Normal ageing is characterized by cognitive decline across a range of neurological functions, which are further impaired in Alzheimer’s disease (AD). Recently, alterations in zinc (Zn) concentrations, particularly at the synapse, have emerged as a potential mechanism underlying the cognitive changes that occur in both ageing and AD. Zn is now accepted as a potent neuromodulator, affecting a variety of signaling pathways at the synapse that are critical to normal cognition. While the focus has principally been on the neuron: Zn interaction, there is a growing literature suggesting that glia may also play a modulatory role in maintaining both Zn ion homeostasis and the normal function of the synapse. Indeed, zinc transporters (ZnT’s) have been demonstrated in glial cells where Zn has also been shown to have a role in signaling. Furthermore, there is increasing evidence that the pathogenesis of AD critically involves glial cells (such as astrocytes), which have been reported to contribute to amyloid-beta (Aβ) neurotoxicity. This review discusses the current evidence supporting a complex interplay of glia, Zn dyshomeostasis and synaptic function in ageing and AD. Currently, normal ageing is considered to be associated with an overall decline in cognition occurring via structural and functional brain changes over a period of time  depression and schizophrenia  exist as chelatable Zn  and also maintaining the architecture of gray matter (Kettenmann and Verkhratsky, 2+ levels in response to synaptic transmission (Morris et al., 2+ influx through NMDA receptors. A recent study by Han et al. (Additionally, astrocytes increase intracellular Can et al. , which gn et al. . This deThe role of Zn at synapses is particularly germane to both normal and pathological ageing. Neuroplasticity deteriorates in normal ageing and loss of synapses is a key indicator and currently the best correlate of cognitive decline in AD (Takahashi et al., Though the link has previously not been made, the evidence presented here suggests that there may be an interaction between neurons, astrocytes, Zn and glutamate that is critical to normal synaptic health and function, potentially affecting neurotransmission and other cellular cascades involved in cognition, as discussed earlier. This is an area of research that clearly needs further investigation, as the diminished learning and memory abilities seen in ageing may be caused by a failure in neuron-glia communications at the synapse that disrupts Zn homeostasis to result in downstream modifications to, among other things, synaptic ion channels.In addition to the role of astrocytes at the synapse, recent studies investigating microglia suggest this tripartite system may be just as constraining to synaptic research as the previous model. Currently, the literature is dominated by what is thought to be the primary function of microglia; surveying the environment for damage and protecting neural material (Stollg and Jander, 2+ and a subsequent increase in neuronal voltage-gated K+ currents as caused by the release of ROS from activated microglia lead to neuronal cell death. This suggests the primary mechanism of neuronal apoptosis may in fact, be the earlier damage to glial cells. This is accordance with findings by Kaindl et al. (in vitro (Kaindl et al., Microglia also release cytokines, which have central physiological roles in synaptic plasticity, neurogenesis and learning and memory in the normal brain (Morris et al., l et al. , 2012 th2+ in the progression from normal to pathological ageing is illustrated in Figure Both Zn and glia appear to have multifarious roles within the brain, especially within synapses. Indeed, synaptic loss is the fundamental feature of the ageing brain that links neuropathology to cognitive decline in AD (Talantova et al., Herein evidence supporting a link between Zn, glia and cognitive decline has been presented and discussed. The research thus far suggests the possibility of a feedback loop between Zn homeostasis, synaptic excitation, neurons, astrocytes and microglia. Perhaps the most appropriate definition is that of Morris et al.  that a sThe 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.


Brain histamine promotes wakefulness and orchestrates disparate behaviors and homeostatic functions. Recent evidence suggests that aberrant histamine signaling in the brain may also be a key factor in addictive behaviors and degenerative disease such as Parkinson's diseases and multiple sclerosis. The intent of this research Topic is to provide an overview of the recent advances in the understanding of the many functions of brain histamine and to propose neurobiological substrates and mechanisms of action that might explain the reasons why the histaminergic system is a potential target for therapeutic interventions. This may justify the search for new histaminergic compounds.The authors that contributed to this e-book offered several approaches to the study of brain histamine function. Tomasch et al.  synthesiHistamine acts as a modulator of several neurotransmitters in the brain and its role in promoting wakefulness has for long overshadowed other important functions. In fact, histamine signaling controls feeding behavior in a complex fashion and it has been considered for long a satiety system as brain histamine decreases the drive to consume food. In their paper, Ishizuka and Yamatodani  demonstr3 receptor (which regulates histamine and other neurotransmitters' release), decreases alcohol drinking in several behavioral tasks, like operant alcohol administration and “drinking in the dark” paradigm (Nuutinen et al., 3 receptor is a key element in alcohol drinking and place preference, the role of histamine in these behaviors is poorly understood and deserves further investigation.Brain histamine is crucial for motivation and goal-directed behaviors as reviewed by Torrealba et al. . The aut3 receptor signaling in the brain to acquire and store short- and long- term memories has been documented extensively. However a limited number of studies have investigated the role of the H3 receptor in anxiety. By using novel behavioral test, Abuhamdah et al. (3 receptor providing new evidence that the H3R may have a role in fear-induced avoidance responses, but not in anxiety. In addition, Vohora and Bhowmik (The importance of Hh et al.  present  Bhowmik  providedDysfunctions of the histaminergic system may also contribute to the pathogenesis of multiple sclerosis and its murine model of experimental autoimmune encephalomyelitis, although the role of the different histamine receptors is complex and still controversial (Passani and Ballerini, 2, Yanovsky et al. (2-induced arousal in hepatic encephalopathy and obstructive sleep apnoea.Histaminergic neurons are sensitive to COy et al.  showed tRecent evidence summarized by Blandina et al.  suggest In conclusion, we believe that this Research Topic offered an inter-disciplinary forum that improved our current knowledge of the role of brain histamine. It also provided the necessary drive to stimulate innovation in clinical practice to manage and treat neurological disorders.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.


The previous contribution of Duffy and colleagues suggests that a chain of behavioral events starting during childhood precedes the development of full-blown bipolar disorder. In this vein, the recent contribution of Keown-Stoneman and colleagues brings a new perspective to the study of prodromal symptoms of bipolar disorder. In 2010, Duffy et al. showed that subjects diagnosed with bipolar disorder (BD) followed a predictable sequence of prodromal symptoms (Duffy et al. Generally, staging models imply that natural history of the disorder moves through a predictable temporal progression, and provision of stage-appropriate treatment can modify such course. Some medical specialties such as cardiology and oncology have advanced in this field, developing strategies to prevent both the onset and the development of established disease. In the same way, bipolar disorder identified in the early stages may be less treatment refractory with a greater probability of response to monotherapy (Scott et al. In 2007, Berk et al. presented a staging model of the longitudinal course of bipolar disorder and the temporal impact of interventions (Berk et al. In the same vein, Kapczinski et al. presented a staging model that emphasizes the assessment of patients in the inter-episodic period and includes the following: latent phase—individuals who present mood and anxiety symptoms and increased risk for developing threshold bipolar disorder; stage I—patients with bipolar disorder who present well-established periods of euthymia and absence of overt psychiatric morbidity between episodes; stage II—patients who present rapid cycling or current axis I or II comorbidities; stage III—patients who present a clinically relevant pattern of cognitive and functioning deterioration, as well as altered biomarkers; and stage IV—patients who are unable to live autonomously and present altered brain scans and biomarkers (Kapczinski et al. Moreover, a recent task force of the International Society for Bipolar Disorders has performed a systematic review on staging models for bipolar disorders (Kapczinski et al. In conclusion, the current paper (Keown-Stoneman et al.


Over the last 20 years, work surrounding theories of embodiment and the role of the putative mirror neuron system (MNS) in humans has been hotly debated. In 2000, Ramachandran . Thus, eTwo of the articles in this collection addressed how the human MNS might underlie the physiological mechanisms that give rise to human emotions. In “Motor empathy is a consequence of misattribution of sensory information in observers,” Mahayana et al.  used TMSIn “Language comprehension warps the mirror neuron system,” Zarr et al.  asked paTwo articles used neuroimaging to identify the neural correlates of embodiment. In an fMRI study entitled “Hand specific representations in language comprehension,” Moody-Triantis et al.  asked paTwo other theoretical/opinion articles also steer away from stricter MNS interpretations and suggest that the motor system influences action perception but is not its sole critical component. In “Homuncular mirrors: misunderstanding causality in embodied cognition,” Mikulan et al.  propose Additionally, we included two response pieces to Bach et al.'s proposal, one by Osiurak  and the Intriguingly, in “Observation and imitation of actions performed by humans, androids and robots: an EMG study,” Hofree et al.  show thaAll of these works expand our understanding of the human MNS by extending previous work and delimiting the boundaries of how we should interpret those findings. As a group, contributing authors seem to agree on less strict interpretations of embodiment and the human MNS, suggesting these are strong contributors to various aspects of action and cognition, but do not represent the sole basis of language, learning, or comprehension. Future work should further explore the precise mechanisms underlying the links between action planning, execution, and semantic processing, as well as the relative dependence of distinct cognitive processes on mirror activity.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.


