Social cognition is a fundamental ability in human everyday lives. Deficits in social functioning also represent a core aspect of many psychiatric disorders. Yet, despite its significance, deficits in social cognition skills are insufficiently targeted by current treatments. Hallucinogens and entactogens have been shown to have the potential to modulate social processing. This article reviews the literature on the influence of hallucinogens and entactogens on social processing in controlled experimental studies in humans and elucidates the underlying neurobiological and neuropharmacological mechanisms. Furthermore, it identifies current knowledge gaps and derives implications for hallucinogen-assisted treatment approaches as well as the development of novel medication for trans-diagnostic impairments in social cognition. Humans are a social species . Social Hallucinogens are psychoactive substance which induce transient perceptual anomalies and an altered state of consciousness. The effect of entactogens is characterized by experiences of oneness and emotional openness. Entactogens as well as hallucinogens have been shown to successfully modulate social processing in rigorous scientific studies –12. ThisModulation of Social Cognition in Clinical Populations). Acute Effects of Entactogens and Hallucinogens on Social Cognition in Healthy Volunteers reviews the acute effects of entactogens and hallucinogens on social cognition in healthy volunteers. Long-Lasting Effects in Healthy Participants provides a summary of long-lasting hallucinogen- and entactogen-induced effects on social cognition, and Neuropharmacological Underpinnings of Alterations in Social Cognition Induced by Hallucinogens and Entactogens explores the neuropharmacological basis of these modulatory effects. This chapter is particularly important for informing the development of novel therapeutics targeting socio-cognitive deficits in psychiatric disorders. Complimentary to the work reviewed here, there is a broad body of literature on the effects of these substances on social cognition in animals , amygdala reactivity was increased in response to fearful faces in treatment-resistant depressed patients the morning after psilocybin administration , but did not reveal significant results . SimilarTesting the performance on the FERT, Schmid et al.  did not vs. neutral faces on amygdala seed-to-voxel connectivity via functional magnetic resonance imaging (fMRI) showed that psilocybin decreased the connectivity between the amygdala and the striatum during angry face discrimination. The connectivity between the amygdala and the frontal pole was decreased during happy face discrimination. No effect was observed during discrimination of fearful faces  of LSD . Howeverul faces .via increased emotional empathy may therefore contribute to clinical efficacy of hallucinogens shown in preliminary studies with addicted patients  participants act altruistically when choosing an option that maximizes the allocation for another person. While MDMA did not change behavior on the SVO when administered in a lower dose (75 mg) , male paInvestigating allocation behavior in more reciprocal tasks, Gabay et al.  showed tIn sum, hallucinogens and entactogens have been shown to increase altruistic behavior. However, it is important to bear in mind the following caveats: these substances may also alter sensitivity to financial rewards; increases in altruistic behavior may occur only in participants with low altruism at baseline; and finally increases in altruistic behavior may occur only when directed toward a friend. A summary is presented in Increased sensitivity to social rejection and exclusion is observed in many psychiatric disorders –69. At tA commonly used paradigm to investigate the reaction to social rejection is called “Cyberball.” This paradigm consists of an interactive virtual ball-tossing game that simulates a real-life interactive experience of social exclusion . While iMDMA (0.75 and 1.5 mg/kg) has been shown to reduce the effect of social rejection on self-reported lower mood and self-esteem. The higher dose of MDMA (1.5 mg/kg) additionally increased the perceived percentage of throws received in the rejection condition . HoweverThe effect of LSD on social rejection induced by the Cyberball game has so far only been tested with very low doses (“microdoses”). Bershad et la.  in pres combinedvia different mechanisms. It is also conceivable that reducing rejection sensitivity is critically involved in the potential therapeutic effects of entactogens and hallucinogens, in particular with respect to therapist–patient interaction. However, this hypothesis has not yet been tested in clinical populations. Finally, the effects of entactogens and hallucinogens on social rejection processing other than psilocybin and MDMA still need to be investigated in future studies.In sum, psilocybin has been shown to attenuate the processing of negative stimuli which extends to negative social interaction , 77. WhiEngaging in romantic relationships and sexual behavior is an intimate social process and disturbances of close inter-personal relationships are prominent in psychiatric disorders . Yet, onGHB has been reported to have pronounced effects on self-reported sexual arousal . In an eVery little research has been conducted to investigate the effect of hallucinogens and entactogens on suggestibility and social influence processing, despite the fact that it is highly relevant for therapeutic interaction. So far, only two studies have been conducted, both investigating the influence of LSD on suggestibility , 84. TheWhile it has repeatedly been shown that hallucinogens increase the personality trait openness , 86, expIt has been reported that recreational MDMA users showed increased cognitive, but not emotional, empathy compared to controls on the MET and the MASC , 88. FurSelf-reported increases in interpersonal closeness and positive/altruistic social effects were reported 1, 2, 6, and 14 months after one and two administrations of psilocybin –92. SelfObjective data on the long-term effects of hallucinogens on social processes is still scarce. Mason et al.  reportedUnderstanding the neuropharmacological underpinnings of alterations in social cognition induced by hallucinogens and entactogens is vital to accelerate the development of novel medication for transdiagnostic social dysfunction in psychiatric disorders. MDMA, GHB, psilocybin, and LSD engage with various targets in the brain. To assess the neuropharmacological mechanisms underlying the prosocial effects of these substances, studies have investigated the neuroendocrinology after drug administration, the effects of these substances after blocking specific receptors or transporters, and have compared the effects between substances with different mechanisms of action.via action on monoamine transporters, and increases plasma levels of oxytocin, prolactin, and cortisol . Psilocin has high affinity and agonist activity on the 5-HT2A receptor and this receptor subtype is critically implicated in psilocybin-induced effects (1A receptor in mediating the effects of psilocybin (2A receptor antagonist ketanserin before LSD administration has been shown to block LSD-induced effects, implicating activity on this receptor as vital for its effects (Molecular studies have shown that the psychoactive metabolite of psilocybin, psilocin, binds to various serotonin receptors (PDSP database:  effects . Additioilocybin . LSD has effects .via blocking specific receptors. Kuypers et al. (1A antagonist pindolol did not block MDMA-induced increases in emotional empathy. A further study showed that neither duloxetine, which inhibits MDMA-induced monoamine transporter-dependent serotonin and norepinephrine release, reboxetine, which inhibits MDMA-induced norepinephrine release, nor clonidine, which inhibits MDMA-induced transporter-independent vesicular release of norepinephrine, blocked the observed increases in decoding accuracy for positive and impaired decoding accuracy for negative stimuli on the RMET after MDMA administration (2A receptor antagonist ketanserin.To date, only few studies have investigated the pharmacology of MDMA-induced alterations in social cognition s et al.  showed tstration . Howeverstration . This isstration  showing The neuropeptide oxytocin has repeatedly, although not unanimously, been related to social behavior . TherefoAdditionally, a number of studies have compared the effects of MDMA with other amphetamines as well as with modafinil. These studies indicated that MDMA has a different effect profile than other amphetamines. In contrast to MDMA, methylphenidate and modafinil increased misclassifications of emotions as angry on the FERT while MDMA increased misclassifications as happy . This isTo illuminate the pharmacology of GHB-induced prosocial effects, one study investigated the relationship between GHB-induced alterations in outcomes on social tasks and neuroendocrine effects . No corrvia agonism at the 5-HT2A receptor and potentially in parallel with downstream effects on aspartate metabolism (2A receptor antagonist ketanserin (Hallucinogens have been reported to exert their prosocial effects predominantly tabolism . Decreastanserin . In linetanserin , 84. Comtanserin  reported2A receptor stimulation. However, the functional and modulatory contribution of other receptors stimulated by these substances is scarcely investigated, in particular with regard to hallucinogens. Additional studies are needed that investigate the role of these receptor systems by selectively blocking them to comprehensively uncover the neuropharmacology underlying hallucinogen-induced modulations of social cognition. GHB which targets mainly GHB and GABAB receptors has a different effect profile implicating these receptors together with the dopamine system in prosexual effects. It has to be noted that entactogens and hallucinogens are not the only psychoactive substances that modulate social cognitive functioning. For example, alcohol has been reported to facilitate social interaction (Given these pharmacological results as well as the similarity of effects induced by MDMA and hallucinogens, it is conceivable that prosocial effects, in particular increased empathy and altruistic behavior, are modulated by a common mechanism, namely 5-HTeraction . While tNeuropharmacological Underpinnings of Alterations in Social Cognition Induced by Hallucinogens and Entactogens, agonism on the 5-HT2A receptor may be a common mechanism of classic hallucinogens and MDMA which underlies their prosocial effects. This is particularly important for the development of highly needed novel therapeutics targeting social deficits in psychiatric patients. Furthermore, these results implicate alterations in social processing as key mechanisms for the efficacy of psilocybin- and MDMA-assisted therapeutic approaches. In addiction disorders, the reinstatement of social reward processing may support reductions in drug intake and help overcome addiction. In anxiety and mood disorders, MDMA and hallucinogens may promote re-connection with patients’ social environment as well as support seeking and reductions in social withdrawal. Acutely, MDMA and hallucinogens may also enhance the patient-therapist relationship. Thus, it is vital that therapists working with MDMA and hallucinogens are aware of the acute effects of these substances on social cognition, including potential increases in suggestibility.The current literature on experimental and controlled investigations of the influence of hallucinogens and entactogens shows that these substances are potent modulators of social cognition and behavior. While MDMA is recreationally used for its prosocial effects, this review shows that hallucinogens such as LSD and psilocybin similarly impact social cognitive measures. GHB, however, has been shown to have predominantly prosexual effects and may therefore not be classified as a typical entactogen. As described in detail in Despite recent efforts to elucidate the effects of hallucinogens and entactogens on social cognition, major knowledge gaps remain. Studies specifically investigating the dose-dependency of modulations in social cognition induced by hallucinogens and entactogens are still scarce, in particular regarding psilocybin. LSD and MDMA have shown some dose-dependent effects on empathy and altruistic behavior , 33, 51,KP has written the manuscript. FV has revised the manuscript.KP and FV are financially supported by grants from the Heffter Research Institute and the Swiss Neuromatrix Foundation.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.


