughout we have used the difference between predation cue and control groups as a measure of effect size see . This isWe used non-parametric analysis where possible because of significant heterogeneity of variance that could not be rectified through transformations. The results of Experiment 1 were analyzed using Mann-Whitney tests, and the amount of grazing in Experiment 2 using Kruskal-Wallis tests. Behavioral data in Experiment 2 were non-independent within trials, requiring the use of a repeated measures design. We used the Repeated Measures General Linear Model in SPSS as there is no non-parametric equivalent to a two-factor repeated measures ANOVA. Data for time out of water passed Levene's test for heterogeneity of variance, but the data for time spent eating could not be transformed to achieve homogeneity. However, Underwood Littorina littorea to spend significantly more time out of the water than did Gibbula umbilicalis, which showed very little standardized response to the predator treatment . In conspecific pairs, Littorina showed little effect of the addition of predation cue .The results of the foraging activity  almost mχ22 = 8.476, p<0.015; Littorina pairs, the amount of grazing in the presence of predation cue was greatly reduced compared with controls, while Gibbula pairs and heterospecific pairs showed little effect of the predator treatment.In the two species trials it was not possible to distinguish the relative grazing by the two individuals. However, we found a significant difference between species-pairs in the relative amount eaten in each treatment  and leopard frog (R. pipiens) tadpoles was reversed in the presence of predatory dragonfly larvae (Anax spp.); largely through the effects of predator-induced morphological plasticity. Similarly, Peacor and Werner R. catesbeiana) tadpoles. Our experiments demonstrate similar predator effects on competition, but mediated through species differences in their behavioral responses to predation cues, which are potentially influenced by differences in predation susceptibility The presence of predators has been demonstrated to influence, and indeed reverse, competitive interactions between prey species through non-consumptive effects. Relyea Carcinus indirectly influences rocky shore algal community structure and diversity by controlling Littorina density, however, the non-lethal effects of Carcinus on herbivorous snails can generate similar outcomes (empirically tested by Trussell et al. With the increasing recognition of the importance of the non-consumptive effects of predators it is becoming clear that many effects originally attributed to direct effects may in fact be the result of non-consumptive indirect effects Littorina was unable to relocate to forage in a low risk habitat, but frequently left the water to avoid predation, reducing overall food intake. Gibbula, in contrast, are less susceptible to crab predation and so following Gilliam and Fraser Gibbula continued to forage, and indeed in interspecific competition they benefitted from predation cues as Littorina departed. Our experiments clearly demonstrate an interaction modification in which an inferior competitor temporarily gains the upper hand as a result of a non-consumptive predator effect. This result highlights one of the many complex ways in which predators may influence the populations of their prey and of their primary resources, and strengthens the argument for further incorporating non-consumptive effects into the study of food-web dynamics as suggested by Peckarsky et al. In our experiments


Due to its transparency, virtually every brain structure of the larval zebrafish is accessible to light-based interrogation of circuit function. Advanced stimulation techniques allow the activation of optogenetic actuators at different resolution levels, and genetically encoded calcium indicators report the activity of a large proportion of neurons in the CNS. Large datasets result and need to be analyzed to identify cells that have specific properties—e.g., activity correlation to sensory stimulation or behavior. Advances in three-dimensional (3D) functional mapping in zebrafish are promising; however, the mere coordinates of implicated neurons are not sufficient. To comprehensively understand circuit function, these functional maps need to be placed into the proper context of morphological features and projection patterns, neurotransmitter phenotypes, and key anatomical landmarks. We discuss the prospect of merging functional and anatomical data in an integrated atlas from the perspective of our work on long-range dopaminergic neuromodulation and the oculomotor system. We propose that such a resource would help researchers to surpass current hurdles in circuit analysis to achieve an integrated understanding of anatomy and function. About 30 years after George Streisinger introduced zebrafish as a model system  maps of whole brain activity, similar in anatomical scale to data obtained from functional magnetic resonance imaging (fMRI) in larger animals. However, whole brain calcium imaging in zebrafish has the benefits of direct activity measurement and high (sub-cellular) spatial and temporal resolution. To reveal the cellular identities of the imaged brain volumes, a correct anatomical framework needs to be available. Anatomical atlases and gene expression databases already exist for zebrafish and are listed in Table Work in rodents allows stereotactic targeting of identified brain nuclei . While Transgenic zebrafish lines expressing fluorescent proteins under the control of specific promoters are frequently used to identify specific neuronal groups or provide additional landmarks. However, only a small number of markers can be used in parallel in any given experiment. In addition, the unavailability of suitable promoters frequently necessitates identification by other means, e.g., based on activity or projection patterns. Therefore, a serial strategy would be beneficial, where gene expression and functional information from different locations in the brain, different times, and different laboratories can be placed and registered to a reference, allowing the community to build a multi-dimensional brain map. While many functional neuronal entities form tight spatial clusters—e.g., cranial nuclei . ViBE-Z detects characteristic landmarks in the fish embryo and early larva based on fluorescent stain of all cell nuclei. Landmarks and subsequent fine elastic registration are used to register experimental data to a reference brain, thereby accounting for inter-fish differences resulting from variations in brain morphology or staining artifacts. The atlas has a precision of about 2 μm, so that expression comparisons can be performed at near-cellular resolution , a microscopy and computational framework to align expression pattern data to a reference brain , The integration of functional and anatomical data will advance our knowledge and facilitate interpretation of experimental results. Moreover, it should also improve the experimental design in the future. If one imagines a functional-anatomical atlas of the future, scientists could use the contained stereotactical information to guide their experiments in a hypothesis-driven fashion. For example, it could be attempted to only stimulate excitatory or inhibitory cells within a certain circuit module or to test different stimulation patterns that are chosen based on the expected connectivity in local circuits. In combination with advanced optical methods, the temporal and spatial photostimulation patterns could evolve to be as physiological as possible and test the combinatorial effects of multiplexed photostimulations in networks of neurons. These perturbation experiments, together with the projection patterns and expression markers in a zebrafish atlas of the future should open up new avenues of circuit analysis. It seems that zebrafish circuit neuroscience has a bright future in which advanced genetic, optogenetic, optical and computational methods will enable circuit analysis in three dimensions, at cellular resolution in the whole brain.conflict of interest.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential


