Its potential is fully exploited in the field of “nutrimetabonomics” that aims at assessing the metabolic effects of active ingredients and foods in individuals. Yet, one of the greatest challenges in nutrition research is to decipher the critical interactions between mammalian organisms and environmental factors, including the gut microbiota. “Nutrimetabonomics” is today foreseen as a powerful approach for future nutritional programs tailored at health maintenance and disease prevention.Metabonomics is a well established analytical approach for the analysis of physiological regulatory processes  Today metabonomics is considered as a well-established system approach to characterize the metabolic phenotype of an individual, which results from a coordinated physiological response to various intrinsic and extrinsic parameters including environment, drugs, diet, lifestyle, genetics and microbiome modulations. Metabonomic analysis refers at the global metabolic profiling of low molecular weight compounds  in biofluids (plasma/serum and urine), and tissue extracts or biopsies. Such complex biochemical fingerprints of hundreds, or even thousands, of metabolites reflect the overall metabolic status of an individual, i.e., its metabonome, as the result of highly complex metabolic exchanges within and/or between diverse biological compartments. Since metabolites are the end-products of multiple interactions between biological processes, applications of metabonomics to nutrition sciences provide an exploratory but unique opportunity to depict the molecular mechanisms involved in individual responses to dietary modulations. With the overall aim to provide health maintenance, these scientific challenges are today modulated through the understanding of metabolic disorders and the efficacy of active ingredients.1H-Nuclear Magnetic Resonance (NMR) spectroscopy, gas or liquid chromatography coupled to mass spectrometry (GC/MS and LC/MS) with lately, the addition of ultrahigh performance liquid chromatography systems coupled to mass spectrometers (UPLC/MS) , but it is also today commonly employed for the study of metabolic profiling of intact tissue biopsies, using High Resolution Magic Angle Spinning NMR (HR-MAS). Therefore, HR-MAS, presents the unique feature of ensuring the integrity and organizational compartmentation of the biological samples.The field of metabonomics employs two major analytical techniques based on UPLC/MS) . High-reHowever, NMR spectroscopy is inherently less sensitive compared to MS. MS methods are commonly employed for global and targeted profiling, and require well adapted sample preparation  with sepMetabonomics has shown in the past numerous applications in the study of diseases diagnostics, and in the investigation of physiological changes caused by toxic insults ,10,11,12The main goal of nutrimetabonomic studies is therefore to study the effects of selected ingredients and foods in healthy individuals , specifiOther works demonstrated the potential of metabolic profiling for surveying the outcome of nutritional interventions for modulating and preventing metabolic deregulations ,18. ReceMuch attention today is also given to the use of probiotic supplements as a means to promote gut health preventing allergies and inflammatory incidences. The effects of a therapeutic intervention with probiotics on normalizing the metabolic disorders acquired in post-infective irritable bowel syndrome were monitored using both systemic and tissue-specific metabolic profiling . These iYet, while many applications in the very next future can be easily envisioned, with personalized nutrition programs as the main objective, nutrimetabonomics remains today an extremely complex science to decipher. Indeed, food-induced metabolic changes are not only the end results of many complex interactions among many active molecules, but also vary extremely among individuals as differences in endogenous factors such as age, environment, genetics, lifestyle, and gut microbiota strongly influence individual responses. For this reason, to maximize the control over these variables and to exclude fictitious interpretations, when analyzing the effects of specific nutritional intervention programs, it is imperative to employ appropriate experimental designs. This is limited most of the time to rigorous inclusion/exclusion criteria and accurate collection of individual dietary and feeding habits.The contribution of the gut microbiota on the mammalian metabolism had been recently deeply investigated ,23,24,25et al. who describe at first a top-down view model of the effects of different gut microbiome on murine metabolic profiles [Indeed, the symbiotic relationships among animals and their gut had been extensively studied by Martin profiles . The autLactobacillus paracasei and Lactobacillus rhamnosus probiotics in mice inoculated with a simplified model of human gut microbiota. Changes in dietary carbohydrate and protein processing by gut bacteria with subsequent influence on host lipids and energy metabolism were revealed by the analysis of systemic fluids, liver, stools, and intestinal contents.The breadth and the depth of gut microbiome modulations of host biochemistry in this mouse model were further explored by modulating the gut functional ecology with pro-, pre-, and synbiotics ,41,42. GAs an alternative, the combined use of prebiotics and probiotics may offer superior effects in health maintenance through modulating the microbial functional ecology . Here, mAdditionally, in a follow up paper, the authors analyzed the effects of single prebiotics and probiotics and their synbiotic effects on the metabolic status of germfree mice during the establishment of