The discovery that somatic cells can be induced into a pluripotent state by the expression of reprogramming factors has enormous potential for therapeutics and human disease modeling. With regard to aging and rejuvenation, the reprogramming process resets an aged, somatic cell to a more youthful state, elongating telomeres, rearranging the mitochondrial network, reducing oxidative stress, restoring pluripotency, and making numerous other alterations. The extent to which induced pluripotent stem cell (iPSC)s mime embryonic stem cells is controversial, however, as iPSCs have been shown to harbor an epigenetic memory characteristic of their tissue of origin which may impact their differentiation potential. Furthermore, there are contentious data regarding the extent to which telomeres are elongated, telomerase activity is reconstituted, and mitochondria are reorganized in iPSCs. Although several groups have reported that reprogramming efficiency declines with age and is inhibited by genes upregulated with age, others have successfully generated iPSCs from senescent and centenarian cells. Mixed findings have also been published regarding whether somatic cells generated from iPSCs are subject to premature senescence. Defects such as these would hinder the clinical application of iPSCs, and as such, more comprehensive testing of iPSCs and their potential aging signature should be conducted. TERRA levels are positively correlated with telomere length and may act as regulators of telomerase expression (Schoeftner & Blasco, et al., These results indicate that, although telomerase activity is clearly reconstituted during the reprogramming process, there is a significant variability in telomere length among various iPS cell lines. This length is sensitive to passage number and can even vary among cell lines derived from the same tissue or parental cell type. This is not unique, however, as it was recently shown that substantial variability in telomere length and telomerase expression exists for ESCs as well. For both iPSCs and ESCs, telomere length was found to be highly correlated with proliferation efficiency and developmental pluripotency (Huang et al., et al., et al., et al., et al., et al., Aging in somatic cells is accompanied by mitochondrial dysfunction and oxidative stress Fig.  (Passos et al., et al., et al., et al., et al., et al. obtained more mixed results (Fig. et al., It was recently shown that the reprogramming process reorganizes mitochondria, causing them to adopt the immature morphology, distribution, and DNA content characteristic of the pluripotent state. Like ESCs, these human iPSCs also displayed reduced levels of oxidative stress, decreased amounts of intracellular ATP, and increased production of lactate. Expression of nuclear factors involved in mitochondrial biogenesis was also comparable (Prigione lts Fig. , findinget al., et al., et al., et al., It is currently possible to generate iPSCs from human centenarian cells (Lapasset et al., et al., et al., et al., et al., Using human tissue, Boulting and colleagues (Boulting et al. reported that reprogramming efficiency declined with age. Knockdown of the Ink4/Arf locus, which encodes for tumor suppressors and is upregulated with age, was sufficient to rescue the age-dependent defect in reprogramming efficiency (Li et al., et al., lamin A/C cause defects in the nuclear envelope and underlie Werner syndrome and Hutchinson Gilford progeria, two diseases of accelerated aging. Recently, iPSCs were generated from patients suffering from these disorders. Compared to their donor fibroblasts, these iPSCs had normal nuclear membrane morphology, suggesting that the reprogramming process could rejuvenate nuclear defects (Ho et al., A few age-related genes have been identified that play inhibitory roles in the reprogramming process. Using mouse and human fibroblasts, Li Although additional age comparisons are necessary, these results suggest that mammalian aging may decrease reprogramming efficiency (for an overview of donor age of the generated iPSC lines, see Table Recent data have emerged suggesting that cells derived from iPSCs may exhibit signs of premature senescence (please see Fig. et al. reprogrammed human skin fibroblasts into iPSCs and then produced differentiated cell lines derived from three iPSC-teratoma explants. Although one line exhibited elongated telomeres, the other two displayed telomere lengths comparable to the input fibroblasts (Suhr et al., et al., et al., et al. successfully differentiated human iPSCs into multiple cell types, although the efficiency was markedly lower than it was for ESCs. Moreover, the authors observed that, unlike cells derived from ESCs, somatic cells derived from iPSCs exhibited early senescence and possessed dramatic defects in expansion capability (Feng et al., et al., Suhr Although it is too early to conclusively determine, issues of premature senescence may, like telomere length, vary considerably from line to line. Subsequent research drawing detailed comparisons between cell types derived from multiple ESC and iPSC lines will help resolve this contention.et al., et al., et al., It is quite clear that the reprogramming reverses many aspects of aging. Even iPSCs derived from senescent and centenarian cells exhibit a more youthful signature, displaying elongated telomeres and gene expression profiles comparable to ESCs (Lapasset et al., et al., et al., et al. found no correlation between the differentiation potential of an iPSC clone and the type of progenitor cell used. Instead, the authors observed that differentiation propensity varied substantially from clone to clone (Nasu et al., et al., et al., et al., et al., et al., et al., Telomere length, for example, has been observed to be shortened (Vaziri et al., That variations in differentiation propensity are observed in iPSCs derived from the same donor (Nasu


Thirty years after the discovery that neurons are generated in the adult brain (Altman and Das, in vivo (Feng et al., in silico (Weisz and Argibay, However, two By taking advantage of the rabies virus to retrogradely infect monosynaptic neurons (Wickersham et al., Previous studies show that newly formed synapses between adult-generated dentate gyrus neurons and CA3 pyramidal neurons can compete with or even displace previously-established synapses (See references in Deng et al., Bergami et al.  show thaThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Humans who eat fish are exposed to mixtures of healthful nutrients and harmful contaminants that are influenced by environmental and ecological factors. Marine fisheries are composed of a multitude of species with varying life histories, and harvested in oceans, coastal waters and estuaries where environmental and ecological conditions determine fish exposure to both nutrients and contaminants. Many of these nutrients and contaminants are thought to influence similar health outcomes . Therefore, our understanding of the risks and benefits of consuming seafood require balanced assessments of contaminants and nutrients found in fish and shellfish. In this paper, we review some of the reported benefits of fish consumption with a focus on the potential hazards of mercury exposure, and compare the environmental variability of fish oils, selenium and mercury in fish. A major scientific gap identified is that fish tissue concentrations are rarely measured for both contaminants and nutrients across a range of species and geographic regions. Interpreting the implications of seafood for human health will require a better understanding of these multiple exposures, particularly as environmental conditions in the oceans change. Clupeififormes) . Neverthiformes) , Table 2Interpretation of these results may be complicated by measurement error introduced by differing methods used for fish sampling and analysis, but some broad patterns in the data are interesting. Analysis of published EPA + DHA values found no statistically significant effect of type of habitat , or temperature of habitat, or their interaction on the PUFA content in fish. To visualize the results of ANOVA, a two-dimensional graph of the PUFA content in the groups of species was created . Since ESardinops sagax from temperate waters, shad Hilsa macrura from warm waters and herring Clupea harengus from cold waters were all similar    studies in a Norwegian lake, the selenium to mercury molar ratio was a better predictor of trout metallothionein levels than was either selenium or mercury (Sørmo et al., et al., et al., et al., et al., et al., et al., et al., et al., There is a long-running interest in nutrient-toxicant interactions between mercury and selenium (Ganther et al., et al., et al., et al., In recent years due to the interest in selenium to mercury molar ratios, a number of studies have assessed mercury and selenium concentrations and the selenium to mercury molar ratios for a variety of fish species from field samples as well as fish purchased from supermarkets (Burger et al., et al., et al., et al., et al., et al., In general, studies of selenium to mercury molar ratios have found that mercury concentrations were positively related to fish length and trophic level but selenium concentrations were not, and selenium to mercury molar ratios are more strongly related to mercury content than selenium content (Karimi et al., et al. (et al., Recent research is beginning to address the need to quantify the overall nutritional and toxicological value of different types of fish and shellfish based on concentrations of multiple nutrients and contaminants in edible tissues. A recent study found unique, relative concentrations of mercury, omega-3 fatty acids, and selenium, or mercury-nutrient signatures, across seafood taxa et al., . Specifi, et al.  found th et al., . Future et al., et al., et al., et al., et al., et al., et al., et al., Advice describing both the types and amounts of seafood consumption, while complex, is necessary to better manage risks and benefits of seafood consumption (Oken et al., et al., et al., To conduct appropriate human health risk assessment for contaminants such as mercury requires an understanding of how mercury, fish oils and selenium co-exposures affect the human body. This work can be informed by studies from marine biology and fisheries science, coupled with epidemiological biomonitoring, anthropological and food science investigations into the role of culinary preparation and gut processing on mercury and nutrient bioavailability (Laird et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Our current ability to properly estimate the risks and benefits to humans of seafood consumption are hampered by the common approaches of separately studying either contaminants or nutrients in fish. To date there are few studies in which fish tissue concentrations have been measured for both contaminants and nutrients across a range of species and geographic regions, even for the restricted set of chemicals considered in this review. There is tremendous variability between and within fish species in their mercury, EPA and DHA concentrations, leading to different versions of the ‘fish intake’ exposure across participants in epidemiological studies (Greenland & Robins,


