Binaural sound localization is usually considered a discrimination task, where interaural phase (IPD) and level (ILD) disparities at narrowly tuned frequency channels are utilized to identify a position of a sound source. In natural conditions however, binaural circuits are exposed to a stimulation by sound waves originating from multiple, often moving and overlapping sources. Therefore statistics of binaural cues depend on acoustic properties and the spatial configuration of the environment. Distribution of cues encountered naturally and their dependence on physical properties of an auditory scene have not been studied before. In the present work we analyzed statistics of naturally encountered binaural sounds. We performed binaural recordings of three auditory scenes with varying spatial configuration and analyzed empirical cue distributions from each scene. We have found that certain properties such as the spread of IPD distributions as well as an overall shape of ILD distributions do not vary strongly between different auditory scenes. Moreover, we found that ILD distributions vary much weaker across frequency channels and IPDs often attain much higher values, than can be predicted from head filtering properties. In order to understand the complexity of the binaural hearing task in the natural environment, sound waveforms were analyzed by performing Independent Component Analysis (ICA). Properties of learned basis functions indicate that in natural conditions soundwaves in each ear are predominantly generated by independent sources. This implies that the real-world sound localization must rely on mechanisms more complex than a mere cue extraction. The idea that sensory systems reflect the statistical structure of stimuli encountered by organisms in their ecological niches Natural stimuli have a very different and richer structure than standard sensory input used in experiments. They are typically noisier and generated by multiple interferring sources . The wavefront of a sound reaches firstly the ear ipsilateral to its source, and after a short time interval the contralateral one. The resulting delay is known as the interaural time difference (ITD), and in narrowly tuned frequency channels it corresponds to the interaural phase difference (IPD). Additionally, sound received by the contralateral ear is attenuated by the head, which generates an interaural level difference (ILD). According to the widely acknowledged duplex theory Existing evidence suggests that in order to increase the coding efficiency, the auditory system adapts to variation in binaural cue statistics. Therefore to understand its functioning in natural hearing conditions it is important to know, what are the typically encountered distributions of binaural cues. Understanding the distribution variability across different types of natural scenes is crucial as well, since it determines how flexible neuronal adaptation mechanisms should be. Binaural sound statistics determine also the complexity of the sound localization task. Natural sounds are typically generated by multiple independent sources, scattered in different configurations at both sides of the head. In such cases, binaural cues do not correspond to a position of a single object - its identification has to rely on algorithms more complicated than those useful in a simple, laboratory setting. One could assess to which extent this is the case in real auditory scenes, by quantifying the degree of dependence of sounds in each ear.This paper attempts to answer the above-mentioned questions. Firstly it characterizes marginal statistics of binaural cues encountered in natural hearing conditions, which to our best knowdledge, has not been done previously. Secondly, it analyzes the redundance of monaural waveforms and in this way estimates the difficulty of a sound localization task in real environments. To achieve those goals we performed binaural recordings of three real-world auditory scenes of different acoustic and spatial characteristics. In the next step we extracted binaural cues - IPDs and ILDs and studied their marginal distributions. Using Independent Component Analysis (ICA), we show that in real-world auditory scenes, monaural waveforms are mutually much less interdependent than in a simple, point-source case. Present results provide a step towards understanding the mechanisms of spatial hearing in ecological conditions.In this work we analyzed 12 minute recordings of three different auditory scenes - nocturnal nature, forest walk and city center , moving sources (city center), and moving subject . A statistical variation among examples analyzed here should therefore capture variability across numerous other cases.Scene selection in this study did not include all possible cases. For instance no recording was performed in an enclosed, highly reverberant environment. Additionally all recordings were done in similar weather conditions, which may have narrowed the range of stimulus properties. The nocturnal nature and city center scenes consisted of constantly active sources - no periods of silence were present, which happens in natural hearing conditions. Despite those limitations, we argue that current data are heterogenous enough to draw general conclusions.While auditory scenes were selected as a representation of diverse environments, recordings of each scene were performed in an unbiased way. Position of the subject was chosen at random in the two static recordings, and his motion was not constrained or pre-designed while walking. In this way, samples of a typical sensory input were collected. By refraining from recording in carefully controlled settings, where some feature (for instance loudness) in each ear would be the same, we avoided the selection bias. Natural auditory scenes are rarely spatially symmetric and stimuli analyzed here provide examples of what one typically hears. Understanding the structure of unbiased rather than fine-tuned stimuli should give better insights into the functioning of the nervous system in natural conditions Frequency spectra of recorded sounds are displayed on An example joint amplitude distribution in the left and the right ear is depicted on ency see . The mosInteraural level differences ILD were computed separately in each frequency channel. Empirical ILD distributions are plotted on Observed ILD distributions revealed very small variation across different frequencies. The variability was much weaker than what can be predicted from known head filtering properties. Additionally, ILD distributions were quite homogenous across different auditory scenes. This means that neuronal codes for ILDs can optimally represent this cue in very different acoustic environments without necessity of a strong adaptation.Marginal distribution of a univariate, monaural phase variable over a long time period is uniform, since it periodically assumes all values on a unit circle. An interesting structure appears in a joint distribution of monaural phases  - a statistical model which optimizes a general-purpose objective - coding efficiency sparse i.e. close to In the ICA model, short :Pronounced differences among IC representations of the three auditory scenes are visible on As data displayed in ICA was performed on each artificial dataset. Exemplary basis functions learned using sounds from the forest scene are depicted on In the next step of the analysis, we computed histograms of the PPR value for each learned IC dictionary. They are depicted in Histograms of binaural dominance of natural scene ICs are presented in the third column of The above analysis points to the fact that in a typical auditory environment, sounds in each ear are much stronger dominated by independent acoustic events that can be predicted from considerations of solitary point sources. In such conditions sound localization requires a sophisticated computational strategy and becomes itself a scene-analysis task.Binaural cues are usually studied in a relationship to the angular position of the generating stimulus As a representation of the real sensory world we recorded and analyzed three auditory scenes. Analyzed recordings were very different from each other in terms of spatial configuration as well as sound quality. We have selected them as stereotypes of numerous possible environments consisting of static and moving sources. This diversity increased the likelihood that any other auditory scene typically encountered by a human listener would resemble one of those recorded in the present study. Selected scenes were not free from limitations. Inspection of sound spectra as well as cue statistics revealed slight biases towards the right ear in nocturnal and forest scenes, which may not be the case in all realistic conditions. Moreover, one could invision analyzing a larger amount of recordings performed also in interior, reverberant environments, which are often encountered by humans. Such analysis should allow to draw stronger conclusions about general properties of natural binaural sounds. Despite their differences and limitations, analyzed scenes revealed common features such as the shape of ILD distributions for instance. If all analyzed cases share some statistical property, one may conclude that it should not change strongly in different hearing conditions.Our current understanding of how the nervous system may localize sound sources was primiarily derived from considerations of solitary, point sources of pure frequency sound in noiseless and non-reverberant listening conditions. In such case, knowledge of head filtering properties and analysis based on physics of sound suffices to predict the range of possible binaural cues and their relationship to the position of a generating source.When considering natural environments, the analytical approach very quickly becomes intractable. In a typical auditory scene, a number of objects unknown to the organism generates interferring sound waves affected by motion and reverberation. Additionally, the number of sources at each side of the head is different. Under such conditions, binaural cues become highly stochastic, and as such should be characterized in statistical terms. In this work we characterized low-order statistics of naturally encountered binaural cues. In many aspects, empirical distributions of natural stimuli deviated from reductionist, analytical predictions. We discuss them below separately for time and level binaural disparities.The human head strongly attenuates high frequency tones, acting as a low-pass filter A neuron maximizes its coding efficiency (defined by the amount of the stimulus information it conveys), if its tuning curve is equivalent to the cumulative distribution function (CDF) of the naturally encountered stimulus In addition to the frequency invariance, ILDs revealed only a small variability across recorded auditory scenes. Despite strong differences between spatial configurations of each scene, ILD distribution parameters fluctuated very weakly. In the nocturnal nature scene, centers of some ILD distributions were slightly shifted away from In anechoic environments, point sources of sound generate interaural time disparities constrained by the head size of the listener - no IPD value should exceed the frequency dependent, physiological threshold. In more complex listening situations larger values can appear, either due to a sound reflection or to a presence of two (or more) desynchronized sound sources The amount of IPDs larger than the head-imposed threshold is another property of an auditory scene, which can not be derived by the analysis of the head filtering - it has to be estimated from empirical measurements. Present results demonstrate that in low frequency channels large proportions of IPDs exceed the “maximal” value. This was true for to up to The natural auditory stimulus consists not only of external sounds generated by environmental sources, but also of self-generated sounds such as speech. We have found that speech alters the IPD distribution by increasing the number of disparities equal to Interaural cues can be directly mapped to a stimulus position only if no other sources of sound overlap with the signal of interest. A natural question