Neural stem/precursor cells in the adult brain reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. These cells primarily generate neuroblasts that normally migrate to the olfactory bulb (OB) and the dentate granule cell layer respectively. Following brain damage, such as traumatic brain injury, ischemic stroke or in degenerative disease models, neural precursor cells from the SVZ in particular, can migrate from their normal route along the rostral migratory stream (RMS) to the site of neural damage. This neural precursor cell response to neural damage is mediated by release of endogenous factors, including cytokines and chemokines produced by the inflammatory response at the injury site, and by the production of growth and neurotrophic factors. Endogenous hippocampal neurogenesis is frequently also directly or indirectly affected by neural damage. Administration of a variety of factors that regulate different aspects of neural stem/precursor biology often leads to improved functional motor and/or behavioral outcomes. Such factors can target neural stem/precursor proliferation, survival, migration and differentiation into appropriate neuronal or glial lineages. Newborn cells also need to subsequently survive and functionally integrate into extant neural circuitry, which may be the major bottleneck to the current therapeutic potential of neural stem/precursor cells. This review will cover the effects of a range of intrinsic and extrinsic factors that regulate neural stem/precursor cell functions. In particular it focuses on factors that may be harnessed to enhance the endogenous neural stem/precursor cell response to neural damage, highlighting those that have already shown evidence of preclinical effectiveness and discussing others that warrant further preclinical investigation. The concept that the adult mammalian brain contains populations of resident neural stem/progenitor cells (hereafter collectively referred to as NSPCs) was generally accepted two decades ago  controls the multipotent progenitor state of NSCs through activation of Sox2  to the OB where they differentiate into neurons of the OB. The formation and proliferation of NSPCs is dependent on the Sox family of genes, in particular Sox2 has a role in maintaining the precursor pool via Sonic hedgehog (Shh) in adult SGZ and a role in proliferation of NPCs along with Pax6 and CCAAT/enhancer binding protein β (C/EBPβ)  cell and induced pluripotent stem (iPS) cell field, in which specific transcription factors are induced by addition of extrinsic factors for defined periods of time and in a specific sequence to allow production of desired neural cell types. For example, such a system has been used to generate floor plate cells which can subsequently generate mesencephalic dopaminergic neurons , brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), fibroblast growth factor 2 (FGF2), glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor 1 (IGF-1), pituitary adenylate cyclase-activating polypeptide (PACAP), and vascular endothelial growth factor (VEGF) are increased and modulate neurogenesis and NSPC biology. Additional exogenous application further augments NSPC proliferation and sometimes survival , and resulted in 25% surviving for at least 7 weeks; however the majority of cells that differentiated were astrocytes with a small percentage of neurons and oligodendrocytes  play a major role in neural development with some data to suggest they may also play a role in the NSPC response to neural damage.While Wnts are endogenously expressed in adult neurogenic niches . While this has not presented major issues for use in animal models, it raises concerns for potential clinical use. Therefore, several Epo derivatives have been developed to try to promote neuroprotective effects while avoiding effects on erythrocyte production. Carbamylated Epo does not bind to classical Epo receptor and does not stimulate erythropoiesis but does promote SVZ and dentate gyrus proliferation and neuronal differentiation of adult NSPCs , mainly basic, secreted molecules that are primarily known for regulating chemoattraction of immune cells to sites of tissue damage. They have been reported to have widespread non-immunological effects in the CNS, including regulation of neural cell proliferation, migration, survival, and synaptic transmission and can act in a paracrine or autocrine manner  and tumor necrosis factor alpha (TNFα) appear to be major regulators of chemokine and chemokine receptor expression in many tissues  and leukemia inhibitory factor (LIF), activate Janus kinase [JAK/signal transducer of transcription 3 (STAT3)], mitogen activated protein (MAP) kinase and PI-3K/Akt pathways following ligand binding. These cytokines have been shown to regulate NSC proliferation and differentiation . NO has been reported to have proliferative  is still very limited. It would be prudent to combine use of mitogens with other factors that enhance neurogenesis or oligogliogenesis respectively, as well as factors that enhance their subsequent survival and integration. Which factors are chosen to combine will likely depend on the injury or disease model to be examined, whether neurons and/or oligodendrocytes need to be replaced and may also be species dependent to a certain extent, although the combination of a mitogen such as EGF and a survival factor, such as BDNF may be generally beneficial. Some factors, such as Epo, have multiple actions, including NSPC proliferation, neuronal differentiation, and oligodendrocyte maturation, as well as being neuroprotective, which makes them particularly attractive as potential therapeutics for treatment of the damaged brain. Most of the work described above was conducted in rodents and to date little work has been performed following neural injury in brains of gyrencephalic species, such as non-human primates (Tonchev et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Abnormalities in reinforcement learning are a key finding in schizophrenia and have been proposed to be linked to elevated levels of dopamine neurotransmission. Behavioral deficits in reinforcement learning and their neural correlates may contribute to the formation of clinical characteristics of schizophrenia. The ability to form predictions about future outcomes is fundamental for environmental interactions and depends on neuronal teaching signals, like reward prediction errors. While aberrant prediction errors, that encode non-salient events as surprising, have been proposed to contribute to the formation of positive symptoms, a failure to build neural representations of decision values may result in negative symptoms. Here, we review behavioral and neuroimaging research in schizophrenia and focus on studies that implemented reinforcement learning models. In addition, we discuss studies that combined reinforcement learning with measures of dopamine. Thereby, we suggest how reinforcement learning abnormalities in schizophrenia may contribute to the formation of psychotic symptoms and may interact with cognitive deficits. These ideas point toward an interplay of more rigid versus flexible control over reinforcement learning. Pronounced deficits in the flexible or model-based domain may allow for a detailed characterization of well-established cognitive deficits in schizophrenia patients based on computational models of learning. Finally, we propose a framework based on the potentially crucial contribution of dopamine to dysfunctional reinforcement learning on the level of neural networks. Future research may strongly benefit from computational modeling but also requires further methodological improvement for clinical group studies. These research tools may help to improve our understanding of disease-specific mechanisms and may help to identify clinically relevant subgroups of the heterogeneous entity schizophrenia. The “dopamine-hypothesis” of schizophrenia was initially built upon the observation that dopamine receptor antagonists, such as haloperidol, attenuate psychotic symptoms . EvidencEmbedded in this context, the central attempt of this article is to review studies on reinforcement learning in schizophrenia and