One strand of evidence comes from Proffitt, who has shown that changing a person's ability to act affects how they judge their ability to perform an upcoming task. The most famous example  mentally simulate things they doWe do this simulation ahead of time, in anticipation of an encounterThis simulation will require more effort with out-group members, because they do things differently to youThis increased simulation effort will affect your judgment of distance, as per ProffittTherefore out-group members should look further awaySoliman et al.  applied The results seem promising; for example, American and Arab participants who rated themselves with an interdependent self-construal did rate their in-group members as closer than did participants with an independent self-construal. Soliman et al. argue that these results support an analysis of culture within Proffitt's embodied framework, which would be interesting if true because it would let us talk about both perceptual and cultural effects within a unified framework.There is a major problem, however. Proffitt's research very clearly shows that increasing the effort required to perform a task only affects distance perception related to that task. For example, making walking harder by fatiguing the legs increases the perceived distance if you plan to cross it by walking, but not if you plan to cross it by throwing (Witt et al., Task specificity is central to Proffitt's theory. In a recent debate, Firestone  highlighonly way in which a friend could help make a hill look more climbable is by doing something that recalibrates the embodied hill-climbing system. Discovering what this something is would be an invaluable contribution to the unification Soliman et al. propose, but it remains to be done.Soliman et al. rest their non-task-specific analysis on one paper (Schnall et al., Soliman et al.  claim thThe current data (plus Schnall et al., I am personally all in favor of an embodied approach to unifying psychology, but as I have argued (Wilson and Golonka, The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Recent, primarily technology-based advances in microbial ecology have opened an immense treasure chest of microbial diversity that has been observed in the vast majority of all investigated habitats. Additionally, habitats which were assumed to be sterile for a long time are now known to be colonized by diverse microorganisms; e.g. within the placenta and stomach of humans or reproductive organs of plants. Through the implementation of new techniques, deeper insights into the structure of microbiomes mainly by amplicon sequencing and microscopy have been gained. Now the current focus of research is on analysis of their function implementing meta-(genomic/epigenomic/transcriptomic/proteomic) techniques. The management of the accumulated metadata and the gleaning of new information is the challenge we are facing, but that challenge will be solved in the near future Jansson, . By looket al., et al., Enterobacteriaceae play a substantial role within the vegetable microbiome ; however, the microbiome in/on our diet opens many more potential insights into the complex interactions. A third example is the indoor microbiome, which has enjoyed enormous attention during the last years due to the fact that we spend most of our time in built environments. The indoor microbiome is also a mixture of variably fixed niches such as bathtubs, kitchen sinks, furniture etc., as well as more moving carriers of microbiomes including the inhabitants (humans and pets), outside air and also of plants (indoor plants as well as outside vegetation). Although we know who contributes to the composition of the indoor microbiome, we don't know how those influences affect the function of the microbial ecosystem. The indoor microbiome is also strongly shaped by cleaning procedures. Can indoor plants and their microbiome positively contribute to human health? Is there an optimal rate of microbial turnover and exchange? All these questions can be answered by studying the shared fractions of microbiome or ‘microbiome connections’. In the three microbiomes presented above, organisms of all domains of life, archaea, bacteria and eukaryotic microorganisms interact to fulfill ecosystem functions. Most of the published studies so far focused only on one microbial group, and therefore it is necessary to make a short note on the interplay between microorganisms from different kingdoms. Recent research has shown that there is a lot of interaction between members of the different groups; e.g. bacteria and fungi interact in the broad range between symbiosis and antagonism (Frey-Klett et al., In recent decades, deeper insight into many aquatic and terrestrial microbial communities was gained using omics approaches. Although this is now possible, considerable time must be invested in the future in order to assemble all pathways and understand the interactions within microbiomes Jansson, . In contet al., et al., et al., Sphagnum mosses, stress protection is identified as the main function (Bragina et al., et al., The control of microbial growth is an important area of microbiology, which resulted in significant advances in agriculture, medicine and food science. Biological control is an environmentally sound and effective means of reducing pathogens and pests and their symptoms through the use of natural antagonists or enemies. While in the past mainly single organisms were used, often correlated with inconsistent effects, it is now possible to develop predictable microbiome-based biocontrol strategies (Berg Looking even further ahead, I see the continued development and implementation of ABTs and advanced biocontrol products like pro-, pre- or synbiotics containing synergistic microbial consortia or those which induce specific beneficial microbiomes that will contribute to the maintenance and enhancement of microbial diversity for plant and human health and for our environment. The idea to restore the ‘missing microbes’ Blaser,  is not o


Boea hygrometrica  regulatory genes involved in dehydration stress responses. Moving into resurrection plants we were fortunate to have received such a comprehensive review by Dinakar and Bartels  covering five continents, almost six, although unfortunately we did not quite get there. We were certainly incredibly fortunate for the kind responses of colleagues in Africa (Berjak and Pammenter,  Bartels  of the v Bartels  have dona et al. . The auta et al.  show thaMedicago truncatula, a seed model system, by Terrasson et al. (S. stapfianus, to buttress their hypotheses on how senescence may be differentially activated and suppressed in resurrection plant evolution. The first sequenced genome of a resurrection plant, the Chinese B. hygrometrica (reviewed here by Mitra et al., at the end of the beginning” in our quest to understand the remarkable biological secrets of these fascinating plants.Farrant and Moore  proposedn et al. . This won et al.  and procn et al.  on the rThe 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.


Most studies of plant viruses have focused on the acute viruses that cause disease in crop and ornamental plants. These viruses are transmitted horizontally, often by insect vectors, and are occasionally transmitted vertically. Although known for at least four decades, the persistent viruses of plants are very poorly studied. These viruses were previously called “cryptic” because they did not appear to illicit any symptoms in infected plants  RNA genome, based on their RdRp, and encode a large polyprotein that does not have any apparent coat protein, but encodes a number of additional domains that appear to be derived from diverse sources  RNA genomes, and encode only an RNA dependent RNA polymerase (RdRp) and a coat protein. Of the well-characterized persistent plant viruses, those in the Viruses of fungi have very similar lifestyles to plant persistent viruses, and several virus families are shared between plants and fungi. Phylogenetic evidence indicates that virus transmission has occurred within and between the two kingdoms (Roossinck, Cryphonectria hypovirus 1 that suppresses the disease phenotype of the chestnut blight fungus led to a search for other examples that could be exploited to mitigate the effects of plant pathogenic fungi .Deep sequencing is proving to be a useful technique for just about everything these days, and the methods have been applied to metagenomic studies of viruses. Unlike studies of other microbes, viruses cannot be analyzed through the use of any universal conserved sequences or motifs, and a variety of techniques have been employed to enrich for viral nucleic acids before sequence analysis. Studies in aquatic viruses have been reported for a number of years (Angly et al., Different methods of detection have yielded different levels of persistent viruses. Use of dsRNA-enriched samples yielded very high levels of persistent viruses in plants (Roossinck, Virus discovery in fungi is very limited. Most analyses have been done on fungi of economic importance such as plant pathogenic fungi. A survey of viruses from endophytic fungi derived from two plant species in a wild plant community indicated that the diversity of viruses in this system was much greater than the diversity of fungi, which was in turn much greater than the diversity of plants (Feldman et al., In most cases of fungal virus studies, viruses have been discovered from cultured fungi. This eliminates the majority of fungi, which are not culturable (Blackwell, Partitviridae and the Endornaviridae are recognized by the International Committee for the Taxonomy of Viruses (King et al., Totiviridae and Chrysoviridae families that traditionally are considered fungal viruses (Roossinck, Sclerotinia sclerotiorum was shown to be infectious as a purified virus particle, although it is not clear if this is a mechanism for transmission in nature (Yu et al., Cryphonectria hypovirus (Liu et al., Heterobasdion (Vainio et al., Plants and fungi share several families of viruses. The Heterobasidion species, virus lifestyle was dependent on the fungal environment (Hyder et al., Persistence and high levels of vertical transmission in parasites are correlated with commensal or mutualistic lifestyles (Villarreal, The abundance of persistent viruses in plants and fungi imply functions that may contribute to the biology of the host. Unfortunately we have little ecological data about these viruses, and since they often cause no disease they have not been the subject of intensive study. Data-mining from transcriptomic, genomic and metagenomic studies may allow us to address the true ecological role of these viruses. For example, the partitiviruses have poly-A tails, and may be detectable in transcriptome analyses (Jiang et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Although pathological gambling (PG) is a prevalent disease, its neurobiological and psychological underpinnings are not well characterized. As legal gambling increases in prominence in a growing number of casinos as well as on the internet, the potential for a rise in PG diagnoses warrants investigation of the disorder. The recent reclassification of PG as a behavioral addiction in the DSM-5 raises the possibility that similar cognitive and motivational phenotypes may underlie both gambling and substance use disorders. Indeed, in this Research Topic, Zack et al.  tested tIn this Research Topic, Paglieri et al.  report aVentral striatal activation is thought to be critical for the attribution of incentive salience to reward-related cues. In this Research Topic, Lawrence and Brooks  found thTwo papers in this Research Topic suggest a role for cortisol in modulating incentive motivation in the ventral striatum. Li et al.  demonstrIn this Research Topic, Clark and Dagher  provide The investigation of neural mechanisms underlying PG is currently at an early stage. As emphasized by Potenza  in this 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.