to ask is - how often does this happen in the natural environment? This is equivalent to asking - how useful are instantenous, one-dimensional cues to localize typical, real world sources?Since a direct estimation of a number of auditory objects in real environments is technically very difficult, we approached this problem indirectly. By performing Independent Component Analysis, we learned redundant patterns of natural binaural stimulus. If signals in each ear originated typically from the same source - their dependence was maximized and independent components captured a signal structure in both ears. However, if sounds in each ear were dominated by independent sources, they were best represented by monaural basis functions, where the signal power in one ear was greatly exceeding power in the other one. In order to obtain a frame of reference, we performed the same analysis using simulated datasets. One of them consisted solely of solitary point-sources. Monaural sounds were therefore maximally dependent given the head filter, and sound localization could have been easily performed using simple cues. In the second dataset, sound waves in each ear were completely independent, and binaural cues carried no spatial information.Basis functions trained on natural auditory scenes had a very different binaural composition than those trained on simulated point sources. In two out of three environments analyzed here, two equinumerous, clearly separated subsets of independent components emerged (in the third one the separation was not so prominent). Each of them was dominated by the signal in only one of the ears. This structure was rather reminiscent of basis functions trained on the artificial, maximally independent data.These results allow us to conclude that in real-world hearing conditions binaural sound is rarely generated by a single object. Actually, sounds in each ear seem to be dominated by independent environmental causes. In such settings, an inversion of a binaural cue to a sound source position becomes an ill-posed problem. This is because multiple scene configurations can give rise to the same cue value  were recorded by a non-moving subject, therefore sound statistics were unaffected by listener's motion patterns and self generated sounds. In the third scene  the subject was moving freely and was speaking sparsely. Scene recordings are publicly available at the following URL: Recordings were performed using the Soundman OKM-II binaural microphones which were placed in the left and the right ear channels of the recording subject. Soudmann DR2 recorder was used to simultaneously record sound in both channels in an uncompressed wave format at Prior to analysis, raw recordings were down-sampled to To obtain a spectral decomposition of the signal, sound waveforms from each ear were transformed using a filterbank of A Hilbert transform of each frequency channel was performed. In result, instantenous phase IPDs with absolute value exceeding In each frequency channel The above calculations assume a spherical head shape, which is a major simplification. It was, however, satisfactory for the sake of the current analysis.Independent Component Analysis (ICA) is a family of algorithms which attempt to find a linear transformation of the data which minimses redundancy Prior to ICA learning, the recordings were downsampled to After learning, we rejected spectrally non-localized independent components as they typically reflect noise, not data structures Two artificial datasets corresponding to extreme cases of binaural redundance were generated using sounds from each recorded scene. Binaural recordings were transformed to a single channel by averaging sound in both ears. Point-source datasets were created by drawing random intervals of the mono recording and convolving them with Head Related Transfer Functions (HRTFs) corresponding to one of the Figure S1Results of the goodness of fit test for ILD distributions. Curves plot p-values of the Kolmogorov-Smirnov test. The purpose of the test was to compare empirical ILD distributions at each frequency with the logistic distribution. The null hypothesis was that both distributions are equal. Black dots mark frequency channels, where one of the p-values was below (TIFF)Click here for additional data file.Figure S2Spectrotemporal representation of independent components. Panels in the left and right columns correspond to the left and the right ear IC parts respectively. Rows correspond to auditory scenes. To obtain a time-frequency representation, Wigner-Ville distributions were computed for each monaural part of each IC. This transformation localizes energy of a temporal waveform on a time-frequency plane. Each component is represented by the iso-probability contour of the Wigner-Ville distribution corresponding to (TIFF)Click here for additional data file.


New research suggests that magnetoencephalography (MEG) contains rich spatial information for decoding neural states. Even small differences in the angle of neighbouring dipoles generate subtle, but statistically separable field patterns. This implies MEG  is ideal for decoding neural states with high-temporal resolution in the human brain. However, a recent paper by Cichy et al. invites us to re-evaluate this classic dichotomy. Using a combination of empirical data and theoretical modelling, they argue that the signals measured with magnetoencephalography (MEG) actually contain rich spatial information that can be used to differentiate extremely subtle neural states A major challenge in cognitive neuroscience is to discriminate brain states with high spatial and temporal resolution. These two dimensions are often considered mutually exclusive for non-invasive human studies. Functional magnetic resonance imaging (Just over a decade ago, fMRI experienced a major breakthrough inspired by a relatively simple idea: idiosyncratic patterns of activity carry important information. The test case was orientation decoding. It turns out that activity patterns in visual cortex can reliably predict the orientation of a grating stimulus presented to the subject e.g., . The genThe key insight for the fMRI community was that subtle biases in the distribution of neurons tuned to one feature or another could lead to subtle differences in the activity of a sampled voxel (schematised in et al. set out to show that MEG could also be used to decode spatially overlapping neural states. Other studies have shown that orientation information can be decoded from the visual evoked response in MEG and EEG using multivariate pattern analysis et al. present an impressive set of experiments all seemingly pointing to an important conclusion: MEG can resolve spatially overlapping representations.As orientation decoding was the test-ground for fine-scale pattern decoding in fMRI, Cichy et al. propose a surprisingly simple idea (schematised in As reviewed above, previous fMRI studies argued that orientation decoding is driven by subtle differences in sampling small-scale biases in the distribution of tuned cells. However, the spatial resolution of MEG is far coarser than fMRI. So what is the mechanism that could explain genuine orientation decoding? Cichy It is well-established that electrical activity in aligned cells generates a dipole which projects to the scalp surface. EEG measures the electric potential at the scalp surface, whereas MEG measures the magnetic field. The spatial distribution of the field depends on the location of the dipole, but critically, also on its angle. Cichy and colleagues argue that because the surface of the cortex is irregular, even dipoles from neighbouring clusters of cells will have different angles, resulting in separable field patterns at the scalp surface see B i. AlthIf MEG/EEG can be a source of such rich spatial information, then why are these non-invasive methods so often considered to have poor spatial resolution? The classic problem limiting spatial resolution in MEG/EEG is source ambiguity. Strictly, it is not possible to localise with certainty the source of the field measured at the scalp surface. There is no unique solution, but theoretically infinitely many solutions that could generate the same pattern of observed activity. To reverse engineer the location of the source from the observed scalp distribution runs up against the obstinate inverse problem. Although sophisticated methods have been developed to constrain probabilistic solutions e.g., , the inhWe predict that multivariate decoding will revolutionise MEG/EEG just as it did fMRI. The key insight is that these measures contain rich spatial information, even if the source localisation is inherently ambiguous. As the fMRI community has moved from localising blobs of condition-specific differences to measuring information coded in activity patterns, so the MEG/EEG community will embrace MVPA for decoding neural states. Moreover, coupled with the exquisite temporal resolution inherent to electromagnetic measures of brain activity, MEG/EEG could really become the method of choice for exploring the spatiotemporal dynamics of human brain activity.


Mitochondrial diseases are potentially severe, incurable diseases resulting from dysfunctional mitochondria. Several important mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA), the genetic material contained within mitochondria, which is maternally inherited. Classical and modern therapeutic approaches exist to address the inheritance of mtDNA disease, but are potentially complicated by the fact that cellular mtDNA populations evolve according to poorly-understood dynamics during development and organismal lifetimes. We review these therapeutic approaches and models of mtDNA dynamics during development, and discuss the implications of recent results from these models for modern mtDNA therapies. We particularly highlight mtDNA segregation—differences in proliferative rates between different mtDNA haplotypes—as a potential and underexplored issue in such therapies. However, straightforward strategies exist to combat this and other potential therapeutic problems. In particular, we describe haplotype matching as an approach with the power to potentially ameliorate any expected issues from mtDNA incompatibility. Mitochondria are vital energy-producing organelles in eukaryotic cells. Mitochondrial diseases are pathologies in which the ability of mitochondria to produce energy and fulfill their normal cellular roles is compromised. These diseases are relatively common, but diagnosed infrequently, because the majority of patients exhibit only very mild symptoms (Mitochondria have their own DNA (henceforth mtDNA), which is the only DNA outside the nucleus in humans. MtDNA is unique in having its own genetic code and subtype of ribosomes. It codes for a minority of subunits required for the respiratory chain, the array of multimeric proteins that form the production line for energy on the inner mitochondrial membrane, and for transfer and ribosomal RNA. The majority of essential respiratory chain proteins are encoded by the nucleus, as well as many proteins required for mtDNA maintenance and replication. Therefore, mutations in either the mitochondrial or nuclear DNA of the cell may cause pathological loss of function in mitochondria and lead to mitochondrial disease  and targDiseases resulting from mutations in mtDNA have unique characteristics of onset, severity and inheritance, largely due to the fact that there are thousands of copies of mtDNA in a typical nucleated cell . In mostMtDNA is maternally inherited, producing a characteristic disease distribution down the maternal line. MtDNA haplotypes can modulate the pathological effects of mutated nuclear encoded genes   and m.14Another striking feature of mtDNA disease inheritance involves the observed large shifts of heteroplasmy between mother and offspring. For example, it is possible for a phenotypically healthy mother, harboring 50% mutated mtDNA, to produce both healthy and severely affected children , and othIn the most extreme examples of the bottleneck, there may be rapid switching from near homoplasmy in one mtDNA type to near homoplasmy for another between mother and child. Using a heteroplasmic