to disentangle dimensions of symptom formation and potential disease-specific mechanisms in the existing literature. The primary focus of this article is to provide an up-to-date overview of the existing literature with the aim to review existing evidence for two influential theories. Therefore, we only include a brief introduction see  to theseA series of studies used the monetary incentive delay task (MID), a paradigm invented by Knutson and colleagues , the grIn contrast to reward anticipation, fewer studies used the MID task to examine the delivery of monetary outcome. One study  found thTwo studies examined classical conditioning that actually took place outside the MRI scanner , 33. TheIn summary, fMRI studies in reward processing using the MID task have so far provided important insights into the neural processes underlying outcome anticipation and delivery in schizophrenia. In particular, the finding of reduced ventral striatal activation during outcome anticipation was consistently replicated across three studies involving a total of 68 unmedicated patients. An association of anticipatory ventral striatal activation with negative symptoms was reported in five studies involving 10 unmedicated patients and 52 medicated patients. Antipsychotic medication remains a crucial issue since these drugs specifically block those striatal D2-receptors that are (among others) activated by potentially prediction-error-associated dopamine release  andper se  may also influence the elicitation of prediction errors and thus potentially corrupt learning processes. Based on these two main time points, we will proceed with a brief summary of two influential hypotheses with respect to the potential contribution of reinforcement learning to symptom dimensions and disease-specific features in schizophrenia.Reinforcement learning represents a promising, theory-driven tool  which aiBox 1R and an expected value, here denoted as Q. t and a denote indices that refer to time and the value associated with a chosen action, respectively.A prediction error is defined as the difference between a delivered reward In model-free learning, this error signal can be used to update values:Qa,t on a,tQ + 1 with natural boundaries between 0 and 1. For examples of clinical studies using this algorithm, please compare Murray et al.  and aberrant salience (speeding up for irrelevant cues). This work by Roiser et al.  showed rStudies from Gold and colleagues have contributed an important body of work to the field. These studies provide evidence for the second hypothesis that postulates a deficit in value representation . With reTogether, these findings indicate that schizophrenia patients are surprisingly unimpaired in short hedonic experiences. It is important to ask how these experiences are used to learn values that may guide behavior. Studies showed that delay discounting is altered in schizophrenia in such a way that immediate rewards are preferred over larger rewards in the future and with the degree of this difference being associated with working memory deficits –62. A stHypothetically, this deficit may be based on a shift from a goal-directed to a more inflexible learning system. Even in relatively simple tasks learning speed may increase based on additional use of a goal-directed system that accurately maps separate stimulus values to their potential outcome consequences, which may then be used for appropriate action selection. Models of reinforcement learning do not map perfectly on this distinction. Instead, several agents that update values based on prediction errors can be summarized as model-free controllers of learning and decision processes, because they neglect the contribution of additional environmental features (task structure) to the learning process (compare Box n = 11), the reversal learning deficit was more pronounced. This was best explained by the actual presence of their positive symptoms, which is a remarkable contrast to several studies examining stable-medicated, chronic patients with attenuated positive symptoms. This subgroup of patients was additionally characterized by the model in terms of reduced reward sensitivity and showed a relatively better  fit by the simple, model-free Rescorla–Wagner algorithm. Parameters of the models were used to generate regressors for the analysis of fMRI data and the results are discussed in the subsequent section.The deficit of using outcomes to guide behavior may exacerbate when patients are confronted with situations where they are required to adapt their behavior flexibly. This can be examined in tasks like the Wisconsin Card Sorting Task or reversal learning. Indeed, a deficit in such tasks has been reported repeatedly in chronic, medicated states of schizophrenia –73. StudThere is convincing support that deficits in flexible behavioral adaptation and reversal learning, in particular, are important features of schizophrenia patients with an increased tendency to switch as a potential specific mechanism , 77. ThiThere is indeed evidence that working memory capacity limits the ability to learn multiple stimulus values to guide decisions and the degree of model-based behavior , 82, whiIn this section, we summarized results from studies on behavioral impairments during performance of instrumental tasks and only three studies, to date, have implemented reinforcement learning modeling to the observed behavioral data , 77, 89.This section will summarize studies that collected fMRI data during reinforcement learning to examine neural substrates of the behavioral alterations discussed in the previous section of this article. First, we summarize studies that examined classical conditioning. This process of associative learning has not been discussed in the previous section because classical conditioning paradigms do not usually require an instrumental response. Nevertheless, physiological responses reflect associative changes in stimulus contingencies, namely the unconditioned and the conditioned stimuli (US and CS). Second, we report studies that investigated instrumental conditioning during fMRI. In both parts, we explicitly describe the application of reinforcement learning models, how parameters underlying these models were inferred, and how these measures were further applied to the imaging data.Jensen et al.  studied With regard to appetitive classical conditioning with monetary reward, one study investigated neural activation to reward-associated CS in 25 medicated patients. They reported that relatively lower ventral-striatal and ventro-medial-prefrontal activation depended on the degree of anhedonia , which iWe now proceed with further studies that investigated neural correlates during instrumental learning. In line with evidence for aberrant learning from classical conditioning, a recent multimodal imaging study using the instrumental “salience attribution task” [; for behn = 13, 8 medicated) used an instrumental learning task with two choice options: one signaled a potential monetary feedback and the other a potential neutral feedback (n = 40) during fMRI. Albeit impaired performance in all patients, a small number of patients were able to apply a similar strategy to the task as controls did (n = 8 patients) during the presentation of stimulus combinations, patients displayed reduced activation in striatum and dorsolateral PFC. Patients exhibited stronger activation in a more rostral region of dlPFC and parietal cortex. Results from this task are hard to compare with instrumental reinforcement learning tasks due to the experimental design that primarily tests classification learning at different levels of difficulty.One exemplary study that assessed the association between impaired reinforcement learning and brain activation in dopaminergic target brain areas of first-episode schizophrenia patients . A second fMRI analysis based on the latter model was applied to define subjective informative punishment trials, i.e., when participants believed that a change in reward contingencies had appeared. Both patients with good and poor task insight showed reduced ventral striatal activation during these trials . In this case, a lack of activation to