White sharks are highly migratory and segregate by sex, age and size. Unlike marine mammals, they neither surface to breathe nor frequent haul-out sites, hindering generation of abundance data required to estimate population size. A recent tag-recapture study used photographic identifications of white sharks at two aggregation sites to estimate abundance in “central California” at 219 mature and sub-adult individuals. They concluded this represented approximately one-half of the total abundance of mature and sub-adult sharks in the entire eastern North Pacific Ocean (ENP). This low estimate generated great concern within the conservation community, prompting petitions for governmental endangered species designations. We critically examine that study and find violations of model assumptions that, when considered in total, lead to population underestimates. We also use a Bayesian mixture model to demonstrate that the inclusion of transient sharks, characteristic of white shark aggregation sites, would substantially increase abundance estimates for the adults and sub-adults in the surveyed sub-population. Using a dataset obtained from the same sampling locations and widely accepted demographic methodology, our analysis indicates a minimum all-life stages population size of >2000 individuals in the California subpopulation is required to account for the number and size range of individual sharks observed at the two sampled sites. Even accounting for methodological and conceptual biases, an extrapolation of these data to estimate the white shark population size throughout the ENP is inappropriate. The true ENP white shark population size is likely several-fold greater as both our study and the original published estimate exclude non-aggregating sharks and those that independently aggregate at other important ENP sites. Accurately estimating the central California and ENP white shark population size requires methodologies that account for biases introduced by sampling a limited number of sites and that account for all life history stages across the species' range of habitats. Apex predators play an important role in marine community structure through both consumptive and non-consumptive effects on prey Carcharodon carcharias) is one of the largest and most widely known shark species, is cosmopolitan in distribution, and is known to aggregate off the coasts of California, Baja California Mexico, South Africa, New Zealand and southern Australia. While some life history aspects are poorly quantified, their diet The white shark  and State of California endangered species lists. Under the Federal Endangered Species Act, an endangered species is defined as “any species which is in danger of extinction throughout all or a significant portion of its range.” As limited resources are best used in protecting species that are truly at risk of extinction, unwarranted petitions may draw resources away from more deserving species.et al. Orcinus orca: 1145 individuals in the ENP, Gulf of Alaska and Aleutian Islands) and the polar bear , suggesting that healthy white shark populations should be of similar magnitude. Although the comparison to air breathing mammals may be inappropriate, the central California abundance estimate of Chapple et al. et al. Chapple et al.'s et al.'s We therefore revisit Chapple et al. Chapple et al.'s Closed population models fundamentally assume that a population under study does not include birth, death, immigration or emigration over the period of sampling. Although violated routinely in practice, provided these changes occur randomly, only a loss of precision should result, with estimates remaining unbiased et al. Satellite tagging of white sharks at aggregation sites off central California has revealed clear seasonal movement patterns, with sharks present near coastal and insular pinniped rookeries during the fall and swimming to an offshore focal zone or Hawaii in the spring and summer et al. Jorgensen et al. et al.'s Long-term photo identification of five individual sharks at the Farallon Islands from 1987 to 2008 showed that all individuals were absent from data records for periods of 1–9 yrs et al. et al. et al. study.Chapple et al. h model of Otis et al. et al. Therefore, based on their own data, Chapple et al. et al. et al. The technique employed by Chapple et al. et al. Chapple et al. et al. et al. study represents only a sub-sample of central California as they did not sample elsewhere, particularly other known white shark aggregation sites in the region, notably Año Nuevo Island The most serious violation of the assumptions of the models employed by Chapple White sharks are known to enter and leave the sampled aggregation sites during the time that the photo-identification study was conducted, and hence they would not be available for sampling during the purportedly closed sampling periods Recent stable isotope analyses also suggest that some white sharks do not specialize on mammals but instead forage mostly on bony fishes and perhaps squid et al. Several factors we discuss above could have a positive bias resulting in an overestimation of population size , while several other factors could lead to a negative bias resulting in an underestimation of population size . While the net effect of certain biases cannot be determined, our detailed analysis of the assumptions required of the mark recapture model chosen by Chapple We now evaluate the potential numerical effects of the biases associated with the differential residency patterns apparent at those two aggregation sites.et al. et al. Having evaluated the hypergeometric model and assumptions used by Chapple et al. et al. Fearnbach et al. et al. ix, indicating if the individual was alive across five simulated years:et al. itx = 1), then at time t+1 its status was given as a Bernoulli random variable with parameter itφ, the survival probability from time t to t+1. If an individual was not within the population during the previous time steps 1,…,t , then probability of entry into the population between intervals t and t+1 was a Bernoulli trial with parameter γit = 1. For simplicity we assumed a stable population, fixing survival at φit = 0.857 and entry into the sub-population, through birth, at γit+1  = 0.153 ity is the identification history for shark i at time t, ip represents the probabilityof individual i being observed at any given time. These individual probabilities were simulated using conservative detection probabilities drawn from the time-averaged posterior resident and transient distributions of Fearnbach et al. To illustrate the potential bias induced by non-random sampling, we compared the hypergeometric approach of Chapple ru ∼ N for residentstu ∼ N for transientset al. across a range of sub-population mixtures, from all residents to mostly (90%) transients. By simulating across this range of population mixtures we were able to explore the effect of varying proportions of transients on estimates of population size. We consider the parent detection distributions to be conservative because marine mammals must surface to breathe and therefore are expected to be more frequently available for sampling than sharks that do not need to surface at all. Our approach included some probability of death and birth through time, which Chapple Given the presence of both deaths and births in the simulated sub-population, two sources of hypergeometric bias become apparent through time. First, there are high and increasingly positive biases in the estimated number of individuals for sub-populations of residents only, even over two survey years . This ocSecond, because the model cannot distinguish individuals, cumulative hypergeometric sub-population estimates  are consistently low-biased, relative to the discovery curve for the known simulated population . This reet al. study. Such an estimate would require a stratified-random survey that sampled all insular and coastal aggregation sites as well as juvenile and other adult habitats, throughout the region. However, it is feasible to use the Chapple et al. data, accounting where possible for the biases discussed above, to estimate the minimum population required  to account for the estimated number of sharks that visit the Farallon Islands and Tomales Point sites.Our simulation results clearly show the large biases expected in a hypergeometric model given realistic population dynamics for a large, highly-mobile marine predator population. Failure to recognize that sub-populations sampled at a fixed locations include both resident and transient individuals generated downward population biases of between 22–33% in the first two years of sampling when 70% of individuals are transient We now address those calculations using demographic modelling.et al. et al. et al. et al. et al.'s minimum population sizes for all life stages of white sharks whose matures and sub-adults consistently visit these two locations. We do not extrapolate beyond this minimum number to estimate a total population size for white sharks in the ENP as data are lacking.To extrapolate a population estimate for mature and sub-adult white sharks in central California to all life stages in the ENP, Chapple et al.'s et al. et al. et al. 's In extending Chapple et al. et al.'sWe then used natural mortality and life history estimates based on an assumed longevity of 30 years and increased fertility to insure that lambda equaled 1.0, based on life history information in Mollet and Cailliet Demographic analyses are a useful method for estimating population sizes and age distribution, and have been applied to several species of sharks, including white sharks et al. et al. et al. et al. et al. The size-frequency and sex of the sharks sampled by Chapple et al. et al. Chapple et al. The sex ratio of our sample data from Jorgensen We used established demographic methodology et al. et al.'s et al. We then fit the size (age) frequency data for the 130 animals enumerated by Jorgensen et al. Our results demonstrate that Chapple Recent length-at-age estimates of five male sharks from central California and eight sharks from the northwest Atlantic  suggest that growth rates may be much slower than our growth model predicts and that longevity may be much longer  et al.'s et al.'s Our demographic analysis, based on Chapple Formal listing of a species as “endangered” places substantial demands on governments, which must devote considerable resources to protecting listed species, and on segments of the public, who must forgo social and economic opportunities to comply with applicable laws. Consideration and listing of species that are not under the threat of biological extinction may divert resources away from those that are genuinely at risk. It therefore is critical that the best possible information be used in listing reviews to minimize undue burdens and insure that limited resources are applied to recovery of the neediest species. Unfortunately there is considerable incentive for some conservation organizations to quickly support listing species, often after minimal critical scientific review, as listings can be cited as tangible achievements in the effort to preserve the environment and attain other conservation goals.et al. et al. et al. et al. et al. Chapple et al. In stating that the ENP white shark population is small relative to other apex predators such as killer whales and polar bears, Chapple et al. Our new estimate is comparable to white shark population estimates from other locations and, importantly, our estimate is similar to that from a recent independent status review of the ENP white shark population, which estimated ∼3,000 individuals. The status review team had access to virtually all available data from white shark researchers throughout the eastern North Pacific and used multiple modeling approaches A mark-recapture study using photo-ID techniques at two adjacent white shark aggregations in Gaansbi, South Africa resulted in an abundance estimate of 908 (808–1008) sharks. This sub-population abundance is more than three times the Chapple et al. et al. et al. et al. Genetic techniques were used to estimate the effective population size of white sharks off southern Australia at approximately 1,512 individuals Elasticity analyses have typically concluded that juvenile survival exerts the greatest influence on population growth rate of sharks in general et al. minimum estimate for the numbers of predominantly male sharks that annually return to two pinniped rookeries in central California; we suspect, however the estimate of 328 (222–433) from the Chao model et al. Despite the many flaws outlined here, the Chapple