length variant in noncoding mtDNA  (A third therapeutic strategy involves selecting low risk early (‘cleavage’) embryos, through the use of preimplantation genetic diagnosis (PGD)  and chorionic villus sampling run the risk that differences between tissues and individual cells may lead to an inaccurate inference of heteroplasmy levels, and thus erroneous risk estimation. PGD of cleavage stage embryos however appears to be robust and accurate  human embryos, with positive results. However, some questions regarding the subsequent behavior of mtDNA populations in offspring produced using these treatments remain, which have been flagged by researchers and noted in the literature. These issues are not fatal flaws in the concept of mtDNA therapies, but do represent areas of uncertainty associated with these therapies. All of them are connected with the mtDNA haplotype of the third-party ‘recipient’ providing an oocyte with healthy mtDNA. In a random pairing, it is likely that the donor and recipient haplotypes vary considerably: pairwise comparisons in human mtDNAs show up to 130 single-nucleotide polymorphism (SNP) differences  and the nucleus of M. m. domesticus, behavioral differences and varying susceptibility to experimental autoimmune encephalomyelitis were found  experiences a proliferative advantage over that from the ‘recipient’ healthy oocyte , an arbitrarily small amount of carryover donor mtDNA could subsequently come to dominate the cellular population Fig. C.In this scenario, the amplification of donor mtDNA is due to haplotypic differences alone, without any segregation specifically arising from pathological mutations. This mechanism can lead to the amplification of a pathological mutation even if that mutation does not affect segregation. Specifically, if the proliferating donor mtDNA haplotype is associated with a pathological mutation, the amplification resulting from haplotype segregation will lead to a concomitant amplification of the mutation, which ‘hitchhikes’ upon the proliferating haplotype as illustrated in Fig. We focus on segregation effects in particular, for two reasons. First, the aforementioned phenomenon of mtDNA carryover potentially creates a situation in which segregation has to be taken into account: that is, where several different mtDNAs are present within a cell, a situation that has so far rarely been described . Second,Due to the potentially dramatic physiological implications of mtDNA mutations and progressive segregation documented in tissue culture (In mice containing a mixture of wild-type mtDNA and mtDNA with a 4696-bp deletion (denoted Δ mtDNA) that leads to lethal renal failure, the Δ mtDNA was observed to preferentially accumulate in several tissues over time  (In a mouse model harboring a slightly deleterious tRNA mutation (m.3875delC), the mutational load was reduced through a mechanism acting at the cellular or organelle level in the developing embryo  mutation was retained  mtDNA  leads to tissue-specific segregation effects: the proportion of NZB mtDNA increases with time in liver and kidney and decreases in blood and spleen. This mixture of mtDNAs leads to detrimental physiological  cellular level (The basic mechanisms of these segregation effects are largely unknown. One nuclear gene has been found to influence segregation in blood (Gimap3) (ar level .Bos primigenius taurus/B. p. indicus) has revealed segregation effects during blastocyst development and during gestation, with the B. p. indicus mtDNA being removed over time . The wild-derived haplotypes we used display a spectrum of genetic differences with C57BL/6N, thus enabling us to control genetic distance . We also developed a mathematical framework to facilitate the direct comparison of many of these mice. We found that tissue-specific segregation was very common (including within post-mitotic tissue types), with the magnitude of segregation increasing with the genetic distance between the mtDNA haplotypes, and identified several contrasting mechanisms related to mtDNA turnover and organismal age by which this segregation occurred , also found segregation in liver, with the M. m. molossinus mtDNA increasing , and cover inter- and intra-species heteroplasmy , and hence is likely not a key issue in mtDNA therapies  associated with modern mtDNA therapies can be ameliorated by employing a simple ‘haplotype matching’ protocol: that is, ensuring that the donor and recipient mtDNA haplotypes are as similar as possible. This approach will minimize nDNA-mtDNA mismatching ; mtDNA-mtDNA mismatch (due to the genetic similarity); and mtDNA segregation (as two very similar haplotypes are expected to show very little segregation). The ideal recipient would be of the same haplotype as the donor , for example, from a healthy maternal relative. Alternatively (or in addition), further research on the segregation of different pairs of mtDNA haplotypes could be used to choose suitable recipients for a given donor, in order to minimize segregation effects.Experts in the field of karyoplast transfer have noted that ‘it is possible to match mitochondrial haplotype between the mother and the mitochondrial donor to avoid any concern, even though the evidence says it should not be needed’  and the Wellcome Trust (WT0948685MA). Funding to pay the Open Access publication charges for this article was provided by the Medical Research Council.I.G.J. gratefully acknowledges funding from the UK Medical Research Council; J.P. is supported by the None declared.


Amyloid protein structure has been discovered in a variety of functional or pathogenic contexts. What distinguishes the former from the latter is that functional amyloid systems possess dedicated molecular control systems that determine the timing, location, and structure of the fibers. Failure to guide this process can result in cytotoxicity, as observed in several pathologies like Alzheimer's and Parkinson's Disease. Many gram-negative bacteria produce an extracellular amyloid fiber known as curli via a multi-component secretion system. During this process, aggregation-prone, semi-folded curli subunits have to cross the periplasm and outer-membrane and self-assemble into surface-attached fibers. Two recent breakthroughs have provided molecular details regarding periplasmic chaperoning and subunit secretion. This review offers a combined perspective on these first mechanistic insights into the curli system. In contrast to disease-associated amyloids that underlie neurodegenerative disorders like Alzheimer's and Parkinson's disease, organisms often exploit amyloid structures for their unique mechanical and biological properties. Many bacterial species are programmed to produce extracellular amyloid protein fibers as part of a switch to a biofilm lifestyle, as such fibers offer protection from environmental stresses as well as mediate adherence to both biotic and abiotic surfaces . Moreover, attempts to translocate CsgA-fusion proteins of various lengths and folding states show that much longer polypeptides (up to 8 times) are acceptable so long as their structure remains dynamic prior to export . The fact that CsgC interacts with CsgA and affects its folding pathway makes much sense of the previous data, however there remains one unexplained observation: Wild type cells are resistant to bile salt influx, however they become sensitive upon deletion of the csgBA genes (see Figure 6 in Taylor et al., csgBAC genes are deleted bile salt resistance returns, suggesting a difference in the CsgEFG complex. One explanation is that CsgC plays a role in structural preparation of CsgF for export and in its absence CsgF blocks the pore. CsgF is somewhat amyloidogenic and is as rich in Asn/Gln residues as curli subunits. Alternatively CsgC may interact with CsgE to promote release from CsgG or a conformation change that renders the pore accessible. These intriguing results suggest that CsgC may play a wider role in curli biogenesis than just inhibition of amyloidogenesis by CsgA and CsgB.The structure of CsgC is known and it was originally proposed that it may influence the porosity of CsgG via a redox mechanism employing its CxC motif (Taylor et al., The outstanding questions within the curli field concern the structure and location of secretion components CsgE and CsgF and the mechanisms of nucleation by CsgB and fiber extension. There is growing interest in use of the curli secretion system for biotechnological purposes, for instance by decorating fibers with bespoke chemistry, creating nanowires, and as adhesive materials (Chen 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.


Plants use their roots to forage for nutrients in heterogeneous soil environments, but different plant species vastly differ in the intensity of foraging they perform. This diversity suggests the existence of constraints on foraging at the species level. We therefore examined the relationships between the intensity of root foraging and plant body traits across species in order to estimate the degree of coordination between plant body traits and root foraging as a form of plant behavior. We cultivated 37 perennial herbaceous Central European species from open terrestrial habitats in pots with three different spatial gradients of nutrient availability . We assessed the intensity of foraging as differences in root placement inside pots with and without a spatial gradient of resource supply. For the same set of species, we retrieved data about body traits from available databases: maximum height at maturity, mean area of leaf, specific leaf area, shoot lifespan, ability to self-propagate clonally, maximal lateral spread , realized vegetative growth in cultivation, and realized seed regeneration in cultivation. Clonal plants and plants with extensive vegetative growth showed considerably weaker foraging than their non-clonal or slow-growing counterparts. There was no phylogenetic signal in the amount of expressed root foraging intensity. Since clonal plants foraged less than non-clonals and foraging intensity did not seem to be correlated with species phylogeny, we hypothesize that clonal growth itself  may be an answer to soil heterogeneity. Whereas unitary plants use roots as organs specialized for both resource acquisition and transport to overcome spatial heterogeneity in resource supply, clonal plants separate these two functions. Becoming a clonal plant allows higher specialization at the organ level, since a typical clonal plant can be viewed as a network of self-sustainable harvesting units connected together with specialized high-throughput connection organs. This may be an effective alternative for coping with spatial heterogeneity in resource availability. For plants, soil is the source of various essential resources with contrasting repletion and depletion dynamics and spatial patterns . PhenotyDifferences among individuals in growth rate and overall root system size constitute their passive plasticity. In contrast, differences in the processes that determine the size-independent component of root system shape, and result into change in allometric patterns of the body form, constitute active plasticity. It typically occurs as a result of responsive behavior to an environmental signal. A common example of this is root foraging, that is, changes in spatial root system allocation in response to a nutrient or water gradient . AlthougGrowth and the resulting size patterns constitute one of the most fundamental ecological differences . With anPassive plasticity is very unlikely to be the only factor underlying interspecific differences in root system plasticity, namely, root foraging. If root system plasticity is more pronounced in fast-growing species simply because of multiplicative growth effects , it woulDiversity in root plastic responses to various cues . We avoSupplementary Table S2). Data on species phylogeny are taken from Daphne phylogeny (The following species life-history traits (hereinafter referred to as “traits”) were selected from several databases to represent the size and growth dynamics of the species involved: plant height at maturity, mean area of leaf, specific leaf area, shoot life span .These srcorr  for the remaining data. All