a simplified model of human microbiota. In this paper, to properly assess the dietary modulations of the gut microbota at a system level, multicompartmental modeling approach with metabolic imprints from 10 tissue/fluid samples was applied . InteresWhile deciphering the interactions between the gut microbiota and the host remains a very challenging process, research advances in recent years have positively elucidated key metabolic processes disclosing in depth how the gut microbiota exert control over the host’s biochemistry. Imperative for the development of nutritional management programs and for the amelioration of individual health will be in the very next future to comprehensively embrace the full dynamics of these interactions.As previously expressed one of the greatest challenges in modern nutrition research is to decipher how changes in the environment and lifestyle conditions regulate not only human physiology but additionally human ability to attain different nutritional needs. With these aims, the analysis of biofluids by metabonomic means permits the assessment of spatiotemporal interorgan metabolic cross-talk, while the analysis of such information by complex data mining techniques allow the assessment of the functional relationships among different biological compartments. Specifically, the combination of metabolic profiling and multivariate analysis was successfully proved to infer inter-compartment metabolite relationships from plasma, liver, pancreas, adrenal gland and kidney cortex samples . Such a Modern nutritional research focuses on health promotion and disease prevention through diets. Nutritional solutions have indeed been developed for the management of several chronic conditions, such as obesity and type 2 diabetes. It is therefore expected that, for this scope, nutrition and health will commonly aim in the very next future into the optimization of food products specifically tailored to match consumer specific needs to promote health and wellness. Metabonomics will provide the required instruments to monitor the metabolic health of consumers and maintaining homeostatic balance. Indeed, adjusting the diet according to the health status will be one of the projected benefits. The change of adapting personalized nutritional programs will not only lie in the diagnostic tools, consumer demands and awareness, or measuring technology, but will mostly rely on sound scientific bases. Such processes had been already proven to be well initiated.


Our results show that, in both central and peripheral cell models, isoprenaline could not only shorten the action potential duration, but also increase the amplitude of action potential. The mutation impaired the SAN pacemaking. Simulated vagal nerve activity amplified the bradycardic effects of the mutation. However, in tissue case, the pacemaker activity may show temporal, spatial, or even spatiotemporal cessation caused by the mutation. Addition of isoprenaline could significantly diminish the bradycardic effect of the mutation and the SAN could restart pacing and driving the surrounding tissue. Positive effects of isoprenaline may primarily be attributable to an increase in iNa and iTCa, which were reduced by the mutation.The mechanism of isoprenaline exerting its effects on cardiac pacemaking and driving in sick sinus syndrome is controversial and unresolved. In this paper, mathematical models for rabbit sinoatrial node cells were modified by incorporating equations for the known dose-dependent actions of isoprenaline on various ionic channel currents, the intracellular Ca Compared with Figures iNa  was reduced or even zero in Figures iLCa, and irK,) were not greatly affected (data are not shown). Thus, we can conclude that the slowing of the pacemaking was primarily attributable to the mutation-induced decrease in iNa and iTCa, , iNa was significantly increased as well as iTCa,  Iso could accelerate the pacemaking rate and affect the shape of action potentials in both the central and peripheral SAN cells, which are consistent with experimental observations , 24. (2)


During functional magnetic resonance imaging studies of meditation the cortical salience detecting and executive networks become active during “awareness of mind wandering,” “shifting,” and “sustained attention.” The anterior cingulate (AC) is activated during “awareness of mind wandering.” The AC modulates both the peripheral sympathetic nervous system (SNS) and the central locus coeruleus (LC) norepinephrine systems, which form the principal neuromodulatory system, regulating in multiple ways both neuronal and non-neuronal cells to maximize adaptation in changing environments. The LC is the primary source of central norepinephrine (C-NE) and nearly the exclusive source of cortical norepinephrine. Normally activated by novel or salient stimuli, the AC initially inhibits the SNS reflexively, lowering peripheral norepinephrine and activates the LC, increasing C-NE. Moderate levels of C-NE enhance working memory through alpha 2 adrenergic receptors, while higher levels of C-NE, acting on alpha 1 and beta receptors, enhance other executive network functions such as the stopping of ongoing behavior, attentional set-shifting, and sustained attention. The actions of the AC on both the central and peripheral noradrenergic systems are implicated in the beneficial effects of meditation. This paper will explore some of the known functions and interrelationships of the AC, SNS, and LC with respect to their possible relevance to meditation. During a recent functional magnetic resonance imaging (fMRI) study of focused mindfulness meditation the cortical salience detecting and executive networks, were shown to become