Stem cells drive embryonic and fetal development. In several adult tissues, they retain the ability to self-renew and differentiate into a variety of specialized cells, thus contributing to tissue homeostasis and repair throughout life span. Alcohol consumption is associated with an increased risk for several diseases and conditions. Growing and developing tissues are particularly vulnerable to alcohol’s influence, suggesting that stem- and progenitor-cell function could be affected. Accordingly, recent studies have revealed the possible relevance of alcohol exposure in impairing stem-cell properties, consequently affecting organ development and injury response in different tissues. Here, we review the main studies describing the effects of alcohol on different types of progenitor/stem cells including neuronal, hepatic, intestinal and adventitial progenitor cells, bone-marrow-derived stromal cell, dental pulp, embryonic and hematopoietic stem cells, and tumor-initiating cells. A better understanding of the nature of the cellular damage induced by chronic and episodic heavy (binge) drinking is critical for the improvement of current therapeutic strategies designed to treat patients suffering from alcohol-related disorders. Alcohol+/NADH) .Fig. 1MaEthanol has an impact on virtually all tissues, and some effects can persist long after stopping alcohol intake. Growing and developing tissues are remarkably susceptible to alcohol due to incomplete antioxidant protection. In fact, epidemiologic studies have provided evidence that drinking during adolescence can be dangerous for brain development, possibly inducing irreversible damage. Most importantly, alcohol exposure in pregnancy affects embryo development and can cause permanent birth defects. Similarly, early postnatal alcohol exposure might result in immunological and neurological disorders in later life. Accordingly, teen and prenatal alcohol drinking are serious social and health problems with increasing incidence. While the fact that acute and chronic alcohol abuse severely damages tissue and organ functions is well-established, only recently the role of ethanol exposure in deteriorating stem-cell properties has been investigated. Different organs of an individual may have different sensitivities to alcohol. The hypothesis that ethanol has nefarious consequences on stem cells in different tissues is consistent with alcohol’s widespread, long-term effects observed in the developing and adult human organisms.Evidence of direct toxicity of ethanol and/or its metabolites on stem and progenitor cells in different tissues offers a new perspective on the biological consequences of alcohol intake Fig. . AccordiThe devastating effects of fetal exposure to ethanol on brain development and function in the context of FASD conceivably reflect major consequences of alcohol on early neuronal maturation and by extension on proliferation, differentiation and survival of embryonic neural stem and progenitor cells (NSC) , 10. FurInterestingly, compromised adult neurogenesis may also be implicated in the long-term neural consequences of fetal exposure to ethanol. In particular, adult neurogenesis appears preserved  or even Molecular cascades connecting exposure to ethanol with the defects in NSC proliferation, differentiation and survival that overall result in impaired developmental and adult neurogenesis are still elusive. A reduction of brain-derived neurotrophic factor (BDNF), a major neurogenic neurotrophin, has been reported in plasma of alcohol-addicted patients . ConsistAlcohol consumption causes a wide spectrum of hepatic disorders ranging from mild fatty liver (steatosis) to more severe steatohepatitis, progressive fibrosis, cirrhosis and hepatocellular carcinoma, which are collectively recognized as alcoholic liver disease (ALD) . The higIn addition, in vitro studies suggest an hepatotoxic effect of alcohol exposure on hepatic stem cells . PrimaryAlcohol ingestion causes alteration of the intestinal microbiota composition and the disruption of intestinal barriers promoting local and systemic inflammation and tissue injury . IntestiAlcohol abuse is associated with impaired bone homeostasis leading to pathologic remodeling and impaired healing of bone fractures , 50. BonA crosstalk between the Wnt/β-catenin and the mammalian target of rapamycin (mTOR) signaling has been identified in maintenance of bone-marrow-derived  and epitInterestingly, the effects of chronic alcohol intoxication on bone remodeling are not permanent and can be improved by abstinence . A betteAlcohol abuse, in association with other co-morbidity factors such as poor nutrition, vitamin deficiencies, and smoking, may lead to periodontal disease . Dental The vessel wall contains a heterogeneous population of stem cells, referred as adventitial stem/progenitor cells, able to differentiate into vascular and non-vascular cells . These sN-methyl-d-aspartate (NMDA) receptor subunit gene expression [Embryonic stem cells (ESCs), which are derived from the inner cell mass of blastocysts, and induced pluripotent stem cells (iPSCs), which are adult cells genetically reprogrammed to an embryonic stem cell-like state, represent attractive in vitro models for the study of human developmental studies , 73. Alcpression . Alcoholpression , indicatpression . Exposurpression .Collectively these data suggest that ESCs are more sensitive to ethanol than differentiated cells , 86 provAlcoholic patients may experience anemia, bleeding disorders, and compromised immune response . AlteratAlcoholic patients may experience also reduced granulocyte levels and show weakened host immune defense against bacterial infection . It has + stem cells which mainly contain hematopoietic and endothelial progenitor cells. Hepatic recruitment of CD34+ stem cells correlates with liver fibrosis [Hematopoiesis also involves the interaction of the developing cells with the BM stroma, which provides the microenvironment suitable for cells differentiation. Besides damaging HSC directly ethanol could affect the BM progenitor cells also in an indirect fashion by altering their microenvironment. Alcohol has a detrimental effect also on BM stromal cells, which has been associated with the reduction of bone mass and decreased bone formation observed in alcoholics . In addifibrosis . TherefoAlcohol beverages consumption is classified as carcinogenic by the World Health Organization. In particular, acetaldehyde, the first compound of alcohol metabolism, is a known carcinogen and a key generator of free radicals which can promote cancer development through multiple mechanisms . EthanolAccording to the cancer stem cell hypothesis, only a small subgroup of tumorigenic stem-like cells within a highly heterogeneous cancerous cell population initiates and drives tumor growth . These cDespite intensive research, the mechanisms leading to alcohol toxicity are still largely unclear. In the following sections, we review the main putative mechanisms by which alcohol might exert negative effects on stem cells Fig. .Endogenous reactive metabolites, such as ROS and aldehydes produced during ethanol metabolism, are key players in induction of mutagenesis and ageing. In particular, high cellular levels of ROS can be detrimental, leading to lipid peroxidation and DNA damage. Alcohol intake can lead to ROS production by several mechanisms including ethanol and acetaldehyde oxidation by the ADH and ALDH, cytochrome P450 2E1 (CYP2E1) induction, raise in the cellular amount of free iron, conversion of xanthine dehydrogenase to xanthine oxidase . IncreasThe mTOR–mitochondria–ROS axis plays a pivotal role in regulating stem-cell quiescence and self-renewal . Ethanol+/NADH), leading to altered gene expression and epigenetic changes [+ determine a reduction of self-renewal and differentiation capabilities of neural stem cells [+ repletion has been associated with improved retention of muscular, neural and melanocyte stem cell pools in aged mice [+ beneficial effects likely involve several NAD-dependent pathways and effectors, including sirtuins, a class of protein deacylase extensively linked to extended longevity in model organisms and to health span in mammals through antioxidant, prosurvival and metabolism-regulating functions [+ levels ethanol may negatively impact on the preservation of adult stem cells and by extension on tissue regenerative capacity, while pharmacologic treatments aiming at increasing intracellular NAD+ content may help to prevent stem-cell functional decline upon alcohol intake.Hepatic ethanol oxidation causes a significant change of the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide  family which provides the main detoxification activity against acetaldehyde. Moreover, ALDH affects HSCs self-renewal via inhibition of the retinoic acid signaling . NoteworCell membrane-mediated interactions play a pivotal role in regulating stem cell proliferation and differentiation . EthanolStem-cell differentiation is a strictly orchestrated process involving multiple regulatory pathways. A complex network of soluble factors such as cytokines, hormones and growth factors, regulates stem cell fate . AlcoholIn addition, broad alcohol‐mediated changes in microRNA (miRNA) and miRNA‐target gene expression have been observed in utero, possibly contributing to the harmful effects on the developing fetus . ConsequEmerging evidence for the impact of ethanol on stem and progenitor cells has added a new layer of biological complexity to our understanding of how alcohol misuse affects adult and developing tissues and especially fetal brain. However, the underlying biochemical mechanisms appear manifold, complex and overall incompletely identified. Hopefully, intense research aimed at delineating the pathogenic molecular interactions that link ethanol intake to stem-cell damage will in the next few years provide the immediate benefit of uncovering the processes leading (or at least contributing) to alcohol toxicity. This will be in turn instrumental to develop novel therapeutic strategies to reverse or prevent the effects of alcohol intoxication.