cues associated with monetary as well as, probably, social reward may reflect reduced motivational or incentive salience in terms of apathy or other dimensions of negative symptoms, which may be a result of aberrant salience attribution. However, this requires more systematic studies along symptom dimensions. Evidence for neural correlates of aberrant learning was demonstrated in fMRI studies on classical conditioning that showed elevated striatal activation to cues indicating the delivery of a neutral event , 93, 98 The combination of model-derived learning signals with functional brain measures is very promising. This mechanistically informed quantification of signals reflecting learning processes provides a more fine-grained insight into neural trial-by-trial correlates of learning mechanisms and disease-specific alterations as compared to standard event-related fMRI analyses which rather rely on event definitions such as correct responses or experimenter-defined changes in reward contingencies. In fact, the latter may not always reflect the way study participants solve these tasks. On the other hand, a small number of healthy volunteers, in most studies, exhibit behavior that cannot be described better than chance by any reinforcement learning model. This may indicate the need to extend from standard reinforcement learning models to other types of models, for example Bayesian learners , 114. SuFurther, the generation of trial-by-trial model-derived time-series for fMRI data analysis is sometimes performed based on random-effects parameters  or based on one set of parameters (fixed-effects). One group recommends the latter approach for studies in healthy volunteers by arguing for more robust correlations of BOLD signal with model-derived regressors . On the In this last section, we describe research that pharmacologically manipulated the dopamine system during reinforcement learning or acquired an additional molecular measurement (PET) of dopamine. There are a substantial number of groups researching these questions in healthy volunteers, and this section does not aim to present a complete picture of all such studies. We will instead refer to studies that are particularly important for a better understanding of the above reviewed studies in patients.l-DOPA, and haloperidol, have opposing effects on behavior and neural correlates of model-derived prediction errors, and that these effects are selective for the reward-approach condition: l-DOPA administration enhanced reward-approaching behavior and associated ventral striatal reward prediction errors whereas haloperidol reduced such effects  in an overdosing manner  Aberrant prediction errors drive learning of otherwise irrelevant stimuli and actions in schizophrenia, and that there is a potentially close link between this mechanism and the emergence of positive psychotic symptoms, in particular delusions. (2) A deficit of expected value representation may characterize patients suffering from schizophrenia, and this may fundamentally contribute to the formation of negative symptoms.There is evidence for aberrant learning with most specific findings derived from the salience attribution task , 55. AltOur summary of fMRI studies during reinforcement learning clearly demonstrates that a reduction of these learning signals, namely blunted coding of ventral-striatal prediction errors, was consistently observed across studies. This deficit may actually be involved in aberrant learning as well as in a failure of value representation depending on fluctuating symptom states. During acute psychotic clinical states this may provide a conduit for aberrant learning, while the persistence of a noisy learning signals may provide the ground for a failure of building value expectations, ultimately contributing to the development and progress of detrimental negative symptoms. A large body of evidence from behavioral studies supports the hypothesis of a deficit in value representation and that this impairment is pronounced in patients with high levels of negative symptoms , 64. NevN-methyl-d-aspartate receptors (NMDAR). Abnormal modulation of NMDAR-induced plasticity by neurotransmitter systems such as dopamine, acetylcholine, or serotonin are at the heart of this idea. In the present article, we have described a close link between reinforcement learning, symptom dimensions of schizophrenia and dopamine, which acts as a neuromodulator of NMDAR-function: Animal research demonstrated that D1-receptor agonists and D2-receptor antagonists facilitate NMDAR-dependent long-term plasticity while D2-receptor agonist suppress it (per se that is abnormal but its modulation during reinforcement and perceptual learning.” (The psychosis spectrum has been characterized by imprecise and inefficient cortical information processing as a potential mechanism for cognitive impairments observed in patients and their first-degree relatives as well as in at-risk mental states. As a potential mechanism behind this, a disrupted cortico-cortical synaptic plasticity was suggested by a comprehensive biological hypothesis of schizophrenia, the “dysconnectivity” hypothesis , 101. Thpress it , 135. Eapress it , 88. Furarning.”  These moarning.”  and the arning.” , 138. HeSo far, there is converging evidence that dysconnectivity may indeed account for the repeatedly described prefrontal inefficiency observed in schizophrenia during the performance of cognitive tasks: Using models of effective connectivity for fMRI, reduced working-memory-dependent prefrontal-parietal connectivity was reported, initially in medicated patients  and subsThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sphenodon. We then ran a series of structural finite element analyses to assess the correlation between bone strain and skull form. With comprehensive loading we found that the distribution of peak von Mises strains was particularly uniform throughout the skull, although specific regions were dominated by tensile strains while others were dominated by compressive strains. Our analyses suggest that the frame-like skulls of diapsid reptiles are probably optimally formed  with respect to functional forces; they are efficient in terms of having minimal bone volume, minimal weight, and also minimal energy demands in maintenance.The vertebrate skull evolved to protect the brain and sense organs, but with the appearance of jaws and associated forces there was a remarkable structural diversification. This suggests that the evolution of skull form may be linked to these forces, but an important area of debate is whether bone in the skull is minimised with respect to these forces, or whether skulls are mechanically “over-designed” and constrained by phylogeny and development. Mechanical analysis of diapsid reptile skulls could shed light on this longstanding debate. Compared to those of mammals, the skulls of many extant and extinct diapsids comprise an open framework of fenestrae (window-like openings) separated by bony struts , a cranial form thought to be strongly linked to feeding forces. We investigated this link by utilising the powerful engineering approach of multibody dynamics analysis to predict the physiological forces acting on the skull of the diapsid reptile  This is probably also true for other diapsids that lack large brains, such as lizards, crocodiles, and theropod dinosaurs, which share comparable skull morphologies , applying bite forces at several different bite positions. We combine the powerful computational techniques of multibody dynamics analysis (MDA) Sphenodon, and in turn analyse the strains within the skull under these forces. This enables us to evaluate the degree of correlation between skull form and three strain modes: tensile , compressive  and von Mises . Multibody dynamics analysis has recently been applied to study skull biomechanics Sphenodon during fifteen separate biting simulations. These simulations covered a range of biting types and locations. They include four bilateral and eight unilateral bites at different tooth positions, a bite on the anterior-most chisel-like teeth, and two ripping bites that incorporate neck muscles  is a virtual technique that is used