Drug addiction is manifested by a compulsive drive to take licit or illicit substances despite repeated severe adverse consequences  and nitric oxide (NO), followed by the propagation of free radicals that damage cells  has also been studied in animal models of addiction  because they generate oligodendrocytes during early postnatal development (Nishiyama, Oligodendrocytes are cell types responsible for providing myelin for rapid propagation of action potentials Nave, . The brain utero (Cao et al., At present, there is very little information available on the potential effects of drugs of abuse on oligodendrocytes. For example, Lin et al.  used a 3Animal studies have also revealed certain white matter abnormalities after extended cocaine use. For example, George et al.  investigThese animal studies are consistent with the suggestion that myelin dysfunction might account for some of the deficits in white matter integrity described in studies of humans addicted to various substances (Cadet et al., Microglial cells are the immune cells that reside in the brain parenchyma (Sierra et al., In addition to their toxic effects, microglia can alter neuronal excitability by affecting both inhibitory and excitatory synaptic transmission (Sierra et al., Addiction of licit and illicit substances can be viewed as maladaptive plastic responses to exposure to agents that impact the expression of various genes and proteins in the brain. Some of these proteins are known to be involved in developmental processes that are dormant during adulthood Cadet, . Drug-inThe 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.


Environmental Health Perspectives, James et al. reported that life-time exposure to low levels of inorganic arsenic in drinking water was associated with increased risk of coronary heart disease (CHD). The study was well performed and reported, except for the omission of two possible confounders related to an individual’s drinking water—magnesium content and total hardness.In a recent issue of Several studies worldwide have demonstrated a relationship between low levels of magnesium in drinking water, or softness, and an increased risk of death from myocardial infarction . A recen


Autophagy is a major cellular degradation pathway in which materials are delivered to the vacuole in double-membrane vesicles known as autophagosomes, broken down, and recycled (Li and Vierstra, Several contributions to the Research Topic address the emerging concept of selective autophagy, well established in animal cells but only described recently in plants. Zientara-Rytter and Sirko  in a resArticles also discuss the selective autophagy of cellular organelles. Lee et al.  review rVeljanovski and Batoko  also disAuxenochlorella protothecoides in a research article. They analyze lipid droplet degradation and show that while macroautophagy is induced during the heterotrophic to autotrophic transition, lipid bodies are degraded in the vacuole by a microautophagy-like mechanism. Hanamata et al. (The degradation of lipid droplets by autophagy-related mechanisms is also a theme of the Research Topic. Zhao et al.  study tha et al.  discuss a et al. , as breaFinally, Ren et al.  review tThis collection highlights some of the recent advances in our understanding of plant autophagy and its role in numerous physiological processes and we hope that it will stimulate further discussion and research into this exciting topic.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.


To ensure the addition of only high quality scientific works to the field of scholarly publication, paper [We have been made aware that text, figures and experimental data reported in the title paper  are duplet al. . At the et al.  had alren, paper  is retra


This commentary on the articles published in the special section on the developmentand implementation of measurement feedback systems (MFSs) discusses three challenging themes in the process of MFS implementation: design and planning,organizational context, and sustainability and unintended consequences. It is arguedthat the implementation of MFSs is complex, but is an important step in improving outcomes in routine care for children and young persons. In the past decade, the implementation of measurement feedback systems (MFSs), also referred to as progress feedback or (routine) outcome monitoring, has taken a leap worldwide. Several countries have mandated the use of MFSs as part of routine care , and in other countries large public or private initiatives exist . By using an MFS, the client’s progress in treatment is tracked by frequent administration of standardized measures. The MFS supports the clinician in deciding to adapt treatment when insufficient progress has been made. There are several feedback systems available , and by now MFSs have been introduced in a variety of settings , populations  and disorders  (Bickman et al. The first implementation theme is the design and planning of the introduction of the MFS. The way Dixon-Woods et al.  define tThe design of the MFS is another important factor within this theme. MFS design has been discussed in detail in several of the articles in this section (Bruns et al. The second theme that Dixon-Woods and colleagues address is organizational and institutional contexts, professions, and leadership. This is an important theme in the articles in this special section. Both Nadeem et al. and Gleacher et al. conclude that higher organizational and leadership support improved implementation of the MFS. Interviews with clinicians in the article by Bickman et al. shed a light on what type of support was particularly helpful: on-site implementation support, and having a local champion in using the MFS. These results are in line with the conclusion of Aarons et al.  that leaThe third theme mentioned by Dixon-Woods et al.  refers tThe issue of unintended consequences is a complex one. Research on the efficacy of MFSs has predominantly taken place in adult populations. To my knowledge, in youth mental health care only two randomized controlled studies have been conducted (Bickman et al. A different class of potential unwanted effects has to do with forming partnerships with the industry. Modern MFSs have become so technologically complex and costly that researchers often need to form partnerships with software developers in order to be able to develop a MFS (as for example was done by Bruns et al. The articles in this special section teach us that the implementation of MFSs is a complex process in which many challenges need to be faced. They also show us good examples of successful implementation processes or creative solutions to challenges faced, which will be extremely helpful to future implementers of MFSs. The implementation of MFSs in routine care has the potential to improve outcomes for large groups of future clients. This is especially important, given that the effect sizes of interventions in routine care are much smaller than those found in clinical trials (Hansen et al.


In humans, the only known inducer of VEGF111 is DNA damage but its natural presence in the uterus of the viviparous lizard, Saiphos equalis, suggests other mechanisms of regulation. Most interestingly, the possible relationship between the evolution of viviparity and the associated increased risk in developing cancer may be important in understanding the mechanisms underlying tumor development.Vascular endothelial growth factor is a secreted glycoprotein that acts on endothelial cells to induce developmental and physiological angiogenesis. It has also been implicated in angiogenesis occurring in several pathologies, most notably, cancer. Alternative splicing of VEGF mRNA transcripts results in several isoforms with distinct properties depending on their exon composition. Recently, a new isoform has been identified, VEGF Angiogenesis is a crucial process during tumor growth, invasion and metastasis for the rapid development and maintenance of a blood supply to developing tumors , a major mitogen that acts selectively on ECs to stimulate angiogenesis  and resveratrol (a phenol produced by some plants) inhibit VEGF111 production (Munaut et al., While hypoxia and hypoglycemia induce VEGF expression by increasing the stability of the mRNA transcript (Stein et al., in vivo, indicating its importance in tumor angiogenesis. Several anti-VEGF therapies have been developed as cancer treatments, some showing success in improving survival rates (review by Jain et al., Angiogenesis is critical in the growth of solid tumors, as a tumor cannot grow beyond a size of 2 mm without its own vascular support (Gimbrone et al., An issue that has recently emerged is the detrimental effects of VEGF inhibitors on treatment progression, particularly regarding increased malignancy and metastasis (Paez-Ribes et al., 111. Genotoxic drugs such as campothecin and mitomycin C, both of which induce VEGF111 production, are common chemotherapeutics, and thus it is possible that the production of VEGF111 during cancer therapy increases drug resistance (Mineur et al., 111 in angiogenesis and EC activation may provide a significant contribution to understanding this process.Genetic mutations, such as those caused by UV-B radiation and genotoxic drugs, are a major cause of cancer, resulting in abnormal cellular functions (Brash et al., 111 are poorly vascularized in comparison to tumors expressing other isoforms. However, the vessel density in the surrounding tissue is highest in the VEGF111 tumors compared to all other isoforms tested, which have significantly lower vessel density (Mineur et al., 111 to freely diffuse from its point of secretion because it is not restricted by extracellular matrix binding. VEGF111 has a longer half-life compared to VEGF165 and so its actions remain active for longer (Mineur et al., 111, would result in both a highly vascularized tumor and surrounding tissue, potentially increasing the ability to metastasize.When nude mice are injected with cells expressing equal concentrations of different VEGF isoforms, the vascular structures differ. Tumors expressing VEGF145 (Poltorak et al., 162 (Lange et al., 145 lacks exons 6b and 7, and is secreted primarily from cancer cell lines derived from the female reproductive system (Poltorak et al., 162 only lacks exon 7 and is secreted by ovarian carcinoma cells (Lange et al., in vitro and in vivo and their biological activity is similar to the other isoforms (Lange et al., 111 however, is that they still encode the site of plasmin cleavage, and thus lose their biological activity upon exposure to plasmin. Further investigation in mammalian cancers is necessary, however the presence of VEGF111 primarily in reproductive tissues of S. equalis raises questions whether this isoform may also be present in human reproductive tract cancers.Other VEGF isoforms have been identified in transformed cells including VEGFThere are similar molecular mechanisms between how tumors invade and metastasize compared to the trophoblastic invasion in hemochorial placentation that occurs in humans, particularly regarding angiogenesis (Murray and Lessey, 111 as both a potential stimulator of angiogenesis in mammalian tumors (Mineur et al., S. equalis during pregnancy (Murphy et al., S. equalis is transitioning between egg laying and giving live birth with a placenta (Stewart et al., 111 in EC biology may lead to a better understanding of this susceptibility.The discovery of VEGF111 could also be used as a potential therapeutic agent to increase vascularization in ischemic diseases and lesions. The presence of plasmin in chronic wounds results in rapid VEGF cleavage (Lauer et al., 111 to resist this degradation has recently been exploited to improve ischemia and wound healing (Labied et al., 111 to induce rapid angiogenesis and rapid EC proliferation compared to the other isoforms, which results in the earlier formation of a functional vasculature and blood supply to the ischemic region (Labied et al., 111 is necessary, but the initial data are promising.The high angiogenic activity of VEGF111 is an important advance in understanding the mechanisms by which tumors develop their dedicated blood supply and is critical in their ability to grow and metastasize rapidly. While there are several isoforms of VEGF, VEGF111 is the only isoform to resist proteolytic degradation and may provide further insights into the pathogenesis and treatment of diseases that are dependent on angiogenesis. Future work on this molecule should be directed at understanding the mechanisms underlying angiogenesis and has great promise in developing new therapeutics to target tumorigenesis and to treat ischemic diseases. This should involve examining the actions of VEGF111 on EC biology and its capacity to facilitate the formation of functional vessels in several models to specifically address its role in angiogenesis. This should encompass its actions in cancer, both as a potential contributor to metastasis during disease progression, and drug resistance during disease treatment. Further investigation should also expand on the previous work that focused on VEGF111 as a therapeutic agent. Its presence in the uterus of pregnant lizards provides a unique way to understand those mechanisms.VEGF plays a crucial role in normal developmental and embryological angiogenesis as well as contributing to the progression of several pathological conditions. The discovery of VEGFThe 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.