Arbuscular mycorrhizal (AM) fungi establish probably one of the oldest mutualistic relationships with the roots of most plants on earth. The wide distribution of these fungi in almost all soil ecotypes and the broad range of host plant species demonstrate their strong plasticity to cope with various environmental conditions. AM fungi elaborate fine-tuned molecular interactions with plants that determine their spread within root cortical tissues. Interactions with endomycorrhizal fungi can bring various benefits to plants, such as improved nutritional status, higher photosynthesis, protection against biotic and abiotic stresses based on regulation of many physiological processes which participate in promoting plant performances. In turn, host plants provide a specific habitat as physical support and a favorable metabolic frame, allowing uptake and assimilation of compounds required for the life cycle completion of these obligate biotrophic fungi. The search for formal and direct evidences of fungal energetic needs raised strong motivated projects since decades, but the impossibility to produce AM fungi under axenic conditions remains a deep enigma and still feeds numerous debates. Here, we review and discuss the initial favorable and non-favorable metabolic plant context that may fate the mycorrhizal behavior, with a focus on hormone interplays and their links with mitochondrial respiration, carbon partitioning and plant defense system, structured according to the action of phosphorus as a main limiting factor for mycorrhizal symbiosis. Then, we provide with models and discuss their significances to propose metabolic targets that could allow to develop innovations for the production and application of AM fungal inocula. Plant hormones, also called phytohormones, are organic compounds other than nutrients that are naturally produced by plant tissues in response to specific stimuli. They act spatially and temporally as endogenous signals able to organize all plant developmental stages  by regulating at a very low dose various physiological functions. Plant hormones belong to the class of plant growth regulators, which group both natural and synthetic compounds that can regulate plant development . In addi1. They were extensively studied for more than 60 years, as it was shown that they are key components of soil fertility. Many examples suggest to exploit AM fungi for promoting plant performances  as they can enhance nutrition , photosynthesis, protection against biotic and abiotic stresses, regulation of developmental processes  and take part in soil structuration  levels in soils  fungi, colonize the root of most (74%) plant families on earth . These fturation . Howeverin soils .in planta or in vitro.Arbuscular mycorrhizal fungi are obligate biotrophs, the completion of their life cycle requires the absolute presence of host plants that provide a specific habitat  allowing fungal uptake and assimilation of likely several energy sources  . This dein planta but also in vitro, in presence or not of plant, respectively, monoxenic and axenic conditions) and that they are able to produce at least some of them . However, phytohormones represent only part of the signaling in AM symbioses and their concret translations on plant metabolic pathways, especially those involved in energetic partitioning , remain poorly discussed. To fill in the knowledge gap of the definition of favorable or non-favorable plant metabolic framework for AM fungi is a major step toward understanding fungal needs, and can then provide insights about the mode of action of some elements such as phosphorus, as well as clues to artificially promote mycorrhizal performances (root colonization and AM responses on plants).Negatively correlated responses between P concentration in soil and mycorrhizal phenotype and function are well investigated . HoweverThe use of mutant plants or hormonal plant pretreatments (discussed in sections below) suggests that the AM behavior within roots is consequently driven by the metabolic interplay initially set in the plant. The aim of this review is to provide a detailed theoretical picture, based on available knowledge, connecting plant hormones, plant metabolic pathways involved in cell energy, plant defense and AM development and growth. The key point is to define the physiological basis of the plant susceptibility to mycorrhiza prior to inoculation with AM fungi or AM root contact.The first section reviews the impact of 9 plant hormones, strigolactones (SL), abscisic acid (ABA), ethylene (ET), gibberellins (GA), salicylic acid (SA), jasmonate (JA), auxins (AUX), cytokinins (CK), and brassinosteroids (BR), on mycorrhizal behavior . In the second section, we debate about the links between plant defense systems, compounds that induce a primed state (elicitors), plant hormone interplay, and AM fungal development. In the third section, we illustrate the impact of hormone interplay on plant energetic system . As P represents a crucial criterion for the development and functionality of AM fungi, we describe here metabolic interplays under two hypothetic contrasting situations, low and high P, and we discuss whether the role of hormones and regulations within cells can be driven by P concentrations. Then, in a last section, we propose models that integrate signaling and plant energetic systems in mycorrhizal development, and strategies in which specific plant priming could be exploited as a tool to promote mycorrhizal performances Figure .ex vitro (greenhouse/growth chambers) conditions  exos Figure , in whics Figure , (ii) prs Figure . The effs Figure . Moreoves Figure . TherefoAbscisic acid is a stress phytohormone belonging to the class of sesquiterpenes. It regulates negatively plant growth and controls stomatal closure, limiting water loss by transpiration . ABA alsMedicago truncatula, low ABA concentration (5 × 10-5 M) promotes AM fungi development, arbuscule branching and abundance, while higher concentration (5 × 10-4 M) reduces the level of colonization (In vitro plant pre-treatment with ABA (applied in the culture medium) resulted in higher root colonization and arbuscule abundance  was also used, but except for one study in which mycorrhizal development and arbuscule intensity was reduced  and no report evaluated the response of AM fungi to ABA under higher P level. Moreover, no study was conducted in order to connect natural endogenous ABA levels and mycorrhizal susceptibility from various plant species and/or cultivars. It is therefore not clear, if a dose dependence of ABA responses exists.Jasmonate and its derivatives belong to a diverse class of lipid metabolites known as oxylipins  and are -1 year-1) but decreased at 5 mM JA under low P , which is involved in JA biosynthesis, was suppressed by a root application of a MtAOC1antisense construct  was shown to be associated with higher AM fungal colonization and arbuscule formation  can interfere with JA perception, making interpretations quite delicate. This is well illustrated by the lack of mycorrhizal responses when JA is applied at low P, probably because endogenous JA levels are already high , but plaAuxins are mainly formed from tryptophan and indole-3-acetic acid (IAA) is the most abundant auxin. AUX regulate various aspects of plant growth and development, such as phototropism, geotropism and cell elongation and polarity . IAA regin planta indicated that applications of various auxins  are able to promote AM fungal spread and arbuscule abundance (Daucus carota transformed roots (in vitro) inoculated with R. irregulare, and shown a slight decrease in both root colonization and spore numbers.Observation bundance . In axenbundance . The usebundance . AUX effbushy mutant (diageotropica (dgt) mutant shows lower AM fungal development in both monoxenic and ex vitro conditions (polycotyledon (pct) mutant fails to generate an AM symbiosis monoxenically with root organ culture, but shows increased colonization in ex vitro plants, and authors suggested the existence of shoot-derived factors that modulate auxin action (Studies with the auxin (IAA)-deficient y mutant , 2002 isy mutant . Moreovenditions , althougnditions . The AM n action . In anotn action . This