active during “awareness of mind wandering,” “shifting,” and “sustained attention,” while the default mode network (DMN) was active during “mind wandering” . This paThe salience detecting and executive networks include the anterior insula, anterior cingulate (AC), anterior inferior parietal, dorsolateral prefrontal cortex (DLPFC), and anterior medial prefrontal cortex . These aThe AC is a major component of the medial prefrontal cortex (mPFC). In much of the relevant literature, the mPFC is roughly divided into two subregions, relative to the genu of the corpus callosum: the dorsal medial prefrontal cortex (dmPFC) and the ventral medial prefrontal cortex (vmPFC) .Broadly defined, the dmPFC includes areas of the salience detecting/executive FPC network including the dorsal AC [BA24 and BA32], the anterior medial frontal cortex [BA10], and the DLPFC [BA9/46]. The areas of the medial frontal gyrus encompassing the dorsal attention network (DAN), including the pre-supplementary motor area (pre-SMA) and frontal eye fields [BA8], and the supplementary motor area (SMA) [BA6] are also a part of the dmPFC. The vmPFC includes the subgenual AC area [BA25], the vmPFC [ventral portions of BA32 and BA10], and the medial orbitofrontal cortex [BA11 and BA12], areas associated with the DMN and the amygdala (AM).The salience detecting/executive FPC network shifts between and relates to both the externally directed DAN, which receives the stimuli of the present moment from the external environment, and to the internally directed hippocampal–cortical memory system, a part of the DMN .The salience detecting anterior insula and AC of the FPC network also receive the interoceptive information from within the organism, which underlies the sense of oneself and of one’s emotions . The intIn turn, the dorsal AC  and the The more ventral, emotion associated, portions of the AC [BA 25 and BA32] also project to the parasympathetic vagal nuclei including the dorsal motor nucleus (DM), the nucleus of the solitary tract (NTS), and to both the periambiguus and core areas of the nucleus ambiguus (NA) .The NA contains primary source nuclei for the cardiopulmonary branch of the vagus and has myelinated axons thought to rapidly modulate the function of the heart and lungs . Some neThe NA is also closely linked to the rapid expression and regulation of emotional state . A withdRapid autonomic changes, including cardiovascular and respiratory changes, such as respiratory rate, respiratory sinus arrhythmia, and heart rate variability , are thoCentral and autonomic interactions altered by short-term meditation suggest control of parasympathetic activity by the AC [BA25 and BA32] . This coThe AC also directly modulates the central norepinephrine (C-NE) levels by increasing activity in the LC , the priThe AC is normally activated by novel or significant stimuli . In turnThe LC projects throughout the brain, is the principal source of C-NE in the thalamus , and theThe LC acts both synaptically and by volume transmission  on its tSilent only during rapid eye movement (REM) sleep , increasThe integrated P-NE and C-NE systems form the principal neuromodulatory system, a homeostatic system regulating in multiple ways the activity of both neuronal and non-neuronal  cells  to adaptAs a part of the salience detecting/executive FPC network, the AC is in a position to integrate the information  concerniThe LC is thought to optimize attention and behavior in changing environments . ActivatAll the areas of the brain activated by the intentional, impartial, sustained attention of meditation are of significant, interrelated importance, including the insula, the other cortical salience detecting network area . One of Immediately prior to the conscious awareness of voluntary, self-determined conscious decisions there is a consistent decrease in heart rate . StudiesVentral AC activation has been found in fMRI studies to be significantly correlated with HF-HRV suggesting AC control of parasympathetic autonomic activity . The preAs mentioned, rapid autonomic changes, including cardiovascular and respiratory changes, such as respiratory rate, respiratory sinus arrhythmia, and heart rate variability , are thoCentral and autonomic interactions altered by short-term meditation suggest control of parasympathetic activity by the ventral AC [BA25 and BA32] . This coThe decreases in respiratory rate, whether spontaneous or intentional, and the increases in HF-HRV that occur during meditation may all reflect the same vagal inhibition of sympathetic influences.The positive correlation of the FPC cortical areas with HF-HRV also suggests that HF-HRV is low when peripheral arousal is high . As mentThe C-NE of the LC has potent and long-lasting effects on thalamic and cortical neurons  and is iIncreases in C-NE and serotonin in both the thalamic reticular nucleus (RN) and the lateral geniculate nucleus (LGN) shift the thalamic firing pattern from a spontaneous rhythmic bursting mode to a single-spike mode . These mStimulation of the LC, simulating LC burst firing, increases neuronal firing in the LGN resulting in a highly discriminable signal in the LGN. During waking, LGN neurons have a single-spike firing mode when sensory information is faithfully relayed from the retina to the cortex and a burst-firing mode when the transfer of this information is degraded . During Large-scale cortical synchrony, which depends on the integrity of corticothalamic feedback, is thought to act predominantly through the RN . AlthougData suggests that the AC generates electroencephalographic (EEG) task-related theta waves . FrontalThere are both direct cholinergic and serotonergic pathways and indirect modulatory LC and AM