analyzes were performed in the R statistical environment, Version 2.15.1  .In general, high contrast elicited a substantial response in root allocation, whereas low contrast did not (p = 0.004) . Rather surprisingly, few species  avoided nutrient-rich patches in both contrast levels; their responses seemed to be quite stable. Response to the high-contrast treatment was significantly more stable  than response to low-contrast treatment , but the stability of the responses within species across treatments did not correlate substantially .More species exerted a strong foraging response in high-contrast treatment than in low contrast treatment, but the responses under both treatments were substantially correlated to each other .Contrast values did not show any phylogenetic signal. Estimated confidence intervals of Pagel’s lambda for the high-contrast root foraging ability did not differ significantly from zero , while it was highly significantly different from 1  and plant clonality (binary trait) (Table 1). The correlation was negative; that is, clonal plants responded less . Results were approximately the same regardless of the form of reaction  used. The only exception was correlation of root allocation with lateral spread, which showed almost no correlation with the directed response  whereas it showed much higher correlation with “plasticity” :  plants with low lateral spread tend to respond to soil heterogeneity level much more than plants with high lateral spread. We did not detect any other substantial correlation between root foraging or plasticity and the other traits. The results did not qualitatively change in phylogenetic analyzes (data now shown).Root foraging ability substantially negatively correlated with vegetative reproduction potential  and root foraging when the latter was expressed using a size-invariant measure. Therefore, we assume that such relationships, reported in a previous study , are pasThe difference between clonal and non-clonal plants is the strongest pattern in root plasticity found in the experiment. This is, to our knowledge, the first systematic report of such a difference between clonal and non-clonal plants, although both It is likely that the low root foraging ability of clonal plants may derive from their ability to form stands of several ramets. Low root foraging of individual ramets may thus be compensated at the level of ramets , if foraIn theory, lack of root preference for nutrient-rich patches may also result from the lower nutrient optima of clonal plants . We do nIn any ecological setting, the effects of the species traits are multiplied by growth, and the modification becomes stronger with greater growth differences. We therefore believe that differences in growth rates among species are the basis of previously reported strong correlations between root foraging ability and growth rate or leaf economy spectrum . These dGlechoma hederacea when the patch is small. While G. hederacea is capable of rapid growth in culture or at the sites without any other competing species, it is not the most productive or dominant species in the species pool.In a similar vein, it may be noted that our data support the idea of scale - precision trade-off in root foraging , since wOur data do not show any indication of the phylogenetic signal in the root foraging or root plasticity. Regardless of the relative significance of active or passive plasticity in the root foraging process, it may be useful to quickly identify species capable and not capable of root foraging, for example, in community assembly research. However, traits  that have been previously linked to root plasticity  are rathAs usual for comparative studies, several caveats should be noted. First, phenotypic plasticity in the strictest sense is only detectable comparing individuals of the same genotype, and genotypes may vary in the amount of phenotypic plasticity they allow. However, since genotypes within species are more related than genotypes across species, phenotypic plasticity at the species level seems to be a reasonable estimate when resources are too limited to involve good number of replicates per genotype per species. Second, similar objections can be raised against using trait data mined from  databases. Database data represent “mean potential” of the species, although particular genotype or particular experimental treatment may exhibit different values. Third, even though most of the plants did not resemble seedlings at all, they were harvested young given that species examined were perennial, and, maybe even more importantly, they were harvested in a single point of time. It is quite possible that, e.g., new clonal ramets will be deployed at the rich patches later, so the clonal foraging became apparent, or that foraging plants would later produce more roots also in poor patches just to use the tiny surplus of nutrients the poor patches provided. Temporal variation in root placement may be an adaptation to belowground competition .Simple life-history species traits  seem to be good correlates of root foraging as a form of active behavior. The unexpected effect of clonality on root foraging may shed new light on our understanding of clonal species growth patterns in response to resource availability and spatial heterogeneity . This isFurther, our findings shed new light on the existing reports that plasticity may contribute to the ecological success of species. This has been reported for plasticity in root placement  and a siMW analyzed the data and wrote the manuscript; MW and TK carried out the experimental work; TH and TK helped draft the manuscript. All authors designed the study and interpreted the results. All authors gave final approval for publication.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.


Identification of critical life-stage habitats is key to successful conservation efforts. Juveniles of some species show great flexibility in habitat use while other species rely heavily on a restricted number of juvenile habitats for protection and food. Considering the rapid degradation of coastal marine habitats worldwide, it is important to evaluate which species are more susceptible to loss of juvenile nursery habitats and how this differs across large biogeographic regions. Here we used a meta-analysis approach to investigate habitat use by juvenile reef fish species in tropical coastal ecosystems across the globe. Densities of juvenile fish species were compared among mangrove, seagrass and coral reef habitats. In the Caribbean, the majority of species showed significantly higher juvenile densities in mangroves as compared to seagrass beds and coral reefs, while for the Indo-Pacific region seagrass beds harbored the highest overall densities. Further analysis indicated that differences in tidal amplitude, irrespective of biogeographic region, appeared to be the major driver for this phenomenon. In addition, juvenile reef fish use of mangroves increased with increasing water salinity. In the Caribbean, species of specific families  showed a higher reliance on mangroves or seagrass beds as juvenile habitats than other species, whereas in the Indo-Pacific family-specific trends of juvenile habitat utilization were less apparent. The findings of this study highlight the importance of incorporating region-specific tidal inundation regimes into marine spatial conservation planning and ecosystem based management. Furthermore, the significant role of water salinity and tidal access as drivers of mangrove fish habitat use implies that changes in seawater level and rainfall due to climate change may have important effects on how juvenile reef fish use nearshore seascapes in the future. Coastal habitats play an important role as nurseries in the early life history of many marine fish species. Juvenile and adult habitats of various marine fish species are spatially separated, and habitats where juveniles spend most of their life are often referred to as nursery habitats Several habitats, such as mangroves, seagrass beds, patch reefs, mudflats, salt marshes, estuaries and associated habitats, act as nursery grounds for juveniles of numerous fish species The nursery value of shallow-water tropical ecosystems depends partly on habitat accessibility to juvenile fishes With the steadily increasing number of studies that have focused on nursery function, the role of mangroves, salt marshes, and seagrass beds as habitats for aquatic organisms has been the subject of several reviews We searched the literature using Thomson Reuters' Web of Knowledge and Elsevier's Science Direct electronic databases using the following keywords as topics: 1) a combination of mangroves* and seagrass*, together with ‘fish’, ‘fisheries’, ‘decapods’, ‘crabs’, ‘prawns’ or ‘juveniles’; 2) a combination of mangroves* and seagrass*, together with ‘growth’, ‘biomass’, ‘density’ or ‘survival’. The results were thereafter filtered using ‘nursery’ as a keyword to narrow the output down into relevant studies before carefully examining the methods and the species studied therein. In addition, we searched the reference lists of several review papers rd of the maximum species TL  A particular study must have sampled in more than one habitat: at least in one juvenile habitat (e.g. seagrass beds or mangroves) and including the adult reef habitat. Studies that had sampled artificial seagrass, mangroves or coral reefs were excluded; 2) Studies must have provided mean density data of juvenile fishes, standard deviation (SD) and number of observations (N). In the case where only the standard error of the mean (SE) was provided we calculated SD as the product of SE and square root of the number of observations (N); 3) Studies must have provided length or size range of the juvenile fish sampled; and 4) Each species included in the study must be associated during its juvenile phase with a vegetated habitat other than the adult coral reef habitat, in accordance with the definition of ‘nursery species’ as proposed by others dd requires a mean, standard deviation (SD) and number of observations (N) for each value to be compared between habitats. Hedges' d describes the difference between experimental and control group in terms of SD units. A positive d indicates that the experimental group has a larger value than the control group, while a negative value indicates the opposite. For all comparison made  for comparisons across species and study locations (i.e. samples) for each of the three habitat comparisons, using a random-effects model. The cumulative effect size of a sample is a weighted average  of individual effect sizes to reduce bias due to studies with few vs. large sample sizes Hedges' Confidence intervals around the average effect sizes were generated using bootstrapping methods (5000 iterations). We used biased-corrected confidence intervals to reduce bias due to small sample sizes. If the confidence intervals do not overlap zero, then the effect size is considered significant.TQ) of a sample was calculated to determine whether the variance among individual effect sizes calculated for a sample was greater than expected due to sampling error TQ is a weighted sum of squares and is comparable to the total sum of squares in an Analysis of Variance (ANOVA). Significance of TQ was tested against a χ2-distribution. A significant TQ would indicate that other explanatory variables should be investigated as there may be some underlying structure to the data. As the TQ for all, but one, comparisons was significant (see TQ is partitioned into MQ (variation explained by the model) and EQ . The significance of MQ was calculated using resampling techniques (based on permutations). Due to the often small sample sizes of meta-analysis, statistics generated through randomization techniques are considered more conservative than parametric methods, because there is no underlying assumption about the distribution of the data www.oceancolour.gsfc.nasa.gov) and tidal range measurements from tide-forecast (www.tide-forecast.com).Total heterogeneity . A rank correlation test (Spearman rank-order) was used to test for publication bias.A total of 91 relevant articles were identified from Web of Knowledge and Science