to predict how a structure will deform when forces and constraints are applied to it, and has been used previously to predict stress and strain distribution within skulls Total bite and quadrate-articular joint forces  are similar whether the animal is biting unilaterally or bilaterally. However, the bite force on each side of the skull during bilateral biting is half that of unilateral biting . Also, forces located at the balancing side joint during unilateral biting are always in excess of those at working side joint . Bite foSphenodon  are apparent over the skull, with some regions subject to high strains and others subject to low strains  are extracted from all fifteen individual biting analyses to generate a combined loading peak strain map, the obvious strain gradients (or heterogeneous strain magnitudes) noted during separate bites are considerably reduced . During Overall strain distributions over the skull remain largely unchanged with the addition of a fascial sheet over the upper temporal fenestra, but there were some striking reductions in localised peak strains, as highlighted in Sphenodon is strongly linked to feeding forces. We show that both tensile and compressive peak strains are relatively evenly distributed throughout the skull when several loading cases are analysed  we show that over 91% of the skull is at strains of between 100 and 625 microstrain, well within the equilibrium window  as inferred by Martin We simulated peak bite forces in our study  to deal with the full range of loadings applied here. The term ‘optimally’ refers to the minimum amount of material (i.e. bone) necessary to ensure sufficient skull strength. An optimally formed skull as defined here will be more efficient than a sub-optimal, e.g. heavier skull form, in ensuring minimal bone volume, minimal weight, and also minimal energy demands in maintenance. For clarity, we would predict a non-optimised skull to display one of two contrasting conditions. It would either appear weak in relation to the normal forces applied to it, and experience very high and potentially damaging stresses and strains during normal loading, or, conversely, it might appear overly robust, with very low stresses and strains during normal loading and with excess bone mass that is not mechanically necessary. Since our findings infer that the skull of Sphenodon is well formed to resist the everyday forces applied to it, it is not unreasonable to suggest this may also be true for other diapsids with a frame-like skull.The extent to which general skull form is determined by selection or growth remains uncertain, but our findings show that the skull of Sphenodon may also be significant . In this case the fascia serves to reduce peak strains , is adapted  to resist a range of load cases, not just single biting loads. The lower temporal bar, secondarily acquired in SphenodonTyrannosaurus rex Osborn, 1905 and Allosaurus fragilis Marsh, 1877 this would be important as they would likely generate extremely large biting forces and experience heavy cranial loading Sphenodon lack a lower temporal bar, the primitive condition for the group The skull of Sphenodon indicates that the bone has adapted to tensile and compressive strains generated during normal feeding activities. The combined peak von Mises strain distribution over the skull is relatively uniform, showing that all regions are strong enough mechanically to withstand normal everyday forces, while no region is overly robust and ‘over-designed’. Based purely on this finding, the skull form of Sphenodon can be considered optimal  in the sense that it comprises the minimal amount of bone material for the required skull strength. This optimal form is more efficient in terms of minimal bone volume, minimal weight, and minimal energy demands in maintenance over a sub-optimal, heavier skull form. While this study has not investigated potential forces associated with the brain, sense organs, and non-biting activities such as swallowing and tongue movements, its results are relevant to a broader understanding of skull form and not just to the skulls of diapsid reptiles. However, to test whether all skulls are optimally formed  with respect to bone strains (both tensile and compressive) would require the application of similar methods to other animal groups. Preliminary findings in macaques are encouraging in this regard  but skulls with large vaulted braincases may be subject to additional quasi-static or high frequency low loads (e.g. associated with the brain) that could impact on skull form To conclude, our analysis of the skull of Sphenodon specimen  were scanned in-house by micro-computed tomography (micro-CT), from which three-dimensional (3D) geometries were constructed using AMIRA image segmentation software . Neck vertebral geometries were generated from additional micro-CT scans . These 3D geometries were imported into ADAMS multibody analysis software  in preparation for an MDA. Within ADAMS detailed muscle anatomy was incorporated onto the geometries, and accurate jaw joint and tooth contact surfaces were specified. Where the neck meets the skull a spherical joint was assigned that permitted the skull to rotate freely about all axes while constraining translational movements. The major adductor (jaw closing), depressor (jaw opening), and neck musculature were included, with each muscle group split into several sections and defined over the anatomical origin and insertions areas on the skull and lower jaws respectively in vivoDetailed descriptions of the MDA model development have been presented elsewhere The biting simulations covered a range of biting types and locations, including four bilateral and eight unilateral bites at different tooth positions, a bite on the anterior-most chisel-like teeth, and two ripping bites that incorporate neck muscles , compressive , and von Mises  element strains of all 640,000 elements in the model were stored in element tables. In addition, the peak strain recorded in any one particular element during the fifteen separate simulations was extracted and combined to map the peak strains across the skull. This is referred to as a combined loading model.The same 3D geometry constructed for the MDA skull was converted into a tetrahedral mesh consisting of 640,000 elements. The model was constructed from solid (ten node) higher order elements, which were specified with a Young's modulus of 17 GPa and a Poisson's ratio of 0.3 . Here we applied a total force of 133 N around the perimeter of each upper temporal fenestra (7 N over 19 force vectors – see An additional investigation was carried out to understand the influence of other


The ovalbumin (OVA) model of allergic inflammation, both in rat and mouse is characterised by a late bronchoconstrictive response (LAR) after allergen challenge that can be measured using whole-body plethysmography (WBP) in conscious unrestrained animals.Circadian oscillations of lung mechanical properties have been reported in conscious undisturbed rodents. Potentially, these fluctuations could alter the pulmonary response induced by allergen provocation and the response of pharmacological treatments.This circadian influence has been showed in asthma patients , where aThe aim of this study was to assess whether LAR in OVA-sensitized rats and mice was affected differently when animals were exposed to allergen in different times of day.Firstly, to confirm the circadian oscillations, changes in several respiratory parameters were monitored during 24h in naïve Brown Norway rats or C57/Black6 mice. Afterwards, OVA-sensitized animals were exposed to the allergen in different periods of the day and the pulmonary function parameters were monitored, including the LAR.In rats, LAR evoked in three different times of day  showed no differences in severity, but was more frequent during the evening. In contrast, the LAR triggered in mice in the morning was more severe and more frequent than that evoked during the evening.These results suggest that species and day period of time to induce LAR in allergic animal models are critical and should be taken into account when evaluating the effects of new compounds on this read-out.