pathways in EEG activation , 1998. IAlpha waves, on the other hand, are associated with the DMN, which was found to be active during mind wandering in a focused mindfulness meditation study . Alpha wAlpha waves spontaneously occur intermittently during an awake, relaxed, resting state, particularly with closed eyes , when thUnderstanding of the origins of the occipital alpha rhythm is incomplete, but a plausible scheme is thought to include a complex interplay between the LGN and RN of the thalamus and the visual cortex . The cenIn the resting state a decrease in the release of C-NE and serotonin in the thalamus may promote the occurrence of rhythmic oscillations .Alpha EEG waves are frequently recorded during studies of transcendental meditation . Beyond During mindfulness meditation, increased EEG activity in both theta  and gammAnterior cingulate activity elevates LC baseline firing , and LC The P300 event-related potential (ERP) is thought to index AC activated LC phasic burst responses to stimuli  and the Lower (phasic) baseline firing in the LC is associated with large phasic bursts of firing to selectively attended stimuli  accompanIn meditators, the P3a ERP amplitude to distractor stimuli is reduced  and theyThe increased activation of the AC during meditation would be expected to cause higher tonic LC baseline firing in meditators, while the associated more frequent smaller bursts to various stimuli and their shorter refractory periods may underlie the meditators’ enhanced receptivity to the second target as suggested by the existing hypotheses , 2009.Pupil dilation, under constant illumination, is mediated almost exclusively via C-NE release by the LC . Pupil dPupil dilation following stimuli reflects AC decisions . The dilIn the cortex, relatively low, moderate levels of C-NE act on the alpha 2 adrenergic receptors to enhance working memory in the DLPFC in an inverted U shaped manner . Higher During the salience detecting orienting response there is an initial inhibition of ongoing behavior , a stop,A stop of on going behavior is required for attentional set-shifting, as seen in meditators. As with attentional set-shifting and sustained attention, the stopping of on going behavior is improved by higher levels of C-NE acting on cortical alpha 1 and beta adrenergic receptors , while mThe synaptic specializations of the dorsal AC area BA32 indicate it has complementary roles, potentially enhancing the inhibition of spontaneous firing in the working memory DLPFC area [BA46] and strengthening excitation in the anterior medial prefrontal cortex [BA10], enhancing the capacity for more difficult, complex multi task operations . LC actiThe AC has connections to the SMA, which mediates the preparation and initiation of movement . The intThe SMA and pre-SMA are considered part of the externally directed DAN , but theThe supplementary eye fields, frontal eye fields, pre-motor and motor cortices all share reciprocal connections with the LC . The LC Higher baseline (tonic) firing in the LC is associated with enhanced labile attention and modest burst firing to various low salience distracter stimuli. This enhanced receptivity to the stimuli of the present moment is thought to optimize learning in unknown novel environments .During one of the earliest western scientific studies of meditation, the Zen masters reported that during meditation they had “more clearly perceived each stimulus than in their ordinary awakening state” . Long-teIncreased receptivity to stimuli, as initiated by the activation of the FPC orienting system to oddball stimuli, causes a subjective expansion of time . Such a In contrast, lower, intermediate, more synchronous phasic baseline firing in the LC promotes larger, robust bursts to attended significant known stimuli, rapid well-learned dominant, autoassociative responses, enhanced selective attention, and reduced responding to distractor stimuli. This pattern is thought to optimize behavior in known familiar environments  with a wIn the LC, changes in baseline firing, along with their associated subsequent bursting patterns, differentially modulate the state of the brain, the central nervous system, to optimize behavior in either novel or familiar environments, particularly if they are stressful environments.Similarly, in the peripheral SNS, epinephrine (P-E) and P-NE are differentially released from the adrenal medulla  under stDuring circumstances of novel stress a substantial amount of P-E is released from the adrenal medulla along with a small amount of P-NE . P-E eleIn contrast to novel stress, under conditions of familiar stress , especiaAs mentioned, there is an inverse relationship between cortical arousal and peripheral SNS arousal , 2013. TThe dose-dependent inhibition of baseline firing in the LC by elevated blood pressure  may contIn contrast, enhanced CNV cortical arousal-related activity in the AC, the midcingulate/SMA and the insula is associated with decreases in peripheral SNS arousal , which mA limited number of areas differentially influence activity in the integrated central noradrenergic LC and the peripheral noradrenergic SNS systems.These areas have been briefly addressed above.The orbitofrontal cortex (OFC) is another prominent descending cortical projection to the LC . ActivitThe ascending autonomic tracts from the periphery also influence the LC. Cardiorespiratory, visceral and somatosensory autonomic stimuli regulate LC activity through ascending autonomic tracts with putative implications for psychiatry and psychopharmacology . The carThe parasympathetic vagus nerve influences activity in the LC, primarily via the NTS, while the ascending sympathetic lamina 1 STT projects directly and