Direct, but only 14 articles (with some reporting data from multiple locations) met our criteria for inclusion .. In totIn the Caribbean, juvenile densities of nursery species were significantly higher in mangroves than in seagrass beds, while both mangroves and seagrass beds harbored significantly higher juvenile densities of nursery fish compared to coral reefs , Fig. 2.TQ was significant for all but one habitat comparison  and mangroves  decreased compared to coral reefs, while in mangroves  they decreased compared to seagrass beds . BecauseThe importance of Indo-Pacific mangroves as nursery habitats for juvenile coral reef fishes has been debated for decades see , or do nOur meta-analysis shows that mangroves harbor the highest juvenile densities for most nursery species in the Caribbean, whereas seagrass beds appear to be the primary juvenile fish habitat in the Indo-Pacific region. It appears that the small tidal amplitude in the Caribbean as opposed to the large amplitude in the Indo-Pacific region plays an important role in driving this pattern of mangrove versus seagrass use, with juvenile fish being provided with longer access to mangroves in micro-tidal areas Apart from tidal amplitude, also salinity appears to exert a significant effect on fish densities, with densities increasing in mangroves relative to seagrass beds in areas with higher salinities. Mangroves are often located in estuaries and there is emerging evidence that estuarine mangroves are frequented more by estuarine fishes than juvenile coral reef fishes, whereas the opposite is true for marine mangroves Mangrove inundation patterns and salinity gradients in bays and estuaries may change due rising sea levels and changes in precipitation as a result of climate change. It will be difficult to predict how such modifications to physic-chemical factors due to climate change may alter mangrove habitat use by fishes, and this will be highly dependent on local topographical, environmental and anthropogenic influences. Sea level rise may increase water depth in some mangroves and thus increase their accessibility. However, this may not be the case where mangroves migrate to higher elevations, or in cases where their sediment accretion rates keep up with rising sea levels Sphyraena barracuda, Scarus guacamaia, Lutjanus apodus, Lutjanus griseus, Gerres cinereus, Haemulon flavolineatum, Haemulon sciurus, and Haemulon parra for the Caribbean region and Lutjanus argentimaculatus, Lutjanus fulviflamma and Lutjanus monostigma for the Indo-Pacific region. Potentially this could be related to specific life-history traits that are characteristic of some species within these fish families. For instance, two species of Indo-Pacific haemulid juveniles  have been observed in mangroves, whereas most other members of the Plectorhinchus genus occur in seagrass or on reef as juveniles Overall, there seems to be a tendency of higher mangrove reliance or utilization by various members of the families Haemulidae, Lutjanidae, and Sphyraenidae during their juvenile stages, independent of biogeographic locality. This included species like Haemulon spp. settle in rubble zones, then move to seagrass beds followed by mangroves and rocky substratum, before they move to the adult coral reef habitat The fact that mangrove and/or seagrass habitats harbor high densities of juvenile fish does not rule out the possibility that other shallow water habitats are also used as juvenile habitats. The effect sizes showed relatively large confidence intervals for some species, indicating that the magnitude of seagrass and mangrove habitat use differed for various species across locations within the two regions. This is likely due to complex local-scale interactions between species abundances/size classes, and seascape structure and connectivity. Such interactions make it difficult to single out seagrass beds and/or mangroves alone as primary juvenile habitats, especially in areas where mangroves and seagrass beds are interconnected with each other and/or with coral reefs through diurnal, tidal, seasonal, or ontogenetic movements The results of meta-analyses can potentially be influenced by a number of factors. These include differences in sampling methods among studies, publication bias and both spatial and temporal variability in study context (e.g. habitat proximity/connectivity) and timing (e.g. sampling season). For example, studies conducted during recruitment periods may provide different results and thus affect the outcome. The studies that met our criteria were all based on visual surveys, performed at multiple locations , and we tested for publication bias. Therefore, it seems unlikely that these factors had a large effect on the results. Variation in seascape structure among studies could have had an effect on fish habitat use, explaining some of the variability among studies. The incorporation of seascape variables, along with spatial information on fish densities and movement, into analyses of juvenile habitat use will provide an important step towards better predicting the value of nursery habitats Our global analysis of potential nursery habitat use suggests that mangroves are the preferred juvenile habitat for many nursery species in the Caribbean, whereas seagrass beds seem to fulfill this role in the Indo-Pacific. Tidal regime appears to act as an important driver of these patterns of fish distributions and degree of habitat connectivity, with the relative usage of mangroves decreasing with increasing tidal amplitude. Salinity may play an additional important role in mangrove habitats, restricting their use by juvenile reef fish in more estuarine conditions. To prioritize the management and conservation of these key juvenile habitats it is critical to consider the overarching role that tidal regime can play on patterns of fish habitat use, and how this may be affected by sea-level rise due to climate change.S1 FigFlow of information through the different phases of the meta-analysis.(TIF)Click here for additional data file.S1 TableList of studies from the literature and our own data sources used in the analyses.(DOCX)Click here for additional data file.S2 TableRandom-effects categorical model summary statistics to test for the effect of species identity within habitat comparisons.(DOCX)Click here for additional data file.S1 DatasetHedges' d values and their variance calculated with MetaWin for the comparison of fish densities among mangroves, seagrass beds and coral reefs.(XLSX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.


Between 20-51% of eating disorder clients in inpatient settings and 29-73% in outpatient settings prematurely discontinue treatment. Research has attempted to address this problem by identifying the client characteristics upon entering treatment that predict dropout, but this approach has failed to identify consistent predictors of treatment dropout. Processes that occur early in treatment, such as early weight gain, may be important to consider as predictors of treatment dropout. Weight restoration is a primary goal of treatment for anorexia nervosa and may also be important in patients with bulimia nervosa who are weight suppressed. Previous research has explored the optimal rate of weight gain, but to our knowledge, no research has considered rate of weight gain as a predictor of risk for treatment dropout. Using weekly assessments of body mass index, the current research therefore aimed to identify whether a rapid rate of weight gain in the early stages of outpatient cognitive-behavioural therapy for eating disorders (CBT-E) is associated with a greater risk of treatment dropout. Participants were adult clients who entered CBT-E treatment for an eating disorder at an outpatient mental health service in Perth, Western Australia. Results will contribute to knowledge of early indicators of risk for treatment dropout.


Herpesviruses are ubiquitous double-stranded DNA viruses infecting many animals, with the capacity to cause disease in both immunocompetent and immunocompromised hosts. Different herpesviruses have different cell tropisms, and have been detected in a diverse range of tissues and sample types. Metagenomics—encompassing viromics—analyses the nucleic acid of a tissue or other sample in an unbiased manner, making few or no prior assumptions about which viruses may be present in a sample. This approach has successfully discovered a number of novel herpesviruses. Furthermore, metagenomic analysis can identify herpesviruses with high degrees of sequence divergence from known herpesviruses and does not rely upon culturing large quantities of viral material. Metagenomics has had success in two areas of herpesvirus sequencing: firstly, the discovery of novel exogenous and endogenous herpesviruses in primates, bats and cnidarians; and secondly, in characterizing large areas of the genomes of herpesviruses previously only known from small fragments, revealing unexpected diversity. This review will discuss the successes and challenges of using metagenomics to identify novel herpesviruses, and future directions within the field. Even though virus detection is not a primary target of host genome sequencing studies, viruses present in the sample will form a proportion of the sequence reads, and herpesviruses have been discovered in exactly such data . In thisde novo assembly to generate accurate consensus sequences, and potentially further PCR and sequencing to fill gaps in the assembly or confirm novel sequences  and 1B (EEHV1B), causes of hemorrhage disease in African and Asian elephants, required deep sequencing and equences . EEHVs cequences . Whole gequences , and 25%equences . The usePublic sequence repositories containing mapped and unmapped reads from large genome-sequencing projects are fertile territory for identifying novel herpesviruses. Untargeted deep and ultra-deep sequencing of mammalian genomes from primary samples can serve as metagenomic datasets for researchers able to re-analyze the data in ways that may not have been anticipated in the original project. Daubentonia madagascariensis) and Philippine tarsier (Tarsius syrichta). Aswad and Katzourakis analyzed both mapped and unmapped reads from the primate genomes, enabling them to identify both exogenous, and chromosomally integrated, potentially endogenised, herpesviruses. The tarsier herpesvirus sequences were particularly interesting because they are the first report of a potentially endogenous herpesvirus, related to human herpesvirus 6B which chromosomally integrates in a small proportion of humans (Pan paniscus) herpesvirus Pan paniscus lymphocryptovirus 1 (PpanLCV1), covering an estimated 45% of its genome , which was only previously known from small fragments  rather than cell lines, which do not contain the diversity of viruses found in a primary tissue sample. For example, the bonobo genome was sequenced from a bonobo lymphoblastoid cell line which was immortalized in the laboratory using the human herpesvirus EBV ; this daMetagenomics may be seen as the opposite side of the coin to host genome sequencing projects: while host genome sequence assembly discards all sequences which are not on target to the host genome, metagenomic studies focus on non-host sequences (reviewed in Eidolon helvum) are widely distributed across Africa and eaten as bushmeat—and therefore a potential zoonotic reservoir  to test for associations between herpesvirus-like sequence abundance and disease in cnidarians , not two. The presence of three highly divergent forms of KSHV gene K15, including a form found only in southern Africa, has been suggested by some authors  to indicMetagenomics is a promising technique that provides a further tool to identify novel herpesviruses, reducing our reliance on PCR for herpesvirus discovery while also improving our ability to design PCR primers or baits for sequencing studies. Furthermore, metagenomics is increasing our knowledge of the diversity and evolutionary history of herpesviruses; and emphasizing the importance of studying primary samples rather than cell lines or cultured virus isolates if we wish to discover further novel herpesviruses.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.