stn action .Regarding the interaction with other hormones, it has been proposed that auxins regulate positively SL biosynthesis genes , therebyR. irregularis genome indicates that typical auxin biosynthesis genes are lacking  promotes mycorrhizal development in wild-type but also in SL-deficient plant mutants  under axenic conditions was shown to activate mitochondrial differentiation, number and activity toward fungal cytochrome oxidase (COX) pathway with an increase in NADH and ATP during the pre-symbiotic phase in hyphea, and goes concomitantly with higher hyphal branching , and both of them have been recognized to stimulate mycorrhizal growth. The consensus for the role of SLs in mycorrhiza is clear, and can be confidently classified as promoter. However, the production of SL by AM fungi is not known.Brassinosteroids represent a class of phytohormones defined as growth promoters . They molk  as well as defense .Exogenous soil and foliar treatments with ET or its commercial analogous ethephon have been shown to impair mycorrhizal colonization  and to repinastic), mycorrhizal colonization and arbuscule abundance were impaired at low P , mycorrhizal colonization was found to be repressed (coi1) and ET-insensitive (etr1) tobacco plants, but mycorrhizal growth responses were strongly enhanced in both mutants  and ET-deficient (rin) tomato mutants, while harboring curiously, respectively, lower and higher ET content compared to the wild type  negative correlation was observed within pea E107 (brz)  or in ABt plants ; and  promoted spore germination and germ tube growth  and inhibiting (high P) mycorrhizal colonization.via the surface plant roots. The second one, called mycorrhizal pathway, is builded by the presence of mycorrhizal fungi which are able to uptake and transfer the P from soil to the root via the mycelium. In both cases, P uptake and transfer involves an active translocation mediated by H+-ATPases which create a proton motive force allowing P entering the cell via Pi/H+ symporters localized in the rhizodermis or the root hairs (direct pathway) or in the periarbuscular membrane at the arbuscule branch domain . Complexes I, III, and IV constitute proton pumps during the electron transport, leading to the formation of a proton gradient between the mitochondrial matrix and the intermembrane space . The graionality .+H+/NAD+ ratios. This was demonstrated in Phaseolus vulgaris H+H+ cell pool). It has been also proposed that, concomitantly with AOX pathway, energy demand for plant metabolism is provided by fermentative activity  applied to soybean leaves were shown to induce host stress response, activating AOX and repressing hormone-related components belong to GA signaling (Plant-derived ET and diffusible factors present in germinating spore exudate (GSE) act antagonistically: compounds isolated from GSE (such as Myc factors) can stimulate mycorrhizal plant susceptibility, while ET inhibits GSE-induced symbiotic gene expression . Interesignaling . Moreoveignaling , many ofignaling .via stabilization of DELLA proteins  inhibitors is applied in wild type , enhanced under high P, creates an inhibitory context for mycorrhizal development, as detailed in section Phytohormones Influence the Mycorrhizal Symbiosis. From another point of view, the lack of mycorrhizal colonization was generally described as an economic determinism, so called “cost-benefit” trade between P uptake for plant and carbon delivery for AM fungi  by AM fungi of the energy sources provided by the plant  may depend on the presence of a surrounding metabolic context that integrates favorable signaling . Our literature survey suggests that plant AOX pathway may play one central role in the implementation of a specific metabolism, which occurs consequently to environmental stimuli (stress). Obviously, phytohormone regulations and electron flow partitioning between AOX and COX is dynamic in time and space and this must be taken into account during mycorrhizal development under normal conditions. The AOX pathway coupled with fermentative processes is probably a main component during the first stages of mycorrhizal development, explaining perhaps the well known stunt phenomenon which follows plant inoculation. Successively, electron route to AOX pathway and the related plant metabolism is very likely shifted toward the COX pathway , as a coin vitro conditions, and reports seem lacking for some of them . Moreover, most of the studies conducted with phytohormones within endomycorrhizal systems were set under low P, as it represents suitable conditions to investigate fungal phenotypes. Nonetheless, we recommand to perform more assays with different P concentrations , in order to better define the mode of action of each hormone. Then, it could be interesting to report mycorrhizal phenotype traits under axenic and monoxenic systems that combine a given hormone in presence of various carbon sources. Despite several sugar transporters were localized in arbuscules but also in hyphae of the extraradical mycelium , thus participating at a whole on the responses on the mycorrhizal behavior. It appears also that some methods might create biases. For example, soil hormone application can already affect the mycorrhizal propagules during pre-symbiotic phase, and the eventual release of hormones by AM fungi could interfer with phenotypic responses of mutant plants. Production of several hormones  by AM fungi remains unknown, while they may potentially participate in fungal spread within roots like pathogenic fungi . For examycelium , assimilRAM1, RAM2, FatM, and STR/STR2 were proposed to act as operational unit to synthetize and deliver fatty acid to AM fungi , that might be overexpressed as part of a signaling adaptation.Some aspects were not addressed in this review. This concerns the sporulation process, because the metabolic context that drives this specific fungal developmental step belongs to physiological changes that take place following root colonization at late stage. Moreover, the relationship between hormone interplay and mycorrhizal spore formation is only poorly investigated, despite this structure could reflect the energy status of the fungus . InformaAM fungi . In partt plants . To illuressions , while Gpression . HoweverWe are aware that hormonal interplays and regulations at different environmental conditions and in various plant species are much more complex than our models suggest, which remain largely incomplete. Therefore, next steps should attempt to validate or reject some of the hypotheses deduced from the models with further investigations. The effort that we made was an attempt to define a consensus, but also to propose several research topics aiming to elucidate some fundamental aspects of the endosymbiotic relationship which are still not fully understood and exploited.in planta seems to be promoted by the occurrence of ISR and its related signaling, prior to AM fungi contact. The induction of ISR or SAR system can be primed by application of specific elicitors for one or the other system. The use of specific molecules able to generate a favorable metabolic context to promote an effective colonization can therefore be proposed to master mycorrhizal inoculum applications under practical field condition or other research area as degraded land restauration. In this view and among those stimulatory molecules, potential affordable strategies exist from the application at low doses  of oligosaccharides on plants. Interestingly, oligosaccharides were shown since some decades to act as elicitors and therefore implement specific plant defense responses against biotic but also abiotic stress (via transcription factors (According to our model, AM fungi development c stress . Oligosac stress . Sugar sc stress  or indirc stress , presentc stress  and then factors . Althoug factors  remains  factors . Since tLM took the lead in writing the manuscript and conceived the main subject of this review. AB and LM drafted the manuscript. CS, PF, and EL-M supervised the writing, critically revised the manuscript, and contributed to its final version. All authors approved the final version of the manuscript.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.