The abdominal cocoon syndrome (or idiopathic encapsulating peritonitis) is a rare cause of intestinal obstruction. It has been reported predominantly in adolescent girls living in tropical/subtropical region in which diagnosis is only made at laparotomy in most cases. The cause and pathogenesis of the condition have not been elucidated. Prolonged administration of practalol, meconium peritonitis, and tuberculous infection of the female genital tract have been incriminated as possible causes. The author reports a case of a female patient with recurrent intestinal obstruction treated for years but failed to settle down on conservative treatment during her last hospital admission and had to undergo surgery. Preoperative diagnosis of this syndrome as the cause of her intestinal obstruction was not made until at laparotomy, when a thick fibrotic peritoneal wrapping of the bowel in a concertina-like fashion with some adhesions was found. Excision of this membrane and adhesiolysis were carried out without any need for bowel resection, and this led to relief of the obstruction and patient's complete recovery. Awareness of this benign condition in the differential diagnosis of intestinal obstruction will result in early diagnosis and correct management and prevent unnecessary bowel resections and bad outcomes. Abdominal cocoon syndrome (or idiopathic encapsulating peritonitis) is a relatively rare cause of intestinal obstruction, described mostly in young adolescent girls, and was first described in 1978 [The etiology of this disease is largely unknown and the cases seen so far have been limited to the tropical and subtropical zones and primarily affect young adolescent females, even though several earlier cases have been reported also in males , 3.Thick fibrotic peritoneum encasing the small bowel partially or completely is a pathognomonic feature, and the correct diagnosis is not often made preoperatively.This is the case report of an eighteen- (18-) year-old Nigerian girl that presented with intestinal obstruction  that faiThe author is therefore presenting the case so that practicing surgeons have better awareness of this condition as a possible cause in the differential diagnosis of intestinal obstruction which may facilitate pre-operative diagnosis, prevent inadvertent bowel damage at laparoscopy, and prevent unnecessary bowel resection at laparotomy .An eighteen- (18-) year-old Nigerian girl presented with severe central/lower abdominal pain associated with a few episodes of bilious vomiting which started about two (2) to three (3) days at home before admission to the hospital.She took some self-medication at home which is a common practice in this part of the developing world, but unfortunately her condition did not improve.Clinical examination revealed a moderately ill-looking slightly dehydrated young lady. Temperature 37.8°C; BP 100/70 mmHg; Pulse 80/min; RR 24/min. Abdomen was tender and moderately distended at its central/lower part.A palpable mass at the right lower paraumbilical area was found. Bowel sounds were found to be sluggish.Significant in her past medical is the fact that she had recurrent antibiotic therapy for the past three years following an undisclosed intravaginal medical treatment by a local quack practitioner.Plain abdominal X-rays were unremarkable  month.Abdominal cocoon syndrome (or idiopathic encapsulating peritonitis) is a rare disease of the peritoneum and almost invariably presents as an acute or subacute intestinal obstruction with or without a mass, which is usually diagnosed incidentally at laparotomy .It was first described by Foo et al. in 1978 [Some authors have implicated prolonged administration of practalol therapy as a possible aetiology in some cases, meconium peritonitis, sarcoidosis, orthotopic liver transplantation, indwelling abdominal catheters, or even tuberculous infection of the female genital tract .These conditions may predispose patients to chronic peritoneal irritation and inflammation, which as a final effect leads to peritoneal fibroneogenesis.Cell-mediated immunological tissue damage initiated by microorganisms assessed by immune-fluorescent studies has been documented in some cases as possible cause. Pre-operative tissue culture of peritoneal membrane may also contribute in future in the further evaluation of the aetiology of abdominal cocoon syndrome . In this patient, it was probably secondary to her previous intravaginal treatment a couple of years prior to her presenting with recurrent lower abdominal pain and subacute intestinal obstruction. To the best of the author's knowledge, this the second recorded case in Nigeria . She couDespite anecdotal reports of a preoperative diagnosis especially by medical imaging, in the majority of cases of idiopathic encapsulating peritonitis, it is a fortuitous finding. A better awareness of this condition is what may facilitate pre-operative diagnosis , 12.A high index of clinical suspicion , 14, witClinicians must rigorously pursue a preoperative diagnosis, as it may prevent a “surprise” upon laparotomy , 18 and


Most childhood cancers are rare conditions, so research needs to be efficient. With only a limited number of children available for trials per year it seems sensible to use data from previous research. Systematic review methodology can do this whilst minimizing bias. Others also recommend undertaking a systematic review as part of a trial planning process in order to "reduce unwanted duplication, help ensure that new research builds on lessons from earlier research and place the findings of the new research in proper context". [Clark M 2007] However, there are some who would question the value of undertaking systematic reviews when only less than optimally designed studies are available, which is particularly true in paediatric oncology where non-comparative studies dominate.131I-meta iodobenzylguanidine (131I-mIBG) molecular radiotherapy for neuroblastoma, we aim to present some of the methodological challenges that we encountered during the review, such as study identification, quality assessment and "salami" publications. We will also discuss the presentation, analysis and interpretation of the results. We chose to perform quantitative analyses, which gave estimates of effect sizes, with measures of uncertainty, and evidence on dose/response relationships. We considered that such analyses gave greater insight into the data as a whole, while also being aware that quantitative analyses of generally poor quality data might be seen as providing a false sense of validity to sub-optimally designed studies.Using a recently completed systematic review that investigated the effectiveness of


Pancreatic ductal adenocarcinomas (PDAs) are notoriously aggressive and resistant to treatment. They distinguish themselves further by their robust fibroinflammatory, or desmoplastic, stromal reaction and degree of hypovascularity. Recent findings have revealed multiple mechanisms of stromal complicity in disease pathogenesis and resistance. In this review, we focus on altered physicomechanics as one mechanism of what we term as ‘stromal resistance’ in PDA. Extremely high interstitial fluid pressures and a dense extracellular matrix combine to limit the delivery and distribution of therapeutic agents. We discuss the genesis and consequences of altered fluid dynamics in PDA and strategies to restore them. Pancreatic ductal adenocarcinoma (PDA) is an aggressive disease of the exocrine pancreas, marked by a 5-year survival rate of <5% and a median survival of ∼6 months, making it the fourth leading cause of cancer-related deaths in the United States  tumour suppressor genes are also common  has been clinically approved, and even then provides only incremental improvement in survival . In particular, we highlight physical mechanisms of drug resistance in PDA and recent efforts to target stromal elements in order to improve delivery of small molecule therapeutics. We discuss further how studies in genetically engineered mouse (GEM) models of PDA have yielded unexpected insights compared with more traditional xenograft and allograft models and may help