Ageing is associated with changes in the function of various organ systems. Changes in the cardiovascular system affect both directly and indirectly the function in a variety of organs, including the brain, with consequent neurological (motor and sensory performance) and cognitive impairments, as well as leading to the development of various psychiatric diseases. Post-stroke depression (PSD) is among the most frequent neuropsychiatric consequences of cerebral ischemia. This review discusses several animal models used for the study of PSD and summarizes recent findings in the genomic profile of the ageing brain, which are associated with age-related disorders in the elderly. Since stroke and depression are diseases with increased incidence in the elderly, great clinical benefit may especially accrue from deciphering and targeting basic mechanisms underlying PSD. Finally, we discuss the relationship between ageing, circadian rhythmicity and PSD. If we cannot prevent stroke, we shall try to alleviate its long-term consequences. In particular, great clinical benefit may accrue from deciphering and targeting basic mechanisms underlying chronic PSD in aged animals. So far, the majority of experimental stroke studies have concentrated heavily on acute stroke outcome, which, after all, represents only a snapshot of a complex sequence of events. This limitation may have majorly contributed to the conspicuous discrepancy between laboratory and clinical findings that has been a recurrent theme in stroke research in recent years .Depression in stroke survivors is of utmost clinical relevance. It often takes a chronic course and is associated with increased morbidity, mortality and a poorer functional outcome. Despite the fact that a high proportion of stroke patients develop mood symptoms, the pathomechanisms underlying the development of post-stroke depression (PSD) have so far received little attention from the field of neurobiology. Relevant animal models have only sparsely been investigated. This research gap becomes even more regrettable if one considers the growing body of clinical evidence indicating a beneficial effect of antidepressants and especially of selective serotonin reuptake inhibitors (SSRIs), on post-ischemic outcome. Since old age as such is also associated with an enhanced susceptibility to stroke along with a poorer recovery from brain injury, it deserves to be investigated as a key modulatory factorAge is the most important risk factor for cerebral ischemia and recovery after stroke is significantly influenced by age. A large spectrum of factors, like genetic, epigenetic or environmental factors, contributes to the aging phenotype. One prospective population-based study estimates that the incidence of mental illnesses like anxiety, anhedonia and depression after stroke is about 35% among the stroke survivals and the rate of disabilities and cognitive defficits increasesed with age . DepressComorbidities such as hypertension, obesity, diabetes, dyslipidemia and systemic inflammation increase the probability of silent strokes. Microvascular changes and silent strokes in vulnerable regions may lead to the so-called ‘vascular depression’ , 13. SevTo study the biological processes underlying functional recovery after stroke in ageing brain a variety of physiologically complex organisms like rats, mice or nonhuman primates have been used. But, the rat model is by far the most used in stroke research due to the similarities with human brain neurovascular branching and the available behavioural outcome measurements. The most commonly used ischemic stroke models in rodents are: middle cerebral artery occlusion (MCAO) for transient or permanent occlusion and endothelin-1 model for transient occlusion. To study the rehabilitation process after cerebral ischemia is important to choose an appropriate animal model and to optimize this model. Epidemiological studies reveal that human ischemic stroke occurs frequently in late middle age (50-70 years) than at older ages (over 70 years) , 18. TheThe aged rodent model offers a useful tool to investigate mechanisms and treatments of ischemic stroke in preclinical studies. The models in aged animals have to be designed to create a reproducible lesion which mimics the human pathophysiological changes, to be minimally invasive, and to allow objective measurement and analysis of tissue damage after cerebral ischemia. In agreement with this concept, previous studies have shown that mortality in post-stroke aged rate is higher compared with young animals, most likely because the lesion appears on a background already altered by senescence itself. On the physiological level, functional and cognitive decline are closely connected to morphological changes of the brain during the aging process.Imaging techniques, positron emission tomography (PET) or magnetic resonance imaging (MRI), have revealed a significant reduction in the cerebral blood flow (CBF), mostly in the cortex, which may be linked to these morphological changes in the aged brain. Overall, cerebrovascular dysfunction associated with metabolic changes due to senescence increases the vulnerability of brain to ischemic-hypoxic injuries like stroke. Cerebral ischemia occurs frequently in elderly, and increased vulnerability of the aged brain leads to unfavorable recovery of physical and cognitive functions. Although imaging techniques have already been used in numerous studies in animal models of stroke, few groups have applied MRI methods to characterize and monitor the dynamics of ischemic lesions in aged ischemic animals –33.The aged brain displays a higher susceptibility to hypoxia compared with young animals in the acute phase of stroke , 32. On Modelling psychiatric conditions like depression after stroke in animal models is not trivial. The psychological evaluation by clinicians is not available in animal models and most of these models are validated only by behavioural observation or by behavioural changes in response to treatment. Therefore instead of trying to fully replicate all the human symptoms of depression, we shall try to uncover the underlying signalling pathways in animal models of mood disorders that strongly meet the validating criteria including strong endophenotype similarities, comparable etiology and the same treatment –37. To tAnhedonia (the loss of interest) is an important symptom of depression that can be measured in rodents by a decrease in sucrose consumption. Rodents normally prefer sweet fluids like glucose or sucrose instead of water. Quantifying consumption of sucrose is the most used endpoint for assessing motivation and affective state in rodends after repeated chronic stress exposure. Also, this test can quantify reversal of this effects after antidepressive drugs administration , 43–45. Exposure to unpredictable chronic mild stress (CMS) associated with isolation of animals after ischemia is another way to study experimental PSD. It has been shown that after cerebral ischemia, animals show decreased locomotor activity in the open field test and decreased sucrose consumption when exposed to CMS paradigm for 18 days after surgery .The high incidence rates of stroke patients that develop mood symptoms (between 20-50%) justify the effort of researchers to go further into the neurobiological mechanisms of disease –49. ManyOn the other hand, the prevalence of the memory cognitive impairment like dementia or depression is higher in elderly after stroke. One question is that if cerebral ischemia causes secondary degenerative changes in the brain or that ongoing degenerative changes will be simply aggravated by stroke. From a psychological perspective, the severity of PSD is determined not only by individual differences in emotional reactions to disease (e.g. negative attitude) but also, by the severity of physical and cognitive impairment and by the absence of familial and social support .Many studies suggest that post-stroke vulnerability of the brain can induce PSD and PSD is associated with reduced recovery after stroke in stroke survival patients. However, until now there is no clear evidence to support the etiological mechanisms of PSD, which seems to be a multifactorial disease of the ageing brain.One important issue is how to distinguish the depressive symptoms in patients in the early stages after stroke from cognitive impairments due to neurodegeneration prior to stroke and the ageing process itself. Some longitudinal studies on post stroke patients showed that chronic PSD is highly predictable if post stroke patients are experiencing depression symptoms between 6 month and 1 year after brain injury , 58.Most of these studies analyzed the risk of post-stroke depression in relatively young people’s that have a job and are not living alone. Also, in these studies, patients with language problems like aphasia or neurodegenerative disease like dementia where excluded. However, since stroke occur frequently in people over 65, studies on older patients with stroke and other age-related comorbidities should be more relevant than studies on young people. In this light, multi-therapeutic approach of PSD in the recovery phase that include genetic, social and psychological aspects have the greatest potential for improving post-stroke recovery and the quality of life in elderly post-stroke survivors.Age-related cognitive decline is often associated with decreassed hippocampal neurogenesis and depression, but relatively little is known about the biological significance of neurogenesis in the ageing mammalian brain for the development of depression. Two major hypotheses have driven most of the studies on hippocampal neurogenesis, namely (i) it plays a pivotal role in hippocampus-dependent learning and memory , 60 and,One possible molecular mechanism underlying age-related depression and decreased neurogenesis can be due to an increased level of the dickkopf 1 homolog - Xenopus laevis (Dkk1), that decreases Wnt signaling pathways and has been associated with a decline in hippocampal neurogenesis .Other mechanisms that can be involved in neurorecovery are related to neurotrophin signaling pathway. Neurotrophins are important players in early neuronal gene response to injuries. The neutrophin-signaling pathway activates extracellular-signal-regulated kinases (ERK) pathway and nuclear transcription. Meier and colleagues demonstrated that hippocampal neuronal culture treated with brain derived neurotrophic factor (BDNF) promotes axonal guidance, modulate the synaptic function, stimulate neurite branching and is antagonized by Ephrin (Eph) signaling , 68. AlsEven less is known about the relationship between PSD and neurogenesis in the elderly. The level of hippocampal neurogenesis has been shown to decrease steadily with aging . Since aDepressive behavior in ischemic rats was accompanied by reduced ischemia-evoked hippocampal neurogenesis and this effect was reversed by citalopram administration . Using pCalm2), synapsin 1 (Syn1), tubulin beta 4 (Tubb4) a member of ras-related protein Rab-4B (Rab4b). Also, increased expression of the transcriptional repressor erythroid transcription factor/ GATA-binding factor 1 (GATA1) is responsible for downregulation of these synaptic-function-related genes [Transcriptional profiling is a usefull tool to identify genetic pathways associated with mood symptoms in the elderly. Most studies reporting the use of gene expression profiling to investigate rodent models of depression focused on stress models and did not supply direct evidence for a specific genomic signature in PSD depression. Kang and collegues identified some synaptic-function-related genes that are connected with decreased in number and function of synapse in a rat model of major depression. These genes included: calmodulin 2 (ed genes .Htr2a), neurotrophic tyrosine kinase receptor type 2 and 3 genes (Ntrk2 and Ntrk3), corticotropin releasing hormone receptor 1 (Crhr1) and corticotropin releasing hormone (Crh) were differentially expressed in three animal models of depression: acute treatment with reserpine, olfactory bulbectomy and chronic treatment with corticosterone [Slc6a4) promoter polymorphism (5-Httlpr) [Slc6a4 and 5-Httlpr/rs25531 in general anxiety disorder [In another study, genes related to human major depression like serotonin receptor 2a gene  . Lohon adisorder .) was identified to be associated with catatonia-depression syndrom in the elderly. Using aged heterozygous null mutant mice model of spontaneous catatonia, Hagemeyer and collegues showed that the reduced expression of CNP is accelerated by aging and is associated with neurodegenerative changes in the elderly [An oligodendrocyte/myelin-associated genes, 2’,3’-cyclic nucleotide 3’-phosphodiesterase . These genes could be pharmacological targets in a multimodal therapy of stroke and stroke related diseases [In previous studies we have identified a number of genes that are involved in neuropathic syndrome and PSD signaling pathways in aged brain (e.g. 5- hydroxytryptamine 2a receptor - diseases .