In human beings the immature brain is highly plastic and depending on the stage of gestation is particularly vulnerable to a range of insults that if sufficiently severe, can result in long-term motor, cognitive and behavioral impairment. With improved neonatal care, the incidence of major motor deficits such as cerebral palsy has declined with prematurity. Unfortunately, however, milder forms of injury characterized by diffuse non-cystic white matter lesions within the periventricular region and surrounding white matter, involving loss of oligodendrocyte progenitors and subsequent axonal hypomyelination as the brain matures have not. Existing therapeutic options for treatment of preterm infants have proved inadequate, partly owing to an incomplete understanding of underlying post-injury cellular and molecular changes that lead to poor neurodevelopmental outcomes. This has reinforced the need to improve our understanding of brain plasticity, explore novel solutions for the development of protective strategies, and identify biomarkers. Compelling evidence exists supporting the involvement of microRNAs (miRNAs), a class of small non-coding RNAs, as important post-transcriptional regulators of gene expression with functions including cell fate specification and plasticity of synaptic connections. Importantly, miRNAs are differentially expressed following brain injury, and can be packaged within exosomes/extracellular vesicles, which play a pivotal role in assuring their intercellular communication and passage across the blood–brain barrier. Indeed, an increasing number of investigations have examined the roles of specific miRNAs following injury and regeneration and it is apparent that this field of research could potentially identify protective therapeutic strategies to ameliorate perinatal brain injury. In this review, we discuss the most recent findings of some important miRNAs in relation to the development of the brain, their dysregulation, functions and regulatory roles following brain injury, and discuss how these can be targeted either as biomarkers of injury or neuroprotective agents. MicroRNAs (miRNAs) are a class of endogenous small single-stranded non-protein coding RNA molecules (20–24 nucleotides), often phylogenetically conserved, which play a critical role in the control of gene expression at the post-transcriptional level. Specifically, miRNAs mainly function post-transcriptionally by binding to the 3′ untranslated region (3′UTR) of target messenger RNAs (mRNA) and induce mRNA degradation or translational repression . In addiGiven their abundance in the central nervous system (CNS) and their specific patterns of expression within all of the major cell types during development , it is uIn addition to the aforementioned role of miRNAs in the pathophysiology of perinatal brain injury evidence now suggests CNS cells secrete stable miRNAs into the plasma, which are bound to protein, HDL, or packaged within exosomes/microvesicles following stroke . As theiDevelopment of the mammalian CNS involves a series of intricately coordinated events that requires precise spatial and temporal control of gene expression at both the transcriptional and translational levels . As prevDicer1 gene affects brain development including impaired cortical neuron migration, microcephaly, and precursor differentiation in the spinal cord  is one of its targets , resulting in an increase in intermediate progenitors and suppression of cortical radial glial cells, respectively   . Inhibitlar zone . Furtherfication  and mostfication .Map1b) (Foxp1 and Foxp2)  . Furtherd Foxp2) .Dicer1 knockout models have identified miR-219 as a crucial regulator of oligodendrocyte differentiation , markedly enhanced maturation and restored their expression levels to control transfected cells , myelin gene regulatory factor (MRF), claudin-11 (CLDN11), myelin transcription factor 1-like (MYTL1), myelin-associated oligodendrocyte basic protein (MOBP), myelin protein zero-like 2 (MPZL2), and discoidin domain receptor tyrosine kinase 1 (DDR1). Of interest, the authors showed that within the top 10 differentially expressed miRNAs, spanning early to mid-oligodendrocyte progenitor stages, both miR-199a-5p and miR-145 were strongly biased to C11Orf9, a gene considered to play a critical role in oligodendrocyte maturation and myelin production.Elegant studies by Evidence discussed above, thus highlights the need to define the role of miRNAs in normal neurodevelopment since they may lay the foundations for novel miRNA-based therapies for preterm infants at risk of brain injury.in vivo has been a major constraint when investigating the functions of astrocyte miRNAs. However, in a recent study of glial progenitors induced to differentiate into astrocytes, deletion of all canonical miRNAs by conditional knockout of Dgcr8  blocked astrocyte differentiation in vitro  protein expression, and increased susceptibility to hypoxic-ischemic injury . MoreoveStudies highlighting miRNAs as key regulators of oligodendrocyte development may have significant clinical implications with respect to further understanding the pathogenesis of preterm hypoxia-ischemia brain injury, since loss and subsequent arrested differentiation of oligodendrocyte progenitors is a hallmark of injury. Presently, there is a paucity of information with regard to how miRNA expression contributes to critical events of oligodendrogenesis occurring in response to hypoxia-ischemia within the developing brain.Dicer1 knockout mice  and interleukin-1 receptor-associated kinase 1 (IRAK1) genes in innate and adaptive immune cells   . DespiteACVR2B) , signifiAside from the above clinical investigation, a recent study of global hypoxia-ischemia in newborn piglets has also provided evidence to support circulating plasma miR-374a and the hypoxamiR miR-210 as potential biomarkers . HoweverOther candidate miRNAs have been investigated, namely let7b, miR-29b, miR-124, miR-155, and miR-21 . QuantifAdditional studies that warrant mention are preliminary studies conducted by A caveat: while the field of miRNA research is constantly expanding one must appreciate that the endogenous source of miRNAs within available body fluids including, plasma, serum, urine and saliva can be from a diverse array of peripheral tissue cellular types including those of the brain, thus decreasing in essence the reliability of results. The other point to note is the problem of cell specification of miRNAs; the reality for many miRNAs as biomarkers in body fluids is that they may not be expressed exclusively within one particular cell type. In the last few years, however, since the identification of exosomes , as a cIn the adult, only a few clinical studies have been performed to assess the potential of exosomal-derived miRNAs as biomarkers of acute brain injury. Studies by In vivo Evidence,” it warrants mentioning that because exosomes can potentially act as a therapeutic delivery system they hold great promise in revolutionizing the way we can effectively treat perinatal brain injury.There is also a growing interest as to the regenerative utility of exosomal-derived contents with and without loading with therapeutics . SeveralIn alliance with the discovery of miRNAs as functional regulators of cell development, miRNAs have also been shown to orchestrate a variety of critical signaling pathways involved in injury progression and recovery . Given tIn vitro studies have provided insights into the therapeutic potential of miRNAs that regulate reparative processes following a hypoxic-ischemic insult. For example, stroke-induced downregulation of miR-9 and miR-200b expression in the ischemic white matter region mediated serum response factor (SRF) induced differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes  and phosphate and tensin homolog (PTEN) protein levels, thereby promoting axonal outgrowth (Chondroitin sulfate proteoglycans (CSPGs) are well-characterized inhibitory extracellular matrix molecules expressed by reactive astrocytes, endothelial and oligodendrocyte progenitor cells that inhibit axonal regeneration after injury and are associated with adverse neurological outcome in preterm infants . In vitrutgrowth , 2015a. utgrowth .in vivo studies are eagerly awaited.miR-592 was originally suggested as a possible target for promoting cell apoptosis in various cancers . UnsurprmiR-27 is a potential regulator of cortical neuronal apoptosis whose expression in embryonic mouse cerebral cortices is attenuated in response to maternal hypoxia . FurtherCerebral angiogenesis is a critical reparative process of the microvasculature following hypoxic-ischemic injury, involving cellular cross-talk through neurotropic factors, improving regional blood supply, and facilitating the migration of neurons toward damaged regions . ModulatMSCs have been extensively applied in both experimental and clinical settings of CNS diseases owing to their immunomodulatory, regenerative and reparative properties including stroke , multiplMSC-derived extracellular vesicles are enriched with a variety of proteins and different RNA species (mainly mRNA and miRNA) as well as trophic factors whose functions are linked to MSCs biological effects. Importantly, evidence now suggests that specific miRNAs are necessary to mediate MSC-derived extracellular vesicles neuroprotective effect . While mIn a recent conducted study by in vivo investigations using animal models of perinatal and neonatal brain injury support their application (Additionally, in concordance with lication ; howeverin vivo, in vitro, and ex vivo mouse model of endotoxemia have shown that miRNA-containing extracellular vesicles originating from the choroid plexus epithelium can enter brain parenchymal cells and via astrocytic and microglial processes induce miRNA target repression and inflammatory gene expression (Finally, it is pertinent to mention that exosomes/extracellular vesicles, viewed as potent vehicles by which to deliver potentially therapeutic miRNAs to the brain, can equally participate in the pathophysiological processes of blood-CSF-brain-communication. Recent studies undertaken in both an pression . The trapression , includipression  in this In the past decade, numerous articles have been published on the role of miRNAs within the brain. As post-transcriptional regulators of gene expression, miRNAs most definitely play a crucial role in the development of the brain. Nevertheless, research conducted to define their impact on the developing and injured brain is still in its infancy. Given specific miRNAs can exhibit diverse functional roles throughout development and can act synergistically, identification of their precise functional roles is fraught with difficulties. This is particularly relevant when considering adopting specific miRNAs as biomarkers of perinatal brain injury. Thus, careful interpretation of data is required not only in the context of biomarker potential, but also application as a therapeutic strategy since off-target effects can confound the latter. One attractive possibility to ensuring, at least targeted delivery, is the fast developing field of research involving exosome-based miRNA therapies for neurological injuries and disorders. Exosomes are considered a key carrier of circulating miRNAs. Since they mediate the exchange of miRNAs between cells, readily cross the blood–brain barrier and fuse with cell membranes, they hold promise not only as a miRNA biomarker carrier, but also as a means to deliver miRNA-based therapies to the developing injured brain. Clearly, continued developments in this field of research has the potential to enhance future prospects of effectively treating perinatal brain injury especially those vulnerable to premature injury.KHTC and MF devised main conceptual ideas and outlines and took the lead in writing the manuscript. All authors contributed to the manuscript and provided feedback and discussed the manuscript.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.