to explain the previous divide between preclinical promise and clinical reality.A dynamic fibroinflammatory, or desmoplastic, response is a hallmark of PDA and essentially pathognomonic for the disease. This desmoplasia evolves during disease progression and includes stromal fibroblasts, immune cells, and excessive deposition of a complex extracellular matrix (ECM) . ActivatThe delivery and distribution of small molecules across a tissue are governed by well-defined principles of solute transport involving passive diffusive and convective fluxes  which, together with the development of hypersensitivity reactions, have precluded their use as systemic agents. Chemical conjugation of recombinant human PH20 with polyethylene glycol preserves enzymatic activity and extends the half-life to >10 h. Systemic administration of this agent can deplete HA from implanted tumour xenografts in immunocompromised mice and decrease IFP  mice with established invasive PDA with intravenous injections of PEGPH20. Significant intratumoral depletion of HA and reduction of IFP occurred within 2 h and peaked at 24 h . The apparatus used to measure fluid pressure has also varied. A number of systems have been used to measure fluid and tissue pressures over the last 50 years, including the needle  are profoundly hypovascular, in contradistinction to the systems described above. Second, the vasculature is characterised by widespread collapse. Third, the tumour vessels in PDA appear to be functionally and ultrastructurally intact , to influence the fundamental strategy in treating patients with this dreaded disease.The complex cellular, molecular, and mechanical features of the desmoplastic response in PDA presents challenges to effective treatment, as well potential vulnerabilities to exploit. In creating a drug-free sanctuary, the tumour also presumably remains sensitive, at least initially, to the chemotherapies it has been shielded from rather than selected to resist. Although intrinsic mechanisms of disease resistance will no doubt emerge, breaching the sanctuary with a systemically deliverable enzyme offers the prospect of unprecedented, sustained vascular access to the PDA primary tumour bed and metastases. This will enable not only rigorous evaluation of new treatment strategies, but also exploration of distinct sequencing and schedules of various treatment modalities in the attempt to remain one step ahead of the tumour. Indeed, re-examining the long list of clinically approved agents previously thought to be ineffective in PDA would be an excellent place to start. Additional mechanisms to reduce IFP should also be explored including targeting other ECM components  or inhibiting contractile forces generated by fibroblasts. Restoring physiologic blood flow, oxygen, and nutrients to a pancreas cancer will undoubtedly alter its metabolism, and these changes may present additional therapeutic targets and also new mechanisms of resistance. However, the idea that the complex and impervious pancreas cancer ‘organ’ can be perturbed dramatically is itself encouraging. It cannot be long before this literal and figurative entry into pancreas cancer pathophysiology results in a more effective therapeutic armamentarium.


The airway acts as the first defense against inhaled pathogens and particulate matter from the environment. One major way for the airway to clear inhaled foreign objects is through mucociliary clearance (MCC), an important component of the respiratory innate immune defense against lung disease. MCC is characterized by the upward movement of mucus by ciliary motion that requires a balance between the volume and composition of the mucus, adequate periciliary liquid (PCL) volume, and normal ciliary beat frequency (CBF). Airway surface fluid (ASL) is a thin layer liquid that consists of the highly viscous mucus upper “gel” layer, and the watery lubricating lower “sol” layer. Mucus production, secretion and clearance are considered to play a critical role in maintenance of airway health because it maintains hydration in the airway and traps particulates, bacteria, and viruses. Different types of epithelial cells, including secretory cells, and ciliated cells, contribute to the MCC function. Cigarette smoke (CS) contains chemicals and particulates that significantly affect airway secretion. Active and passive CS-induced chronic obstructive pulmonary disease (COPD) is frequently associated with hyperplasia of goblet cells and submucosal glands (SMGs), thus increasing the secretory capacity of the airways that impairs MCC. Cigarette smoking (CS) is the single largest cause of preventable disease, disability, and death globally. Tobacco use is a major risk factor for heart attacks, strokes, chronic obstructive pulmonary disease (COPD), and cancer. Approximately 90% of lung cancer cases in the USA are attributed to cigarette smoking. Similarly, the United States Centers for Disease Control and Prevention describes tobacco use as “the single most important preventable risk to human health in developed countries and an important cause of premature death worldwide.” CS aerosols are highly concentrated mixtures of particles and gases. This “gas/particle partitioning” is the same type of physical, gas/liquid distribution process by which an atmospheric gas, such as nitrogen, dissolves in blood. When a CS aerosol is drawn into the respiratory tract (RT), a portion of each compound of interest  will initially be in the gas phase, and a portion will be in the particle phase. Both of these phases can serve as pathways for the delivery of the compound to RT tissues include pharyngeal, bronchial, or alveolar regions Pankow, . There aSHS is the inhalation of smoke, called passive smoking, or environmental tobacco smoke (ETS), by persons other than the intended “active” smoker. It occurs when CS permeates any environment, causing its inhalation by people within that environment. SHS contains largely the same components as mainstream smoke, but with varying concentrations. SHS has been shown to produce more particulate-matter (PM) pollution than an idling low-emission diesel engine and it contains not only the gas phase of exhaled smoke, but also the products of combustion of a cigarette. Therefore, persons exposed to SHS are exposed to up to 50 times higher concentration of some chemicals than smokers themselves , but also include small amounts of surfactant from Clara cells and other fluids that are part of the airway epithelium fluid. Cilium is present on respiratory surface epithelium, bearing hair-shaped structures on its surface (cilia). Cilia beat within a PCL layer with low viscosity for which PCL is the “sol” layer with a height that approximates the length of the outstretched cilia (about 7 μm) and keeps mucus at an optimal distance from the underlying epithelia, consequently affecting the clearance of mucus  with variable numbers of electron-dense granules that contain large quantities of enzymes. They have irregularly shaped basally oriented nuclei, a perinuclear zone containing large quantities of rough endoplasmic reticulum (RER) required for protein (enzyme) manufacture. Serous cells are the primary defensive cells of the mucosa because they discharge bactericidal compounds that deal efficiently with pathogens  and emphysema (destruction of pulmonary parenchyma), together with fibrosis and tissue damage, and inflammation of the small airways Chung, . Most COOne major characteristics of airway remodeling in COPD is airway goblet cells metaplasia and hyperplasia, which results in airway mucus hypersecretion. Airway goblet cell hyperplasia is a prominent pathophysiological feature of COPD and is an often-used end point in animal models of respiratory disease Rogers, . The celin vitro and in vivo (Takeyama et al., In vivo, neutrophils and neutrophil products can cause the upregulation and release of mucin from surface epithelial cells (Takeyama et al., It has been supported by epidemiological data that mucus hypersecretion is significantly associated with a more rapid decline in FEV1 and increased hospitalization of patients with COPD. Among all identified mucins, MUC5AC