(fosB) expression has been associated with stem cell and neural progenitor cells proliferation after cerebral ischemia in mammalian central nervous system [Using fosB-Null mice, Yutsudo and colleagues reported impaired neurogenesis and depressive behavior in fosB-Null mice . Intrigus system , 87. Thes system , 89. CntDisturbances in the circadian rhythm may have dramatic effects on our health. Changes in biological rhythm disturbances precede and parallel the occurrence of mood episodes of illness and have been proposed to play a pathogenetic role in major depression and mania –110. TheTo understand the therapeutic action of these mood stabilizing drugs as well as antidepressants, investigators have recently begun to examine their effects on intracellular signaling pathways that regulate clock gene expression. Yang and collegues  utilisedAssessing the impact of agomelatine on depressed bipolar patients , while mNevertheless, it is clear that some fundamental differences exist between nocturnal and diurnal mammals which may be crucial for the study of circadian rhythms related diseases –115. ForCircadian rhythms display an unregular pattern with aging manifested by alteration of sleep quality and cognitive performance , 120. HeSome studies showed that one mechanism that contributes to increased risk of depression is the decrease in the synthesis of N-acetylserotonin with ageing . Since NNorepinephrine (NE), serotonin (5-HT), and dopamine (DA) overlap in the brain and all three transmitters are implicated in the symptoms of depression Depressive symptoms may result from dysfunction of any or all of the monoamine neurotransmitter systems. The effects of NE, 5-HT and DA overlap in the brain and all three transmitters are implicated in the symptoms of depression. Because these monoamine transporters (MATs) are important regulators of the extracellular neurotransmitter concentration, mouse gene knockouts of serotonin transporter (SERT), the noradrenaline transporter (NAT) and also the dopamine transporter (DAT) located in the plasma membrane of corresponding neurons provide interesting models for possible effects of chronic antidepressant treatments. Inhibition of neurotransmitter reuptake by drugs acting at SERT, NET and/or DAT can produce antidepressant effects , 128.The mechanism of PSD was suggested to involve multiple pathways, like immune activation, hypoxia, apoptosis and necrosis of neuronal or glial cells or hyperactivation of the hypothalamic-pituitary-adrenal axis. Many studies reported different therapeutic strategies designed to improve the PSD outcome. Of these, cortisol-lowering therapies and increases of neurotropic factors like BDNF were reported to be novel possible therapeutic strategy for PSD .In addition, a growing body of evidence indicate a beneficial effect of antidepressants and especially of SSRIs on postischemic outcome . AntidepAntidepressants treatment initiated soon after stroke in non-depressed post-stroke patients may prevent the later PSD but the time window of treatment remains to be optimized . A numbeIn conclusion, depression is the most frequent neuropsychiatric disease of brain ischemia, affecting up to 35% of all such patients. PSD is associated with negative outcome of functional recovery, cognition and social reintegration of stroke patients. During de past decade, significant efforts have been made to establish an efficient treatment of PSD in the elderly. So far, preclinical and translational research on PSD is largely lacking. The implementation and characterization of suitable animal models is clearly a major prerequisite for deeper insights into the biological basis of post-stroke mood disturbances and may also pave the way for the discovery of novel therapeutic targets. Nevertheless it is unlikely that monotherapies will provide a cure for PSD. Rather multitherapeutic strategies should be at the focus of future clinical trials conducted on PSD and mood disorders patients without cerebral ischemia that show the same clinical profile. In this light, future research is needed to identify the molecular mechanism of disease and to establish the pathways that are modulated by antidepressant drugs leading to a better cognitive recovery in the elderly patients.


Juvenile Dermatomyositis (JDM) is a systemic autoimmune disorder in which the immune system targets the microvasculature of skeletal muscles, skin and other organs, with for the most part an unknown immunopathogenesis. Moreover, evaluation of disease activity remains challenging in juvenile dermatomyositis as muscle enzyme levels and inflammatory markers, routinely used in clinics, are no reliable biomarkers in JDM, especially for monitoring the disease.To identify a panel of mediators specially related to the inflammatory process in JDM, which might help in clinical assessment and in guiding treatment.We performed a multiplex immunoassay and measured plasma levels of 45 inflammation related proteins in patients with four different disease stages determined by their clinical activity and their treatment. Peripheral blood and clinical data were collected in a prospective way from 25 patients diagnosed with JDM. 15 healthy children and 8 patients with non-autoimmune muscle disease served as controls.Patients with JDM at time of diagnosis had significantly higher levels of three proteins compared to patients in remission, patients with non-autoimmune muscle disease and healthy-age-matched controls.Our results show that these three proteins (which are currently not named due to a pendent patent application) correspond to the activation status during inflammation in JDM and might be instrumental in monitoring disease activity and treatment guiding.None declared.


Counterfactual reasoning is a hallmark of human thought, enabling the capacity to shift from perceiving the immediate environment to an alternative, imagined perspective. Mental representations of counterfactual possibilities  provide the basis for learning from past experience, enable planning and prediction, support creativity and insight, and give rise to emotions and social attributions . Yet remarkably little is known about the psychological and neural foundations of counterfactual reasoning. In this review, we survey recent findings from psychology and neuroscience indicating that counterfactual thought depends on an integrative network of systems for affective processing, mental simulation, and cognitive control. We review evidence to elucidate how these mechanisms are systematically altered through psychiatric illness and neurological disease. We propose that counterfactual thinking depends on the coordination of multiple information processing systems that together enable adaptive behavior and goal-directed decision making and make recommendations for the study of counterfactual inference in health, aging, and disease. The generation of counterfactuals gives us the flexibility in thinking about possible futures and prepares us better for those futures” and elicit a mental simulation of the event . As this activation spreads, it triggers mental simulations of similar situations (previous applications), allowing one to infer how this scenario would have played out under different circumstances . These nearby counterfactual simulations influence ones interpretation of the factual experience  and promote adaptive behavior that guides future planning and problem solving. The process of counterfactual reasoning therefore supports inferences about the factual event that guide understanding, modulate emotional responses, and provide the basis for future planning and decision-making.We propose that counterfactual reasoning depends on three processing stages: Our proposal is that the coordination of systems for: (i) mental simulation; (ii) inference; and (iii) learning and adaptation together enable counterfactual reasoning. In the following sections, we review each of these processes and survey evidence from psychology and neuroscience to elucidate their contributions to counterfactual reasoning.Counterfactual thoughts are automatically employed in response to real world experiences, in particular those situations where negative emotions are linked to violations of expectations and motivations , in the form of implicit or explicit goal failures , or close calls  trigger counterfactual thoughts, representing a probable alternative state of affairs  used to interpret a state of affairs. The Model Theory of counterfactual thought  played the strongest role in the (un-)desired outcome; (2) deviated most from expectancies; or (3) is most under the participants control , contributing to suboptimal decision making  that are central for managing and regulating social behavior  and update prior beliefs and action-values, resulting in behavioral and affective consequences. Counterfactual inference supports adaptive behavior and is known to:value will be important. Is the alternative outcome better or worse  and by how much (magnitude)? This valuation will impact how an individual perceives the factual, experienced outcome and its relative value. Secondly, does the individual perceive a favorable opportunity to improve performance? Will a similar situation take place in the future  and does the individual believe it is feasible to change the outcome: do they perceive to be in control of the situation and that the counterfactual state is attainable? What is the probability that the alternative action(s) can bring about the desired outcome? The third factor is the perspective or processing mode in which counterfactual states are represented. Markman and McMullen , and how we might have personally effected such an outcome (perceived attainability) often elicit an emotional and social reaction. For example, regret will increase as we feel more responsible for the outcome and as the discrepancy between the experienced and counterfactual outcome value increases , elicits However, in situations without opportunity for improvement , upward counterfactual thinking will not be beneficial Sanna, . Consideaffective assimilation effects: the experienced affect is pulled into the direction of the counterfactual outcome. Processing an upward counterfactual in this manner will yield more positive affect (less intense negative emotions), but less behavioral benefits than evaluative upward counterfactuals. Vividly imagining a worse counterfactual outcome can instead lead to increase in negative affect, which can enhance persistence and performance to avoid this potentially worse outcome in the future  depend on the type and amount of information that needs to be processed at a particular time.We review neuroscience evidence to elucidate three neural networks that together support counterfactual thought: (1) the mental simulation network; 2) the cognitive control network; and (3) the reward network  probably supports the construction of the “nearest possible world” by inferring relevant information from prior experience and background beliefs. vmPFC can also integrate the information from the constructed counterfactual event into existing representations, updating prior expectations and action-value