reciprocally to the LC .The LC projects reciprocally to central autonomic nuclei including the sympathetic VLM, the parasympathetic DM, and regions of the NTS. The LC also projects to the region of the parasympathetic NA . The LC As mentioned, the NA contains primary source nuclei for the cardiopulmonary branch of the vagus , has myeThere are alpha 1 , alpha 2Locus coeruleus activation dilates the airways via NA alpha 2 adrenergic receptors , while fThe NA is also, as previously mentioned, closely linked to the rapid expression and regulation of emotional state . A withdFollowing bilateral lesions of the LC, animals fail to show normal cardioaccelerator responses to threatening stimuli . The losThe AM forms the core of a second, early-activated emotional salience detecting network or orienting system comprised of the superior colliculus, pulvinar, and AM . This syThe early AM and the later cortical salience detecting orienting networks are reciprocally interconnected, sequentially activated, and both modulate the activity levels in the LC and in the SNS, each contributing differentially to adapt the state of the whole organism to environmental change.The AM has reciprocal projections to the LC, the AC, and to the NTS and DM, amongst various other regions including the VLM, insula, and OFC .The AM projects reciprocally to both the dorsal AC of the dmPFC and to the ventral AC of the vmPFC. The tract between the AM and the ventral AC is a white matter tract , allowinAlthough the AM was long presumed to project to the NA  to rapidFollowing stimuli, the AM directly receives an early relatively “crude” version of the stimuli via the superior colliculus and pulvinar in10–20 ms . If the When conditions allow for cortical processing, the mPFC, both dorsal and ventral, is believed to regulate and control the AM, either increasing or decreasing AM activity , b. DuriFollowing a familiar, stressful, significant stimulus, with a known coping response available, the AM is thought to “take the PFC “off line” to allow faster, more habitual responses mediated by the posterior and/or subcortical structures to regulate behavior” .The cortical mPFC, however, can in turn regulate and control the AM , 2011b, Meditators exhibit lower activity in the AM , an inhiThe central nucleus of the AM (CeA) projects to the LC. Stimulation of the CeA stimulates the LC, producing a large single or double burst, followed by an extended refractory period . In respActivation of the LC modulates activity in the basolateral amygdala (BLA) by releasing C-NE. The C-NE inhibits spontaneous firing in the majority of the BLA neurons via alpha 2 adrenergic receptors, while exciting others via beta adrenergic receptors .Elevated activity in the LC acts via the BLA beta adrenergic receptors to enhance the consolidation of memory  in the hArousal-induced release, or systemic injection of the peripheral adrenal hormones P-E and cortisol (corticosterone in rats) enhances the consolidation of memory via the action of C-NE on BLA beta receptors .Considerable evidence indicates that peripheral action on the vagus nerve stimulates the LC to release this C-NE in the BLA . SystemiActivation of the LC by exercise has also been shown to enhance memory, including in older people and those with the early stages of Alzheimer’s disease .Following acute stress there is a period of increased connectivity between the AC, LC, and AM, which may contribute to the consolidation of memory for the significant events . The LC In controls, increased norepinephrine in the BLA inhibited spontaneous firing in the majority of the BLA neurons, with some showing excitation at lower doses but inhibition at higher doses. Norepinephrine also decreased responsiveness of these neurons to electrical stimulation of the entorhinal and sensory association cortices . HoweverDuring stress, the CeA is a major source of elevated corticotropin-releasing factor (CRF) in the peri-coerulear LC , 2010, tThe Vpm thalamus is the thalamic relay nucleus for the sympathetic STT, which carries the afferent interoceptive information, including pain, to the anterior insula  and to the somatosensory BA3a , 2009. TThe LC projects reciprocally to the STT . The desActivation of the LC can produce profound antinociception  and can Fear-induced antinociception also occurs via LC pathways , seizureChronic pain stress changes the influence of the AM on the LC from excitation to inhibition .Locus coeruleus responses to noxious stimulation were initially enhanced following experimental neuropathy, however, after 10–14 days microinjections of glutamate into the CeA produced a dose-related inhibition of the discharge rate of LC neurons. There was no significant effect on discharge rates in control groups. Spinal antinociception due to LC electrical stimulation was also weaker in the nerve injured rats. The enhanced inhibition of the LC by the CeA was thought to suppress the noradrenergic pain inhibition and promote neuropathic pain .Long-term pain can increase the likelihood of mood or anxiety disorders by as much as threefold .Long-term chronic pain (>28 days) caused an increase in LC bursting activity, tyrosine hydroxylase expression and that of the norepinephrine transporter; and enhanced expression and sensitivity of the inhibitory alpha 2 adrenoceptors in the LC. This was accompanied by an inability to cope with stressful situations, depressive and anxiogenic-like behaviors . As mentMeditation has been repeatedly found to reduce pain .In a 2012 review of meditation-related pain relief, mindfulness meditation was found to significantly reduce pain through a number of unique brain mechanisms . In mediIn meditators, most of the areas of the brain