appears to be the predominant mucin in healthy human airway epithelial cells, and its expression is augmented in smokers and COPD patients (Peter Di et al., In general, animal models have been essential to the development of every drug and therapeutic used to treat of COPD. One of important reasons for using animal models to tissues and cells isolated from COPD patients is that animals provide experimental settings that allow a clearer understanding of how an active immune system interacts with whole respiratory system. There are a large number of experimental researches on drugs and therapies of COPD induced by CS in laboratory animals. These include celecoxib (Roh et al., CS/SHS induces airway mucus hypersecretion and inflammation through various chemical components and signaling pathways. The significantly increased mucus production and secretion result in excess sputum that may promote airflow obstruction and inflammation. CS/SHS exposure also results in composition changes in airway secretion and impairment of cilia beating that are critical to a normal MCC. Increased mucin production, decreased luminal liquid, and impaired cilia beating motion in COPD have deleterious consequences for airway health, including mucus stasis and airway infection. CS/SHS-impaired MCC results in the increased infection rate and disease severity that could be associated with COPD exacerbations.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Rapid and fast acting anti-malarials are essential to treat severe malaria. Quinine has been the only option for parenteral therapy until recently. While current evidence shows that intravenous artesunate is more effective than quinine in treating severe malaria in endemic countries, some questions remain regarding safety profiles and drug resistance. For imported severe malaria, additional unanswered questions are related to generalizability of the findings from endemic countries and to legal aspects, as there is no Good Manufacturing Practice-conform drug available yet. Here, the implications of existing evidence for the treatment of imported severe malaria are discussed. Plasmodium falciparum malaria in Europe is 0,4% [Treatment of severe malaria requires prompt administration of safe and fast acting anti-malarials. While approximately 4% of all imported malaria cases progress to severe malaria, the overall mortality rate of imported  is 0,4% . Until r is 0,4% ,3. The eFirst, is it of concern that none of the existing trials has been performed as a double blind comparative study? This appears to be less important with respect to effectiveness as the end-point of the two large studies was mortality. However, some limitations regarding outcomes such as adverse events or (neurologic) sequelae remain and from a regulatory perspective this may well be of concern.Second, can the existing evidence from endemic countries be generalized to imported severe malaria in industrialized, non-endemic, countries? Clinical manifestations, supportive intensive medical care and patient characteristics differ in endemic versus non-endemic countries. In particular, the following limitations have to be addressed: i) most evidence has been obtained from children while the great majority of patients with imported severe malaria are adults, ii) quinine monotherapy was used which does not completely reflect the often used combination of quinine with doxycycline or clindamycin in imported severe malaria, iii) the study population included a large variety of individuals from Southeast Asia, India and Africa. The characteristics of the study population with regard to ethnic, nutritional and general health aspects as well as to immunologic aspects (semi-immunity) may be different for patients with imported malaria . And lastly but possibly most importantly, iv), supportive care other than anti-malarial treatment may differ significantly in endemic settings versus hospitals in industrialized countries. Patients with imported malaria are monitored on intensive care units (ICU) and organ replacement therapy can be initiated promptly in case of renal or pulmonary insufficiency. Albeit speculative due to lacking evidence, these aspects appear to be major reasons why mortality is lower in imported versus endemic severe malaria.The beneficial characteristics of artesunate are well known: it is a fast acting drug against several parasite stages including gametocytes ,5, it haQuinine, on the other hand, is rightfully claimed to be a drug with a narrow therapeutic window bearing the risk of a range of potential side effects like hypoglycaemia, agranulocytosis, bleeding disorders, cardiovascular effects and others which are particularly relevant for elderly patients . While tAlthough artesunate has been used for the treatment of large numbers of patients, both in trials and under routine conditions, data on tolerability and safety on artesunate treatment are still limited for various reasons such as short hospitalization and follow-up time or incomplete laboratory measurements of adverse events in endemic countries. For example, cases of late-onset haemolysis have been reported recently occurring after artesunate treatment and this effect had not been documented in the published trials . Further®) rather than pure quinine salt is used in some European countries, which renders the therapy more heterogeneous with respect to pharmacokinetics and pharmacodynamics. While in the USA, a GMP-conform iv-artesunate has been made available but is not FDA-registered quinidine, which is more toxic than quinine still remains the first-line drug [Finally, the currently available artesunate, produced by Guilin Pharmaceutical Company - the same product that was used in the -QUAMAT trials - is not being produced under conditions of full Good Manufacturing Practice (GMP). Guilin Pharmaceutical Company received pre-qualification by the World Health Organization in November 2010 but this is not the same as GMP certification by the European Medicines Agency (EMA) or US Food and Drug Agency. While there is no GMP-artesunate available in most countries and no licensed artesunate in any developed country, the availability of quinine is quite heterogeneous as well. In most industrialized countries, quinine is available through extemporaneous preparation. However, quinine is difficult to obtain or not available for intravenous administration in some European countries and the USA. Instead, a mixture of the four cinchona alkaloids  an unrealistically high number of subjects was needed if the outcome was mortality while other (combined) outcomes may not unequivocally answer relevant questions, ii) returning travellers are a very heterogeneous patient group requiring stratification (e.g. migrants visiting family and friends versus tourist travellers), and, probably most important, iii) many travel medicine experts would not be willing to randomize patients into artesunate versus quinine arms anymore given existing evidence and respective recommendations.Despite the fact that artesunate is not a licensed drug in Europe it has been made available within compassionate use programmes via a few import companies  or it can be ordered directly from the manufacturer, Guilin Pharmaceutical Corporation in China. In the USA, the FDA has approved an investigational new drug protocol and GMP-conform intravenous artesunate has been made available via CDC/Walter Reed Army Institute of Research . There aThe most realistic approach is allowing the product to be used in a controlled fashion and to proactively document efficacy and toxicity. Since there are no established legal procedures for such a careful introduction of a still unregistered drug, clinicians and researchers have to take the lead. We have to organize ourselves and start collecting data on the use of artesunate for severe malaria in a concerted action. Properly collected post-introduction data are the most realistic alternative to the impossible option of prospectively collecting data in a comparative clinical trial. Such initiatives have already been put in place in Europe.The authors declare that they have no competing interests.