Longitudinal, well phenotyped, population-based cohort studies offer unique research opportunities in the context of genome-wide association studies (GWAS), including GWAS for new-onset (incident) cardiovascular disease (CVD) events, the assessment of gene x lifestyle interactions, and evaluating the incremental predictive utility of genetic information in apparently healthy individuals. Furthermore, comprehensively phenotyped community-dwelling samples have contributed to GWAS of numerous traits that reflect normal organ function  and for many traits along the CVD continuum . These GWAS have heretofore identified many genetic loci implicated in normal organ function and different stages of the CVD continuum. Finally, population-based cohort studies have made important contributions to Mendelian Randomization analyses, a statistical approach that uses genetic information to assess observed associations between cardiovascular traits and clinical CVD outcomes for potential causality. As a brief introduction, we would like to highlight important design features of population-based studies. As opposed to hospital-based referral samples, population-based epidemiological studies examine community-dwelling or random samples from the general population. As such, study participants are not selected based on a given disease, but rather to represent the general population of the areas sampled, so that observations from such a sample are generalizable to the underlying source population. It has to be kept in mind, though, that the response rate of some landmark cohort studies is rather low , which Third, many population-based cohort studies perform Since many community-dwelling samples are representative of the general population, population-based studies have served as reference (“control”) samples for many genetic case-control analyses. In essence, genetic case-control studies compare allelic frequencies of genetic variants in prevalent cases (patients who have the disease of interest when they are sampled) and controls. Ideally, the control sample captures the distribution of the exposure  in the source population from which the cases were derived . TherefoThe broad and highly standardized phenotyping of their study participants has allowed many different contributions of population-based cohort studies to GWAS. Specifically, researchers from population-based studies have performed and contributed to numerous GWAS for traits along the cardiovascular disease continuum, including traditional CVD risk factors [e.g., lipids , blood pFurthermore, given the large proportion of apparently healthy individuals in population-based cohort studies , these studies conducted GWAS of many traits that reflect relatively normal organ function, including biomarkers of cardiac structure and systolic and diastolic function . These sIt is an important and growing area of research to quantify the contribution of genes and of different lifestyle factors (and their interactions) to inter-individual variation in cardiovascular risk factor levels and disease risk. Since well phenotyped cohort studies usually have comprehensive genetic data and detailed lifestyle information available, population-based studies represent an ideal setting to study gene x lifestyle interactions. The interaction of a genetic risk score (based on 50 SNPs) and a lifestyle score  on the incidence of CAD has been analyzed in several large community-based cohorts . Key obsThe same lifestyle score as in Reference  was usedPCSK9 gene and a PCSK9 genetic score were associated with lower circulating LDL cholesterol levels and reduced risk of cardiovascular events in the general population  mutations in the PCSK9 (proprotein convertase subtilisin/kexin type 9) serine protease gene were initially identified in families with autosomal dominant hypercholesterolemia . Subsequpulation . Recentlpulation .Due to the availability of repeated measures over time, cohort studies are also suitable to explore the genetic underpinning of changes in cardiovascular risk factors over time, and of the progression of subclinical CVD traits longitudinally. For example, a GWAS for carotid IMT measured at different time points over a 10-year period has recently been published . FurtherOn a parallel note, a genetic risk score consisting of 29 SNPs was not only associated with blood pressure and hypertension prevalence at baseline, but also with new-onset hypertension and change in blood pressure over the life course in a large Swedish cohort study .The longitudinal character of population-based cohort studies allows genetic variation to be studied in relation to disease incidence. For example, population-based cohort studies have facilitated GWAS for incident heart failure , incidenIt is well known that analyses based on prevalent disease cases and those based on incident cases might reveal different results if the association between an exposure and the disease outcome differs by disease severity or disease duration  . In ordeFurthermore, community-based prospective cohorts allow assessing whether genetic information improves risk prediction models beyond traditional risk factors. It was, indeed, one of the main motivations of the human genome project to use genetic information to predict disease risks in healthy individuals and to predict the response to a given therapy among patients. Several analyses conducted in various population-based cohorts assessed whether genetic variation – e.g., in an aggregated form as risk scores – improved performance measures of risk prediction models for a first CVD event, including discrimination, calibration, and reclassification . AlthougGenetic information in population-based cohort studies has also been used to assess causality between cardiovascular risk factors or circulating biomarkers and cardiovascular outcomes (incident CVD events) using instrumental variable analyses, a statistical approach referred to as Mendelian Randomization (MR) . This tePopulation-based studies have substantially improved our understanding of the genetic architecture of normal and abnormal organ function, CVD risk factors, circulating biomarkers, subclinical disease, and overt CVD traits over the life course. Furthermore, they were essential in exploring gene x lifestyle interactions and in evaluating genetic variation in the context of risk prediction models for incident CVD. In addition, population-based cohort studies provided great opportunities to conduct GWAS for incident CVD events, such as MI, stroke and heart failure, and thereby, to overcome classic limitations of case-control GWAS including prevalence-incidence bias. Finally, population-based cohort studies used genetic information as instrumental variables to assess whether cardiovascular risk factors or biomarkers are causally related to clinical CVD .WL and RV wrote the article together.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.