associated with the reduction of pain, including the salience detecting dorsal AC and insula, the primary somatosensory area and the thalamus, receive projections from the ascending STT , 2009. TChemical or electrical stimulation of the vagus nerve alters LC activity and that of its forebrain targets suggesting that the therapeutic effects of vagal nerve stimulation (VNS) may involve the LC-noradrenergic system . It has The initiation of VNS activates the LC , increasA recent review discusses some of the beneficial effects of mindfulness-based stress reduction, mindfulness-based cognitive therapy, and Zen meditation to alleviate depression, anxiety, pain, and psychological distress .The kinds of pain and suffering alleviated by meditative practices, are remarkably similar to those alleviated by stimulation of the vagus. The increased activation of the LC by both practices may contribute to the beneficial similarities.The LC–NE network optimizes coupling of cerebral blood volume with oxygen demand through local vasodilation in active brain areas, while constricting volume in other areas . Of incrYogic meditation downregulated transcripts of pro-inflammat-ory cytokines, decreasing expression of NF-kB associated pro-inflammatory genes . MindfulIn post-mortem studies of depressed humans a loss of glial cells has been demonstrated in the AC, DLPFC, and OFC, amongst other areas . It has Research indicates that LC neuron loss appears with aging  and deprStructural changes are observed in various brain areas of meditators . The eleIn early 2012, when the Hasenkamp paper was published and research for this paper began, some aspects of the AC’s activation of the LC and inhibition of the SNS to maximize adaptation in changing environments were already known. Included were the increased receptivity to the stimuli of the present moment caused by activating the LC; the possible reduction of stress through the inhibition of the stress associated SNS; the LC behavior patterns and the potential importance of understanding that the LC is not activated in tandem with the SNS, but that stress associated elevated P-NE inhibits the LC dose-dependently enhancing the phasic behavior pattern; that higher tonic base line firing is not associated only with stress and arousal, but with increased receptivity to the stimuli of the present moment, with increased awareness. These aspects were already understood and seemed of significant importance to understanding the neuroscientific process underlying the changes in state initiated by meditation.During 2012 and 2013, however, numerous papers have been published that further implicate the integrated norepinephrine systems in the enhancement of cortical executive network functions and in the modulation of the AM, NA, VPm, STT, and pain, as well as in the modulation of astrocytes and glia, blood volume, oxygen supply, cellular energy metabolism, inflammation, and even of neuroplasticity.These aspects were generally unknown in early 2012, and have vastly expanded the understanding of the role of the AC’s activation of the LC and inhibition of the SNS in general, and potentially in the beneficial changes initiated by meditation.The AC and the anterior insula, together, form the cortical salience detecting network, are usually jointly activated, contain numerous recently evolved von Economo neurons, and undergo structural changes in longer term meditators. Reviews of their functions  implicatThe AC is active during salience detecting and monitoring of the stimuli in the present moment, is naturally activated by novel or significant stimuli and normally ceases activity as the event-encoding cycle ends. During mindfulness meditation the AC is active “at the moment of awareness of mind wandering.” This suggests the AC is active “at the moment of awareness” of whatever is occurring now, in the present moment.During meditation, following the initial “awareness of mind wandering,” one “shifts” to “sustained attention,” one shifts to sustain the attention of awareness of the present moment.Without the development of a capacity to intentionally sustain the attention of awareness of the present moment, this quality of attention will normally be lost as the event-encoding cycle ends. The various practices of meditation, however, can develop a capacity to intentionally sustain the attention of awareness of whatever is occurring in the present moment, irrespective of the nature of the stimuli and irrespective of the environment from which they come, whether external, internal, or interoceptive.As mentioned, the salience detecting/executive FPC cortical orienting network, including both the AC and the insula, shifts between the external DAN and the internal DMN, while the AC and insula receive information from the interoceptive STT. This may allow the AC, in coordination with the insula, to monitor and detect the salience of the stimuli of the present moment from all environments, irrespective of the nature of the stimuli, whether known or Unknown.Meditation may develop the capacity for an intentional attention of awareness, which activates the AC of the salience detecting/executive FPC cortical orienting network, initiating a variety of physiological cascades through its modulation of the central LC and peripheral SNS norepinephrine systems, via both parasympathetic and sympathetic routes, to maximize receptivity and adaptation in changing environments.Buddha realized he had found a pathway to the elimination of pain and suffering. The inhibition of the SNS and activation of the LC by the AC during meditation may be a contributing factor worthy of further scientific exploration.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.