Understanding the human gut microbiota has garnered interest from researchers and clinicians to pharmaceutical companies looking at novel mechanisms to manipulate the microbiota for the benefit of the host. Studies on the gut microbiota can be loosely characterized into three areas that include investigating the microbiota's role in the physiology of the healthy gut, in the establishment of gastrointestinal disease, and in extra-intestinal manifestations. With deep sequencing technologies now in routine use in the research environment, novel members of the gut microbiota are coming to light, and our understanding of this complex ecosystem and its relationship to the host is slowly improving.Erysipelotrichaceae, which belongs to the Firmicutes phylum, in host physiology and/or disease are on the rise. However, more often than not, these organisms are mentioned in passing, despite the fact that members of this bacterial family appear to be highly immunogenic and can potentially flourish post-treatment with broad spectrum antibiotics  or animal models of IBD have also been observed; however, the evidence does not appear to be consistent -like transmural inflammation , these mice developed a more severe colitis upon treatment with dextran sodium sulfate than mice colonized by an IgA-negative consortium of bacteria  in diet-induced obese animals (Turnbaugh et al., Erysipelotrichaceae in obese individuals (Zhang et al., Erysipelotrichaceae taxa in a hamster model of hypercholesterolemia treated with an extract to improve cholesterol homeostasis (Martínez et al., Erysipelotrichaceae to respond differently to diet or host health phenotypes (Zhang et al., Erysipelotrichaceae in mice on high-fat or western diet (Fleissner et al., Perhaps the strongest evidence for a role for Erysipelotrichaceae and host cholesterol metabolites (Martínez et al., Erysipelotrichaceae (Etxeberria et al., More recently, in an important study examining the microbiota of hamsters whose cholesterol metabolism was modulated using dietary plant sterol esters, Martinez and colleagues provided strong evidence for a correlation between the levels of Erysipelotrichaceae. Harris and colleagues identified an accumulation of a specific taxon within Erysipelotrichaceae in mice with liver injury associated with parenteral nutrition, and observed a marked reduction in liver injury also corresponding to a decrease in the abundance of the same Erysipelotrichaceae taxon following antibiotic treatment (Harris et al., Erysipelotrichaceae corresponded to the soy oil based-lipid emulsion from the parenteral nutrition solution (Harris et al., Nutrition studies further support the influence of dietary fat on the abundance of Erysipelotrichaceae in CD patients undergoing low-fat (~13.5 g/1000 Kcal; Nahidi et al., Erysipelotrichaceae levels in IBD patients are likely to be associated with patient lipid or cholesterol phenotypes and/or patient diet, but may still have a significant impact on disease presentation and/or activity (Figure In support of these findings, our group has recently observed a decrease in the abundance of Erysipelotrichaceae and host lipid metabolism, warranting additional investigation into the metabolic profiles of these organisms, and the influence they have on the host. Partial loss of fatty acid biosynthesis has been reported in the genomes of some members of Erysipelotrichaceae (e.g., Erysipelothrix rhusiopathiae; Kwok et al., Erysipelotrichaceae may be correlated to inflammation (Dinh et al., Erysipelotrichaceae have on the host are required.Taken together, there is strong evidence supporting an association between NK conceived the idea and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Although perceiving the passage of time is a basic building block of cognitive processes and behavior such as expecting relevant events to happen, the neural underpinnings of interval timing are not well-understood as yet  at the interval onset which is not predicted by the SBF. However, the fluctuations in beta power, which are likely driven by dopamine levels in cortico-striatal circuits, may reflect mechanisms involved in interval timing (Kononowicz and van Rijn, There are some arguments worth considering in conjunction with the proposed interpretation of the theta effects. Firstly, as theta modulation is typically associated with memory Ward, , the obsParker et al.  also anaThe next consideration relates to the range of oscillatory power that was analyzed. Note that although Parker et al.  acknowleInterestingly, the theta effects reported by Parker et al.  also havIn conclusion, the study by Parker et al.  providesThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