Over the past two decades, there has been tremendous progress in understanding the impact of the intestinal microbiota on mammalian metabolism, physiology, and immune development and function. There has also been substantial advancement in elucidating the interplay between commensal and pathogenic bacteria. Relatively more recently, researchers have begun to investigate the effect of the intestinal microbiota on viral pathogenesis. Indeed, a growing body of literature has reported that commensal bacteria within the mammalian intestinal tract enhance enteric virus infections through a variety of mechanisms. Commensal bacteria or bacterial glycans can increase the stability of enteric viruses, enhance virus binding to host receptors, modulate host immune responses in a proviral manner, expand the numbers of host cell targets, and facilitate viral recombination. In this review, we will summarize the current literature exploring these effects of the intestinal microbiota on enteric virus infections. Enteric viruses infect the gastrointestinal (GI) tract following fecal-oral transmission and are collectively responsible for a tremendous disease burden. They are often highly infectious and shed in significant quantities in the stool of infected individuals. Rotaviruses, noroviruses, and astroviruses are all nonenveloped RNA enteric viruses and causative agents of acute gastroenteritis ,2. RotavThe mammalian gut lumen is colonized by a vast population of microorganisms, referred to collectively as the intestinal microbiota. It consists of trillions of microbes from more than 1000 different bacterial species in addition to viruses, fungi, and archaea ,12. The Science in 2011 demonstrated that commensal bacteria stimulated poliovirus, reovirus, and mouse mammary tumor virus (MMTV) infections in the intestines of mice [Considering that all enteric viruses encounter the intestinal microbiota as they traverse the GI tract, it is imperative to consider how virus–bacteria interactions may impact the outcome of viral infections. Indeed, two landmark studies published in  of mice ,25: Mice of mice . Unlike  of mice . Similar of mice ,28,29,30 of mice  and prom of mice . FinallyAlthough the mechanisms underlying commensal bacterial regulation of viral infections are less well-defined than for bacterial pathogens, a multitude of varied mechanisms have begun to emerge. While it is unclear whether all of these mechanisms require direct interaction between the enteric virus and commensal bacteria, certain mammalian enteric viruses including poliovirus , reoviruE. coli resulted in improved capsid antigen integrity and mucin binding ability after heat treatment compared to VLPs alone or after incubation with a non-capsid binding E. coli strain [One consequence of virion binding to bacterial glycans is particle stabilization A. For exi strain . Overalli strain .Another consequence of virus interactions with bacterial glycans is enhancement of virion binding to host cell receptors B. For exA similar model has been proposed for human norovirus infection of B cells : HBGA-exin vivo [Murine norovirus (MNV) attachment to its host receptor may be influenced indirectly by the intestinal microbiota. The MNV receptor has been identified as CD300lf ,44, a moin vivo ,46. Intein vivo . Considein vivo ,28,29. Cin vivo ,47,48.−/− mice. Conversely, no inflammation was elicited in germ-free IL10−/− mice infected with MNV though the inflammatory response could be rescued by colonizing the mice with a defined microbiota, demonstrating that MNV-induced inflammation in the absence of IL-10 is microbiota-dependent.Commensal bacteria are sensed by host intestinal epithelial and immune cells continuously, leading to the establishment of a tolerogenic microenvironment in the steady-state. Though the host immune system normally differentiates between commensal and pathogenic organisms to effectively mount an inflammatory response during infections, it is intriguing to consider what happens when a pathogen such as an enteric virus is attached to, and sensed concurrently with, a commensal bacterial ligand. One possibility is that the commensal bacterial signal will dampen or block the antiviral immune response via bystander suppression. Indeed, this appears to be the case during MMTV infections : As descThe intestinal microbiota also influenced the host interferon (IFN) response during persistent MNV infection in a manner promoting viral infection : Whereas−/− mice [Likewise, the interplay of commensal microbes and host immunomodulatory functions intersected in a manner that influenced acute MNV replication. The disruption of secretory immunoglobulin (sIg) function in the gastrointestinal lumen led to a proinflammatory state of increased type II IFN (IFN-γ) and iNOS production and an altered microbial community in the gut compared to control mice . MNV rep−/− mice . The sam−/− mice  instead −/− mice . It willEfforts to visualize the binding of poliovirus, reovirus, and norovirus capsids to bacterial cells each noted the presence of multiple virions bound per bacterium ,32,33,34The intestinal microbiota is beneficial for the host in several aspects: Gut bacteria aid in host metabolism, gut motility, and nutrient uptake, maintain host physiology and homeostasis, help shape the host immune system, and protect against invading microorganisms. Although bacteria in the gut have been studied for decades, the majority of polymicrobial interaction studies have focused on pathogenic-commensal bacteria relationships, leaving the influence of commensal bacteria on enteric virus infection largely unexplored.Recently, there has been a marked surge in reports exploring the effects of the host microbiota on enteric virus infection. These reports have a highlighted a stimulatory role for the commensal microbiota in the transmission and pathogenesis of numerous enteric viruses, including poliovirus, reovirus, rotavirus, MMTV, and norovirus. Although enhancement of viral infection by interactions with commensal bacteria has emerged as a phenomenon shared by multiple families of enteric viruses, there are myriad mechanisms of interaction through which enhancement occurs. Broadly these mechanisms include: The stabilization of viral particles by bacterial ligands aiding in host-to-host transmission; enhancement of virion attachment to target cells through direct interactions with bacterial molecules; modulation of host immunity by commensal bacteria promoting a tolerogenic environment permissive to viral replication; and enhancement of recombination potential through clustering of multiple virion particles for delivery during initial infection of host target cells . CurrentOne avenue of ongoing work aims to elucidate the effects of bacterial metabolites in shaping viral pathogenesis. Noroviruses benefit from association with bile acid compounds derived from bacterial metabolism. Another class of intestinal bacteria metabolites with potential roles in viral pathogenesis are the short chain fatty acids (SFCA) derived from the microbial breakdown of ingested carbohydrates in the intestinal lumen. It is reasonable to postulate that SFCA interact with enteric virus particles and impact pathogenesis similarly to bile acids. Additionally, both bile acids and SFCA are involved in complex physiological signaling processes spanning the digestive, nervous, endocrine, and immune systems. Research on the role of bacterial metabolites in the indirect shaping of viral pathogenesis through mediating host processes will lead to further insights on mechanisms of enteric virus pathogenesis and host responses to infection.


In the adult nervous system axon caliber varies widely amongst different tracts. When considering a given axon, its diameter can further fluctuate in space and time, according to processes including the distribution of organelles and activity-dependent mechanisms. In addition, evidence is emerging supporting that in axons circumferential tension/contractility is present. Axonal diameter is generically regarded as being regulated by neurofilaments. When neurofilaments are absent or low, microtubule-dependent mechanisms can also contribute to the regulation of axon caliber. Despite this knowledge, the fine-tune mechanisms controlling diameter and circumferential tension throughout the lifetime of an axon, remain largely elusive. Recent data supports the role of the actin-spectrin-based membrane periodic skeleton and of non-muscle myosin II in the control of axon diameter. However, the cytoskeletal arrangement that underlies circumferential axonal contraction and expansion is still to be discovered. Here, we discuss in a critical viewpoint the existing knowledge on the regulation of axon diameter, with a specific focus on the possible role played by the axonal actin cytoskeleton. During development, after reaching their synaptic targets, axons increase their caliber several fold to achieve the large diameters needed for the rapid conduction of action potentials. In the adult nervous system the diameter of axons belonging to different tracts varies by nearly 100-fold (~0.1–10 μm), in accordance with a wide variation in conduction velocity  and the microtubule-associated protein 1B (MAP1B) homolog Futsch form an evenly spaced, grid-like membrane-associated microtubule-organizing complex that determines axon diameter in the absence of neurofilaments  a submembranous stable actin-spectrin network (the membrane periodic skeleton), composed of actin rings regularly spaced by spectrin tetramers approximately every 190 nm . In thece Bray, . Evidency Smith, . In conty Smith, . This loIn vivo, in embryonic Drosophila, when motor neuron axons are slackened mechanically, axons shorten within 2–4 min and restore their straight configuration  were shown to contribute to the actin-spectrin network (Qu et al., 2+ levels. Given that Ca2+-calmodulin controls adducin (Gardner and Bennett, 2+ influx.In addition to longitudinal contractility, using confocal microscopy and spatial light interference microscopy, it has been recently shown that Overall, a mechanism in which longitudinal and circumferential axonal tension are coupled, is supported by recent data (Fan et al., Several data support that axon diameter is dynamic and regulated by activity-dependent mechanisms. In fact, nerves and axons from different species including giant axons of squid (Iwasa and Tasaki, de novo synthesis of membrane might be the source of the activity-dependent net enlargement of axons.Recently, the inability of conventional light microscopy to resolve thin unmyelinated axons, which can have diameters well below 200 nm i.e., below the limit of resolution of an optical microscope, has been overcome by the development of super-resolution microscopy. In agreement with the above seminal studies, using time-lapse STED microscopy in mouse brain slices, axons were shown to swell after high-frequency action potential firing (Chéreau et al., 2+-dependent mechanisms, destabilizing actin and thereby providing a mechanism for activity-dependent structural plasticity of the axon initial segment (Berger et al., Lately, new insights have been provided for the physical mechanisms that may account for the increase in axon diameter during action potential firing (Berger et al., in vitro their courses can be tortuous with complex twisting that may hamper withdrawing straightforward conclusions. If, as suggested by an emergent body of literature, an actomyosin network participates in the fine control of axon diameter, a possible interplay between the axonal subcortical cytoskeleton and the deep axonal actin filaments, as putative anchors of myosin filaments, may need to be explored. This is certainly a very exciting field of research that will further the notion that the cytoskeleton in the axon shaft is likely to be much more dynamic than initially expected.The cytoskeletal arrangement that regulates circumferential axonal contraction and expansion is just starting to be unveiled. Understanding its structure is likely to be a challenging enterprise as it will most probably rely on the simultaneous detection of multiple axonal components by super-resolution microscopy. Additionally, although axons are generally depicted as straight regular structures, even MS, AC, RP-C and SS wrote the manuscript.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.