TCM mainly consists of crude drugs, slices for decoction, extracts and Chinese patent medicine preparations. Crude drugs are the raw and starting materials of preparation of slices, extracted intermediates and the finished products.The crude drugs being collected or cultivated from nature has many factors affecting its quality. Different species/varieties,different produce areas, different harvest times , different processing methods and different storage conditions can all cause an enormous diversity on the quality.It has been evidenced that the multi-originated herbs showed diverse in chemical profiles and consequently un-equivalent in pharmacological potency. This situation may be well recognized by pharmacogosists, however are often neglect or ignored by pharmacologists and TCM doctors in the biological activity screening, in non-clinical investigation research, and in clinical trials, which undoubtedly led to unrepeatability of the results and even wrong conclusive direction.As examples, four species of Rheum are recorded for Rhubarb in Chinese Pharmacopoeia but only one or two species possess diarrhea effects. As for Curcumae Radix, only the root of Curcuma longa L showed potent choleretic activity among the fure species of Curcuma recorded in Chinese Pharmacopoeia.In view of this consideration, the importance of a pre-experiment assessment of the starting material and the standardized and advanced methodologies for the authentication and quality evaluation of TCM herbs/products will be addressed in this presentation.


In the late years of the last century, the Belgian chicken crisis, lasted for more than half a year regarding import/export bans among EU countries and with non-European countries. The total economic costs of this crisis exceeded billion Euro. Since then the European Commission has established a set of instruments, including a rapid alert system, tight control measures and maximum limit values in food , feed and raw materials within the EU and for imported goods and products imported from non-EU countries. The development, introduction, and EU acceptance of fast and high capacity screening bioassays, such as CALUX provide for a methodology that can quickly assess the extent of the contamination, and therefore can limit the spreading of the problem and allow the early market release of food, feed and related products once they have been cleared by the fast screening tool. Nevertheless, the introduction of fast bio-analytical tools by various EU member countries and in the World is slow, mostly due to a variety of barriers  well-known to exist for introduction of novel technologies. However, in food crisis situations, affected countries show a high willingness to quick adoption and implementation of fast screening methods, in order to provide for sufficient analytical capacity and to limit the economic damages due to e.g., prolonged export bans. In this presentation the use and application of CALUX as a fast screening method is given, as well as its application in several food crisis cases will be presented, including the recent German Dioxin crisis in 2011.Environmental pollutants, such as polychlorinated dibenzo-p-dioxins (PCDDs), furans (PCDFs) and dioxin like PCBs keep appearing in the food chains due to their recalcitrant environmental characteristics and due to practices of raw materials, feed and food producers. Despite emission control measures taken, which have resulted in significant reductions in environmental contamination, Dioxin-food crises have appeared and still appear in the media almost every year, or sometimes several times a year since the beginning of the 21


BMC Biology experiments indicating a novel role of the adaptor protein p130Cas in sensitivity to apoptosis induced not only by proteasome inhibitors but also by the unrelated drug doxorubicin.Current interest in proteasome inhibitors for cancer therapy has stimulated considerable research efforts to identify the molecular pathway to their cytotoxicity with a view to identifying the mechanisms of sensitivity and resistance as well as informing the development of new drugs. Zhao and Vuori describe this month in http:// http://www.biomedcentral.com/1741-7007/9/73See research article:  BMC Biology by Zhao and Vuori, of an obligatory role for the focal adhesion protein p130Cas (Cas) in the cytotoxicity of bortezomib and a second proteasome inhibitor, MG132, illustrates some of the issues arising in connection with this quest.The potential of proteasome inhibition in tumor therapy was first suggested by the success of the proteasome inhibitor bortezomib in the treatment of multiple myeloma, for which at the time of its approval in 2003 there was no effective therapy. Since then, the emergence of side effects and resistance  on the oThe ubiquitin proteasome system (UPS) plays an essential part both in the normal turnover of proteins and destruction of defective ones, and in the regulation of cellular proteins that maintain cell cycle progression, growth, and survival -5. ProteAlthough the proteasome is essential for the regulated degradation of proteins whose cyclic destruction is