However, there are occassions in which evolution follows a sort of cycling process. Each time an organism is confronted with a given selective situation, it follows a similar evolution path. However, once the selection pressure is resumed, the organism is outcompeted by non-evolved partners and the evolved lineage disappears. This type of process has been dubbed as “short sighted evolution”  resides in ancient prey/predator relationships , most patients are infected by independent P. aeruginosa clones as the Liverpool strain , just by chance. Evolution during chronic infection allows the adaptation required to persist inside the infected host. However, this happens at the cost of de-adapting for growing in the original habitat, including resistance to natural predators (Friman et al., Short-sighted evolution is a common process in the evolution of microorganisms and has been explained in the frame of a source-sink situation (Sokurenko et al., P. aeruginosa shows that there are common evolution patterns among isolates producing chronic infections. Nevertheless, these mutations are rarely fixed (with the exception of some epidemic clones Yang et al., We can then conclude that while the acquisition and loss of genes are at the roots of the speciation of “professional” pathogens, speciation toward virulence is not necessarily required for bacterial opportunistic pathogens. This does not mean however these pathogens do not evolve for a better adaptation for growing in the human host. Indeed, the study of The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Escherichia coli (ETEC) is a water and food‐borne pathogen that infects the small intestine of the human gut and causes diarrhoea. Enterotoxigenic E. coli adheres to the epithelium by means of colonization factors and secretes two enterotoxins, the heat labile toxin and/or the heat stable toxin that both deregulate ion channels and cause secretory diarrhoea. Enterotoxigenic E. coli as all E. coli, is a versatile organism able to survive and grow in different environments. During transmission and infection, ETEC is exposed to various environmental cues that have an impact on survivability and virulence. The ability to cope with exposure to different stressful habitats is probably shaping the pool of virulent ETEC strains that cause both endemic and epidemic infections. This review will focus on the ecology of ETEC in its different habitats and interactions with other organisms as well as abiotic factors.Enterotoxigenic  Presence of ETEC in rivers, drinking water and in irrigation water has been shown  biofilm formation on sprouts and tomato roots grown in water  transcripts increase over time when ETEC are incubated in water . CsrA controls a large variety of physiological processes such as central carbon metabolism, motility and biofilm formation and has been linked to survival . DsbA is involved in the assembly of the mature LTAB5 holotoxin . Interestingly, ETEC expressing STp in combination with CS6, are significantly associated to diarrhoea in adults, and STp is induced in the presence of bile , which is involved in the secretion of LT toxin . Is has also been suggested that oligosaccharides have structures that resemble the binding sites of pathogenic bacteria and hence may hinder adherence and subsequent disease (Kunz et al., Mucins also contain oligosaccharide moieties. There is increasing evidence that oligosaccharides and glyco‐conjugates present in breast milk and on mucins might affect virulence‐related abilities of pathogenic microorganisms (Pacheco and Sperandio, et al., et al., et al., et al., et al., et al., Bifidobacteria. The genera Bifidobacterium and Lactobacillus have been used as probiotics and have been implicated as protective against gastrointestinal pathogens. Lactobacilli were found to protect against Shigellosis (Lindsay et al., In vitro assays also indicated that Lactobacilli inhibits ETEC (Tsai et al., The human gastrointestinal tract harbours a diverse microbial community, which constitutes the microbiota. The microbiota is important for metabolic functions such as production of vitamins, metabolites and short chain fatty acids (den Besten et al., Proteobacteria increased in malnourished children while Bacteroidetes decreased. Particularly the Proteobacteria genera Escherichia and Klebsiella increased in the malnourished children although they did not display signs of diarrhoea. A recent study observed reproducible changes in the microbial community structure after ETEC and cholera infection. The authors found that diarrhoeal infectious species more or less could dominate the microbiota early in the infection. Re‐colonization of facultative anaerobic bacteria that metabolize oxygen introduced to the intestinal system through the diarrhoea then has to occur before the normal commensal obligate anaerobes can begin re‐colonizing the gut. Interestingly, a transient peak of Bacteroides was observed when the patients started to recover 7–10 days after acute infection and the microbiota was restored to normal diversity and structure after 1 month (David et al., Diarrhoea affects the poor and malnourished population in low‐income countries and poses a particular risk of morbidity and mortality for children. Healthy Bangladeshi children had a higher diversity of gut microbiota than malnourished children (Monira Giardia lamblia and ETEC were found to increase symptoms in children in Ecuador (Bhavnani et al., Giardia is contradictory, its immunomodulating properties have been linked to protection although epidemiological studies have clearly defined it as a pathogen (Solymani‐Mohammadi and Singer, Giardia in higher frequencies in asymptomatic children (Kotloff et al., E. coli population could be dominated by a single clone of ETEC in some individuals, while co‐infections of several ETEC clones were observed in other patients (Sahl et al., In addition, the interaction of several pathogens present might either enhance or decrease disease. Co‐infections of rotavirus, E. coli causing disease in humans have a tropism for the human intestine through the expression of colonization factors specific for human receptors. Enterotoxigenic E. coli is however also a zoonotic disease affecting piglets and calves, and most of the studies on ETEC gut ecology has been performed in piglets due to the economic impact of diarrhoeal deaths in weaning piglets. Porcine ETEC is responsible for neonatal and post‐weaning diarrhoeal infections (Berberov et al., et al., et al., et al., Enterotoxigenic Enteric microorganisms such as ETEC exist in two different environments, the environment outside of the human host where they survive and the gastrointestinal tract of the host where they cause infection  Fig. . In the We conclude that a more comprehensive understanding of the pathogenesis of ETEC bacteria in different ecological niches generates important information that can be exploited towards developing methods of controlling infection. Vaccines, oral rehydration solution and antibiotics are commonly used to prevent and treat diarrhoeal diseases, but it is evident that other factors such as diet, food additives and probiotica/microbiota might be able to modify, or even prevent, serious disease. The impact of the bacterial microbiota on ETEC in water and food environments has not yet been addressed at all to our knowledge but could potentially generate means to inhibit transmission pathways. Studies on ecological niches and their influence on survival and virulence of ETEC are therefore important in the continuing fight against diarrhoeal diseases.


In their paper, Baas et al. , take thThe authors did not mention the precise location of the stimulation contact, but previous work from the same group allowed us to piece together a more detailed view of the actual stimulation site. While the distal lead tip was implanted in the nucleus accumbens, the active contact was located in the ventral part of the anterior limb of the internal capsule (ALIC)  the stria terminalis, it is clear that the ALIC is a complex collection of fibers with various destinations (Lehman et al., Note that, if one would actually stimulate the human BST, this might produce various, and even contrasting effects, such as an overall decrease of anxious mood and associated somatic symptoms (as indexed by the Hamilton Anxiety Rating Scale in the DBS for OCD study Baas et al., Recently, major progress has been made in untangling the neuronal circuits of the BST using optogenetics, which allows for very precise manipulation of specific neuronal populations (Deisseroth, The optogenetic approach will undoubtedly continue to deepen our understanding of the BST, as it enables us to parcel out the roles of certain subdivisions or even cell types in the BST (Sparta et al., Apart from these neuroanatomical concerns, we feel that Baas and colleagues could have increased their chance of finding an effect of DBS on context conditioning by promoting the presumed BST activation with their behavioral paradigm. Most evidence for a role of the BST in contextual anxiety comes from animal research (Sullivan et al., In the real world, anxiety-evoking events occur in a complex environment that consists out of multiple stimuli and engages all our sensory modalities (Huff et al., As mentioned above, Baas et al.  providedRegarding the timing of acquisition and expression, it is noteworthy that in rodent context conditioning, training and testing usually take place on 2 days. Due to practical concerns, however, human conditioning experiments are often carried out in one session (but see Huff et al., We acknowledge the financial support of the Medtronic Chair for Stereotactic Neurosurgery in Psychiatric Disorders at KU Leuven.


Approaches to treating autism often emphasize the use of intensive training to gradually improve behavior. Harris et al.'s  recent rHistorically, the effects of ASD on learning mechanisms have received much less attention than its effects on social competence, despite the fact that the behaviors most diagnostic of ASD all depend heavily on generalization of past learning (Dawson et al., Harris et al.  discoverWhile the results reported by Harris et al.  clearly Past studies of perceptual learning in TD adults (Ahissar and Hochstein, Harris et al.  highlighEM developed the critique and wrote the initial commentary, BC developed the critique and edited the initial commentary, AS did background research for the commentary, evaluated the critique, and edited the commentary.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.


De novo assembly of a complete transcriptome without the need for a guiding reference genome is attractive, particularly where the cost and complexity of generating a eukaryote genome is prohibitive. The transcriptome should not however be seen as just a quick and cheap alternative to building a complete genome. Transcriptomics allows the understanding and comparison of spatial and temporal samples within an organism, and allows surveying of multiple individuals or closely related species. De novo assembly in theory allows the building of a complete transcriptome without any prior knowledge of the genome. It also allows the discovery of alternate splice forms of coding RNAs and also non-coding RNAs, which are often missed by proteomic approaches, or are incompletely annotated in genome studies. The limitations of the method are that the generation of a truly complete assembly is unlikely, and so we require some methods for the assessment of the quality and appropriateness of a generated transcriptome. Whilst no single consensus pipeline or tool is agreed as optimal, various algorithms, and easy to use software do exist making transcriptome generation a more common approach. With this expansion of data, questions still exist relating to how do we make these datasets fully discoverable, comparable and most useful to understand complex biological systems? With the advent of Next Generation Sequencing (NGS) technologies and improved extraction methods to accurately purify RNA from smaller amounts of tissue or even single cells  within a cell including protein-coding and non-coding RNAs. Additionally, the transcriptome encompasses all alternative splice forms, alternatively polyadenylated, and RNA-edited transcripts. Together, these reflect the genes that are actively expressed in a particular tissue  assembled, summed contig length, mean transcript length, N50 value, and the proportion of reads that could be mapped back to the assembled transcripts  tool by Parra et al. , are available but are currently relatively slow or computationally intense to use. Another consideration for the annotation process is searching for repeat elements using programs such as RepeatMasker (http://www.repeatmasker.org) or the Tandem Repeats Finder , European Bioinformatics Institute , and DNA Data Bank of Japan . There are support pages and handbooks to help with submitting data, and these are available at the NCBI, EBI, and DDBJ websites. As well as raw sequence data, alignment files in BAM (Li et al., Whilst most journals require raw sequencing reads to be made publicly available in a database such as the Sequence Read Archive (SRA; Kodama et al., de novo transcriptome data (Mariette et al., de novo transcriptome data (Lesur et al., RNAbrowse is an alternative package with a web interface that can be used to store and visualize de novo transcriptome assembly data, where both BLAST and keyword searches can be performed. Another research group released their axolotl read and transcriptome assembly data on a website with a keyword search facility (Stewart et al., Apart from more complete packages such as afterParty and RNAbrowse, there are limited tools with web interfaces that are available for analysis of transcriptome data. CBrowse (Li et al., de novo transcriptome assembly is an important tool in the bioinformatician's arsenal. Whilst rapid progress in single molecule sequencing is being made, it is currently not mature and so assembly, annotation and assessment of transcriptomes from relatively short reads will continue to be essential. To make these methods truly useful, assemblies that are accurately assembled and annotated are essential, but also the availability and openness of assembled transcriptomes not simply raw data must become expected practice.As the desire to catalog and compare the varied transcriptomes of complex organisms continues, JM, AI, and RE wrote the paper, prepared figures, and reviewed drafts of the paper.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.