associations, which serve to guide future behavior . This integration of counterfactual simulations with memory processes can also explain how counterfactual inference can contribute to false memories  enable switching between immediate experiences and counterfactual scenarios; (2) perform the mental transforms required for counterfactual inference and reasoning; and (3) monitor and update representations of the relative values of actions to steer subsequent behavior.outcomes, especially in situations with mixed appraisals , middle cingulate cortex, IPL and precuneus. This network enables the integration of multiple sources of information and supports the regulation and control of thought and behavior , the posterior medial frontal cortex (pmFC), anterior insula (aI)/frontal operculum , and the anterior PFC (aPFC). This network is consistently linked to maintaining task goals and monitoring actions, as well as contributing to slow behavioral adjustments over time  and a stronger deactivation with increasing evidence against current action  and the computation of expected values (vmPFC/mOFC). The literature broadly supports vmPFC/mOFC involvement in inferring the affective meaning of a situation by connecting conceptual information  with its subjective value  and the impulsive-antisocial traits . The former Factor one traits distinguish psychopathy from other antisocial syndromes and make people with such traits particularly pernicious .Adults with psychopathic traits display normal executive functions but decreased arousal for aversive stimuli and aberrant moral behavior , which will avert the activation of counterfactual inference. Individuals with psychopathic traits may assign a different affective meaning to immoral behavior, impacting the content of the counterfactuals they construe . As a result of a reduced spontaneous elicitation of counterfactual thought and different counterfactual content, they may report less remorse and self-blame and correct their immoral behavior less frequently. We predict that these deficits will exist in the presence of largely intact mental simulation and executive processes, except where those processes interact with the impaired moral or emotional processing. MBDI–II = 18.95) generated a smaller number of spontaneous counterfactual thoughts relative to controls (MBDI–II = 3.08). This difference was eliminated by an explicit cue to generate upward counterfactuals regarding a recent negative academic experience . In addition, consistent with the earlier statement that processing upward counterfactuals with low feasibility only contributes to psychological distress but does not result in beneficial reappraisal effects, the post-counterfactual mood of depression groups was more negative than controls. Moreover, subjects with mild-to-moderate symptoms (BDI-II cutoff: 10–23) did not perceive an increase in their ability to exert control over the environment  reported more regret about a hypothetical hiring decision than controls when they were informed about another, better applicant  is muted and this response is related to self-reported apathy-scores  mental simulation in MTL/PFC; (2) cognitive control in the fronto-parietal and cingulo-opercular network; and (3) motivation and valuation in limbic regions and vmPFC.Because counterfactual reasoning depends upon so many inter-related brain systems and mental processes, it provides a broad window onto global brain function. Disruptions to counterfactual reasoning are a productive scientific and diagnostic tool. By identifying the specific sub-components of counterfactual reasoning that are affected clinicians can better understand the day-to-day challenges faced by different patient populations. In our everyday lives, counterfactual reasoning is a ubiquitous source of new insights into nearby possible worlds, and different circumstances, scientific understanding of this process is a critical component of insight into the complex alternate worlds that make up our rich, inner lives.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.


Microglia, glial cells with immunological functions, have been implicated in various neurological diseases and psychiatric disorders in rodent studies, and human postmortem and PET studies. However, the deeper molecular implications of living human microglia have not been clarified. Here, we introduce a novel translational research approach focusing on human microglia. We have recently developed a new technique for creating induced microglia-like (iMG) cells from human peripheral blood. Two cytokines, GM-CSF and IL-34, converted human monocytes into the iMG cells within 14 days, which show various microglial characterizations; expressing markers, forming a ramified morphology, and phagocytic activity with various cytokine releases. We have already confirmed the applicability of this technique by analyzing iMG cells from a patient of Nasu-Hakola disease (NHD; Ohgidani et al.,  Microglia is the only mesomorphic cell in the brain (Kettenmann et al., We first utilized the iMG cells as a “cellular disease model” focusing on one of the most famous primary microglia-oriented diseases, the Nasu-Hakola disease (NHD; Hakola, In this way, we believe that the iMG technique will enable the clarification of novel pathophysiological dysfunctions of human microglia as a translational research tool in various brain diseases including psychiatric disorders. We believe that the iMG technique will enable the exploration and development of psychiatric research especially to the following areas;By combining clinical data, brain imaging data, and the iMG data from the same patient will be able to clarify the dynamic interaction between a specific psychopathology and a specific microglial activation Figure . For exaWe previously reported the neuroprotective effects of psychotropic drugs via suppressing microglial activation using rodent microglial cells (Kato et al., We introduced a novel translational research approach focusing on human microglia-like cells using the iMG technique. Before reaching a conclusion, we need to mention a recent considerable discussion regarding functional differences between yolk sac derived microglia and monocyte derived microglia (Ginhoux 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.


It is becoming increasingly important to understand how epigenetic mechanisms control gene expression during neurodevelopment. Two epigenetic mechanisms that have received considerable attention are DNA methylation and histone acetylation. Human exome sequencing and genome-wide association studies have linked several neurobiological disorders to genes whose products actively regulate DNA methylation and histone acetylation. More recently, a third major epigenetic mechanism, nucleosome remodeling, has been implicated in human developmental and intellectual disability (ID) disorders. Nucleosome remodeling is driven primarily through nucleosome remodeling complexes with specialized ATP-dependent enzymes. These enzymes directly interact with DNA or chromatin structure, as well as histone subunits, to restructure the shape and organization of nucleosome positioning to ultimately regulate gene expression. Of particular interest is the neuron-specific Brg1/hBrm Associated Factor (nBAF) complex. Mutations in nBAF subunit genes have so far been linked to Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NBS), schizophrenia, and Autism Spectrum Disorder (ASD). Together, these human developmental and ID disorders are powerful examples of the impact of epigenetic modulation on gene expression. This review focuses on the new and emerging role of nucleosome remodeling in neurodevelopmental and ID disorders and whether nucleosome remodeling affects gene expression required for cognition independently of its role in regulating gene expression required for development. It has long been understood that gene expression is critical not only for neural development, but also for healthy cognition in the adult. The temporally and spatially specific regulation of this gene expression is critical for the aforementioned processes to occur. One basic regulatory element of gene expression is the spatial organization of DNA, extremely compacted into chromatin. Nucleosomes are the basic subunit of chromatin and consist of approximately 147 DNA base pairs spooled around a histone octamer. These nucleosomes can fluctuate between various levels of compaction, and their state is a critical and limiting factor in allowing transcription machinery to access genes of interest. Recent work has shown that various epigenetic mechanisms can regulate gene expression by altering chromatin compaction as well as providing a signal integration platform necessary to coordinate large protein complexes for transcriptional regulation. These activities have a major role in both where and when necessary genes are expressed  are known to cause Rett syndrome  cause Rubinstein-Taybi syndrome. , and nucleosome remodeling. The majority of attention in neuroscience has been given to histone modifications and DNA methylation as regulators of transcription. Deficits in either of the aforementioned mechanisms can have profound effects on development and adult cognition. For instance, identified mutations in methyl CpG binding protein 2 . These nuclear enzyme complexes are capable of actively sliding, ejecting, or completely restructuring nucleosome structure  remodeling specifically refers to the ATP-dependent enzymatic complexes  that are involved in nucleosome mobility underlying transcriptional regulation. In neuroscience however, the term chromatin remodeling is misused as a catch-all phrase , offspring are developmentally inviable  complex  are implicated in different ID disorders, this is likely due to when during development the mutation occurred, as well as cell type-specific effects. A main characteristic of NRCs is the numerous subunits, including cell type-specific subunits (as observed in the neuron-specific nBAF genes described below), which give rise to combinations that are developmental stage-specific and cell type-specific. This is also quite likely why similar complexes have roles in the adult brain related to cognition that are independent from their developmental roles.Several BAF complex genes have also been implicated with Nicolaides-Baraitser syndrome (NBS) Table . PatientCBP, leading to a heterozygous condition , homologous to SWI/SNF in yeast and brahma in drosophila, is one such complex. In contrast to the SWI/SNF complex, the specific functions of the BAF complex remain unknown, yet are presumed to be similar. The various mechanisms of nucleosome remodeling employed by NRCs have been thoroughly reviewed . Deletions of the hydrophobic domain in BAF53a are known to generate dominant-negative forms of BAF53a  task  distinguishable from their roles in adult cognition. We recently published a study that used two different genetically modified BAF53b mutant mice that allowed us to begin addressing these questions  was unable to rescue the loss of dendritic growth and gene expression  gene expression. The chromatin surrounding Ifnβ is typically compressed, while its enhancer element remains exposed between nucleosomes. Ifnβ expression is relatively suppressed; upon exposure to viral infection, its expression dramatically increases through the assembly of a particular enhanceosome complex to the Ifnβ enhancer. This complex is able to selectively recruit histone acetyltransferases (such as CBP and p300) to nearby chromatin, leading to histone acetylation and SWI/SNF complex recruitment  and DNA methylation binding proteins  and more recently for nucleosome remodeling , that these factors have a role in adult neuronal plasticity, learning, and memory, independent of their developmental roles. It remains difficult to prove that this is also the case in adult ID disorders associated with mutations in these genes, but it gives hope that cognitive dysfunction observed in these ID disorders may one day be at least partially ameliorated.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.