Sarcopenia is a prevalent condition in the elderly population, imposing a significant impact over their functional ability as well as their quality of life. Furthermore, it is associated with greater incidence of major geriatric outcomes, as reduced mobility, falls, loss of independence, cognitive impairment, and all-cause mortality. Physical Exercise Programs directed to improve muscle mass and its function may be key to reduce sarcopenia consequences. However, a significant heterogeneity is found in clinical trials, especially as a consequence of different exercise protocols applied to research subjects.  To access the effects of physical exercise programs compared to no exercise interventions to improve sarcopenia components and its determinants in sarcopenic elder individuals.  A systematic review was conducted in the Pubmed database to identify randomized clinical trials (RCTs) which tested the effects of physical exercise programs to manage sarcopenia components in sarcopenic elder individuals. Two independent reviewers assessed the studies' eligibility according to specified inclusion criteria in a four-step strategy. Data regarding population characteristics, muscle mass, muscle quality, muscle strength, and muscle function were extracted from each one of the included studies. Assessment of quality and individual studies risk of bias were assessed through Cochrane Risk of Bias Tool®. Assuming theoretical expected heterogeneity among studies, especially regarding different physical exercise programs and different outcome measurements, authors decided to be conservative and present study results in descriptive tables.  Search strategy retrieved 298 papers on PubMed database. Three more were identified through manual search, being 301 studies revised for inclusion. 278 were excluded during title/abstract review. After further evaluation of 23 full-texts, 5 RCTs were included. All 5 trials tested the efficacy of isolated exercise programs to improve sarcopenia components in the elderly compared to no physical intervention. Resistance training was the main intervention component in all included trials compared to inactive control groups . Physical training improved muscle strength, muscle quality, and muscle function compared to inactive control groups. Considering muscle mass, no differences were demonstrated. Data meta-analysis was not possible to be performed due to high heterogeneity among trials and small number of studies for each outcome comparison.  Heterogeneity among trials and small number of RCTs limited robust conclusions and data meta-analysis. However, resistance training protocols can improve muscle strength and physical performance in elders previously diagnosed with sarcopenia, although its effect size and clinical impact are barely relevant. According to the European Working Group on Sarcopenia in older people revised consensus, sarcopenia is a skeletal muscle disorder in which muscle strength is the key feature of a clinical condition with increased risk for major geriatric outcomes . It is aIt is postulated that physical exercise programs can shift sarcopenia clinical course. A systematic review was conducted in 2014, and the authors concluded that physical exercise has an impact on improving muscle strength and physical performance; however, interventions did not significantly improved muscle mass. Several limitations were pointed out to explain the low impact of exercise interventions: lack of standardization of exercise protocols, low duration of interventions, heterogeneity in outcome measurements, and selection bias due to heterogeneous eligibility criteria.Most recently, in 2017, the last published systematic review regarding exercise and sarcopenia showed better physical performance after resistance training exercise intervention, but no improvement in muscle strength . Beyond Considering the aforementioned reasons, the main objective of this systematic review is to analyze the effectiveness of physical exercise on improving sarcopenia in older populations. Muscle mass, muscle function, muscle strength, and physical resistance improvement in the elderly will be investigated. Furthermore, we will show these effects on the incidence of major geriatric outcomes.This systematic review protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations .RCT testing effects of physical exercise programs were compared to those of a physically inactive control group on sarcopenia clinical variables in elderly populations previously diagnosed with sarcopenia. The eligible criteria are predefined by the characteristics of the primary studies. At this point, it is only necessary to define the following criteria: the target population, the intervention, and the outcomes. Characteristics of the included study populations, such as intervention types and outcome measure, are presented in Population: elderly (>65 years) with diagnosed sarcopenia; intervention and control: physical exercise programs compared to a control group (no exercise); outcomes: sarcopenia, muscle mass, muscle strength, physical performance, and muscle quality; length of follow-up: not specified; study design: randomized clinical trial. There was no limitation of gender. The types of exercises were predominantly resistance training .A systematic search was conducted in the PubMed electronic articles database using the following strategy: (((Sarcopenia) AND (Elderly)) AND  OR (Exercise)) AND ). No specific date limit was defined; no language limitation was imposed; all available studies were included. Last search was conducted on June 30th, 2019. For those articles with limited access or incomplete data, the authors were contacted directly by email. Additional manual search was performed to increase search sensitivity.(1) Study Selection and Data Collection Process. Step 1: two independent reviewers assessed all titles and abstracts to verify eligibility criteria on Revision. Step 2 included a full-text revision for further eligibility assessment. Step 3: duplicates were excluded. Final inclusion results are presented in the systematic review inclusion flowchart .Different measurement protocols were applied to assess outcomes among studies. In two studies—Strasser et al.  and LiaoResults regarding muscle mass, muscle strength, and muscle quality are summarized in RT exercise protocols significantly improved the muscle function measured by gait speed (GS) as well as by the Timed Up and Go test (TUG) in 3 of 5 studies as described in P < 0.001), especially a relevant difference in the physical component of the SF-36 questionnaire.In , qualityIn this systematic review to assess the effectiveness of exercise training to improve sarcopenia-related outcomes in sarcopenic elder populations, a sensitive search strategy retrieved 301 studies on PubMed database. During the first step review process, 278 papers were excluded and 23 more were excluded after full-paper review, leading to 5 RCTs to be included in this study.RCTs results according to sarcopenia component varied significantly. Only one study evidenced muscle mass gain; muscle quality, on the other hand, was improved in both studies that this factor was measured. Although effects over muscle strength and muscle mass were not clear, muscle function—walking speed and Timed Up and Go test—was homogeneously improved among studies, but the size effect seems to be limited.volume of training—defined as the total work sets per exercise session. Peterson et al. demonstrated that the greater the volume training the greater the muscle mass gain [However, it is presumed that resistance training prevents muscle mass wasting because it stimulates muscle hypertrophy and increases muscle strength, as postulated by Johnston et al. , and alsass gain . FurtherIn comparison with previous systematic reviews that evaluated the effect of physical exercises over sarcopenia components, published in 2014 , this prmixing apples and oranges,” referring to misplaced comparisons by data meta-analysis from theoretically heterogeneous studies, the specific case found in this systematic review.The authors decided not to run data meta-analysis to identify a single summary effect for each dependent variable as a significant heterogeneity among studies was assumed, especially regarding intervention protocols and measurement of sarcopenia components. Also noteworthy is the small sample sizes included in the clinical trials, imputing worrisome power limitations to detect significant outcome differences. All 5 studies have moderate to high risk of bias in accordance with the Cochrane risk of bias tool. Assuming these aforementioned limitations in conjunction with small number of available RCTs, it is not recommended to run data meta-analysis due to high risk of bias as meta-analysis will directly reflect the study biases. Additionally, as described by Borenstein et al. , it is vHeterogeneity among trials and small number of RCTs limited robust conclusions and data meta-analysis. However, resistance training protocols can improve muscle strength and physical performance in elders previously diagnosed with sarcopenia, although its effect size and clinical impact are barely relevant. Two trials were published since last available systematic review, both of it showing positive results of resistance training protocols over muscle quality and muscle function as well as better results in quality of life scores.


Changes in physiological measurements such as blood pressure or temperature may signal deteriorating health before it is apparent. Early warning (or track and trigger) systems provide a framework to use such measurements to identify acute illness and prompt a timely response. They are in widespread use in acute hospitals across North America and Europe, but few have been validated in community settings. Hospitals in the UK have adopted the National Early Warning Score (NEWS) which measures temperature, respiratory rate, pulse, blood pressure, oxygen saturation and conscious level. This presentation describes a multi-method evaluation of the introduction of NEWS into 47 long-term care facilities. Staff with little or no healthcare training were tasked with digital recording of the NEWS. This multi-method evaluation consisted of a survey to explore staff views (n=42), a quantitative analysis of approximately 17,000 NEWS readings, and 21 semi-structured qualitative interviews with stakeholders. Survey and interview findings suggested that use of the score increased staff confidence in communication and care. There were many challenges to implementation, including practical difficulties in measuring vital signs, competing priorities for staff and a persistent lack of shared understanding across professional boundaries. Quantitative analysis of recorded scores described an increase in use of the NEWS over time, but wide variation in uptake between different facilities. Early warning systems may enhance management of acute illness in long-term care facilities but implementation is not straightforward. This presentation will discuss will discuss findings in depth - what worked, lessons learned and implications for the future.