Peptidoglycan performs the essential role of resisting turgor in the cell walls of most bacteria. It determines cell shape, and its biosynthesis is the target for many important antibiotics. The fundamental chemical building blocks of peptidoglycan are conserved: repeating disaccharides cross-linked by peptides. However, these blocks come in many varieties and can be assembled in different ways. So beyond the fundamental similarity, prodigious chemical, organizational and architectural diversity is revealed. Here, we track the evolution of our current understanding of peptidoglycan and underpinning technical and methodological developments. The origin and function of chemical diversity is discussed with respect to some well-studied example species. We then explore how this chemistry is manifested in elegant and complex peptidoglycan organization and how this is interpreted in different and sometimes controversial architectural models. We contend that emerging technology brings about the possibility of achieving a complete understanding of peptidoglycan chemistry, through architecture, to the way in which diverse species and populations of cells meet the challenges of maintaining viability and growth within their environmental niches, by exploiting the bioengineering versatility of peptidoglycan. Peptidoglycan is a component of nearly all bacterial cell walls and has a variety of functions. It is a huge single molecule (sacculus) surrounding the cytoplasmic membrane, and as such it enables the cell envelope to resist the turgor resulting from the difference in composition between the cytoplasm and the external environment. Furthermore, peptidoglycan is the anchoring point for proteins and other polymers. Another common function is interaction with a host: fragments of peptidoglycan shed by commensal or pathogenic bacteria being recognized by the immune system. The observed characteristics of peptidoglycan  are the result of a series of possible reactions which can occur both in the cytoplasm and in the cell wall itself Fig. A.N-acetylglucosamine and N-acetylmuramic acid carrying short peptides  and perpendicular (much like the later scaffold model) models were first articulated in the early 1970s  of negatively stained nds Fig. B, or bronds Fig. C, led toS. aureus, suggesting a far more complex and heterogeneous arrangement of peptidoglycan than had been proposed previously  population of bacteria, digested with an enzyme, reduced and pumped through a column which separates the resulting fragments based on their chemical properties with a strong emphasis on hydrophobicity /all muropeptides)] and glycan strand length. A range of cross-linking degrees have been measured for a variety of et al., et al., et al., et al., E. coli, average strand lengths between 18 and 60 disaccharides have been reported  was applied to measure strands  the addition of the pentaglycine ‘branch’ by three Fem-type amino acid transferases that are critical, as S. aureus is unable to form direct cross-links between the peptides  which are flipped from the inner to the outer leaflet of the cytoplasmic membrane . The action of these enzymes results in further muropeptide diversity.Typically the initial cross-linking reaction liberates the terminal D-alanine of the donor molecule creating a penta-tetrapeptide containing dimer, a penta-tetra-tetrapeptide containing trimer or related higher cross-linked multimers. So in general at this stage there are few possible muropeptide products: an un-cross-linked pentapeptide monomer and cross-linked species with penta and tetrapeptides, and such peptides are seen in HPLC muropeptide analyses. However we have discussed that, for example in S. aureus, a major chemical modification that occurs in the cell wall is O-acetylation of N-acetylmuramic acid  the cell wall is thick enough to accommodate the known length of the glycan strands in this orientation, leading to a scaffold interpretation of NMR data derived from small, soluble synthetic peptidoglycan fragments  or ECT images of the cell wall or of sacculi  outer surface features were visible in ECT images. Some of these appear superficially similar to those seen by AFM and may be related to those observed previously by TEM . Images of freeze etched S. aureus revealed two distinct surface textures demarked by thick lines  and the localization of short/long glycan chains on the sacculus, which is related to the distribution of glycan chain ends.We know that some muropeptides are not randomly distributed across the sacculus. D-alanine-D-alanine motifs are associated primarily with new insertion and adopt a range of species specific localizations, as are muropeptides containing artificially introduced D-amino acids after pulse labelling (Kuru E. coli and B. subtilis, poles are anything between one and in theory a large number of generations old, and in the cylindrical part of the cell old material is dispersed throughout the wall depending on insertion pattern and turnover rate. In B. subtilis cables of peptidoglycan are more apparent by AFM imaging on the inside of the sacculus than the outside – attributed to hydrolase activity (Hayhurst et al., et al., The peptidoglycan sacculus is an inherited structure, with some regions being several generations old. In S. aureus, orthogonal division leads to ‘sectoring’ of the cell wall with smaller sectors being generally made of older material (Turner et al., In Peptidoglycan has been the subject of much controversy over the decades, in some part due to its importance for bacterial life but also because it is the target for some of our most important antibiotics. Advances in understanding have consistently been underpinned by advances in experimentation, such as HPLC and imaging technologies, and further breakthroughs will likely require more technological leaps, most of which will be impossible to foresee!et al., et al., et al., et al., et al., in vivo. AFM and ECT both have demonstrable maximum resolutions far in excess of those which have been achieved in imaging peptidoglycan and further work with these techniques will likely yield more information on the fine structure of peptidoglycan and the way in which strands are arranged to form the larger architectural features, such as ‘piecrusts’ in S. aureus and ‘cables’ in B. subtilis. Variants of AFM can be used to visualize individual polymer chains in ambient conditions (Mullin and Hobbs, et al., et al., et al., et al., et al., et al., et al., in vivo that most of the direct imaging techniques cannot.There are a small but growing palette of fluorescent probes, which enable us to map moieties within the cell wall or isolated sacculus. An expanded repertoire of probes may allow us to address the biological function of aspects of variation in peptidoglycan across species and within the sacculus. Some probes may be combined with super-resolution imaging techniques such as stochastic optical reconstruction microscopy (STORM, Rust Peptidoglycan architecture on the scale of tens to hundreds of nm varies between species and within an individual cell. In Gram-negative bacteria AFM and ECT provide some level of access to the underlying structure, and while the agreement between the two techniques is not perfect, there are strong indications that peptidoglycan organization is similar in all Gram-negatives examined so far, albeit with some species specific characteristics. However, in Gram-positives there is at present no way of directly visualizing the interior structure of the sacculus. Here, there is great controversy as authors propose radically different models of internal structure based on the shape or surface features of the sacculus images.An overarching model of peptidoglycan covering all bacteria is a very appealing prospect, and we have seen that there are statements that can be made about peptidoglycan that apply to all, or to groups of species. However, when one begins to investigate the detail of peptidoglycan chemistry and architecture, diversity is soon revealed and we must be aware of the dangers of over-generalizing. Much of our current data, particularly on the internal structure of Gram-positive peptidoglycan, is indirect, for example in the form of surface images, or population averages. This sort of information puts constraints on the models we can put forward, but sadly does not make it obvious what our models should be. In this imperfect situation, it is critical proposed models are not over-generalized and take into account all available data.in situ. With this type of data we will begin to connect chemistry with architecture and explain the diversity of features that have been observed, yielding further insights into this polymer, which is so important for bacterial life and, through the action of antibiotics, for human health.New advances in high resolution imaging technology bring forward the possibility of directly visualizing peptidoglycan chemistry


Brain activity is considered the physical correlate of mental activity. Accordingly, a change of the state of mind implies a change in the state of the brain and vice versa. This homology between brain activity and cognitive tasks is very difficult to measure due to their very high complexity, temporal and spatial dynamics, as well as individual variability. However, the advancing of technology allows the detection of some states of brain activity with reasonable accuracy and their translation into control messages for devices external to the brain . Moreover, studies on neurofeedback (NF) show that individuals can learn to modulate their own brain activity based on external feedback and thereby induce changes in cognition and behavior which can be used as therapy for various mental disorders.aspects of the training protocol such as instructions, task and feedback as well as psychological traits such as motivation, mood, locus of control, and empathy are investigated as determinants of BCI or NF performance. Moreover, the brain generates a large amount of coherent spontaneous activity independently of the BCI or NF task at hand which negatively impacts the reliable detection of brain activity patterns. Thus, the mechanisms and networks involved in gaining and maintaining control over brain activity as well as its prediction are addressed. Finally, as the ultimate goal of our research is to use BCI and NF for communication or control and therapy, respectively, novel applications for individuals with disabilities or disorders are discussed.Interestingly, roughly about one third of people succeed in controlling computerized devices with brain signals right away; one third gains control after training and one third does not achieve useful control even by using state-of-the-art BCI or NF technology. Various factors have been related to the individual success but to date, no general theoretical framework is available. In this Research Topic, the training protocol in BCI and NF. In the hypothesis and theory article of Lotte et al. (The first part of the research topic deals with the role of e et al. , probleme et al.  report te et al.  demonstrpsychological traits on performance are in line with the above presented results. Subramaniam and Vinogradov (The findings addressing the impact of nogradov  discuss nogradov  do not fnogradov  demonstrcontrol of brain activity are important to address. Ninaus et al. (Besides external and internal factors influencing performance, neurophysiological as well as peripheral physiological correlates of gaining and maintaining s et al.  demonstrs et al.  examine s et al.  investigpredict the ability to control a NF or BCI, Halder et al. (To r et al.  performer et al.  show thar et al.  includedapplications for individuals with disabilities or mental disorders. Risetti et al. (The last part covers potential i et al.  present i et al.  propose In summary, this Research Topic illustrates how different factors impact BCI and NF performance and provides new perspectives that need addressing in the future.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.