required for cell cycle progression, as well as of crucial cell signaling molecules, it is thought to be the accumulation of aggregated proteins that is responsible for the effectiveness of proteasome inhibition in the treatment of multiple myeloma. Multiple myeloma cells are derived from the antibody-producing cells of the immune system, and unlike other tumor cells, produce very large quantities of protein , which makes them unusually susceptible to the toxic consequences of inhibiting the normal degradative mechanisms. Normal cells can survive therapeutic doses of proteasome inhibitors because they have a lower rate of proliferation and consequently less need for proteasomal regulatory functions ,4. MoreoThe studies of Zhao and Vuori  suggest Cas is a docking protein that participates in the transduction of integrin- and/or cytokine receptor-induced growth and survival signaling , and is Several lines of evidence adduced by Zhao and Vuori  indicateThe mechanism whereby Cas mediates proteasome-inhibitor-induced apoptosis is not clear. One obvious possibility is that the proteasome inhibitors are acting by allowing the toxic accumulation of protein aggregates which would normally activate the autophagic pathway, and by preventing this, Cas is promoting the apoptotic response to the resulting stress. However, Zhao and Vuori found similar effects of Cas in response to the DNA damaging agent doxorubicin, suggesting that the role of Cas in response to apoptotic stimuli extends beyond that induced by proteasome inhibitors.Earlier studies have shown that proteasome inhibition promotes Abl-mediated phosphorylation of Crk, disassembly of Cas-Crk complexes , and cell death . A role Zhao and Vuori have been able to rule out one possible contribution of Cas to the apoptotic response to proteasome inhibition and doxorubicin. Cas has a known proapoptotic activity that has been attributed to its cleaved form (Cas-CT), and MG132 indeed induces Cas-CT. In contrast to earlier reports, however, this is not required for the induction of apoptosis since the overexpression of cleavage-resistant Cas mutants in Cas-deficient MEFs increases sensitivity to MG132.in vivo. Cas is an integral molecule linking integrin or extracellular matrix-mediated growth and survival signaling, and disruption of this adhesion-regulated pathway, or lack of Cas, may cause detachment-induced cell death (anoikis) and/or autophagy. Other focal adhesion proteins, such as paxillin, have been implicated in autophagosome formation; and Cas interacts with paxillin. This interplay between Cas and paxillin or other focal adhesion kinases (FAKs) may provide an additional link to autophagy.The mechanism of the effects of Cas on the apoptotic response and on autophagy thus remains unclear, and the answer may require an understanding of the role of Cas in normal cells in vivo animal models, in order to assess clinical relevance. Quantitative assessment of Cas protein levels in patient tumor cells and their correlation with sensitivity to proteasome inhibitors may then provide further insight into selecting patient populations likely to respond. It is also worth pointing out that autophagy can help kill cells as well as rescue them [In any case, it is clear that the specific conditions and cellular context will be important in the influence of Cas on tumor cell survival and drug sensitivity. A number of previous studies, as Zhao and Vuori acknowledge, have shown an association of aberrant expression of Cas with tumor cell survival and drug resistance. For example, the overexpression of Cas activates growth and survival signaling pathways via phosphoinositide 3-kinase/Akt, ERK1/2, epidermal growth factor receptor, Rac, or Src, conferring doxorubicin or tamoxifen resistance ; activatcue them .Future studies in various cancer cell types examining Cas expression and associated responsiveness to proteasome inhibitors (and other drugs) may help to inform clinical trials of autophagy inducers or inhibitors in combination therapies.


Epidemiological observations increasingly implicate nutritional energy balance as a key risk factor for cancer development. Excess body weight is associated with increased risks of cancers of the endometrium, breast , kidney , colon, pancreas and oesophagus (adenocarcinomas), and is also a well-documented risk factor for high-grade prostate cancer. By contrast, regular physical activity reduces the risks of breast and colorectal cancers and potentially other tumour types, and overall, excess weight and lack of physical activity have been estimated to potentially account for one quarter to half of the occurrence of the most frequent tumour types in affluent, industrialized societies. Animal experiments have shown uniformly protective effects of dietary energy restriction against tumor development.Physiologic mechanisms that are thought to account for these effects of nutritional energy balance on cancer risks include changes in the metabolism of endogenous hormones, growth factors and inflammation factors, as well as in energy and nutrient status at the level of single cells. Together, these physiologic changes may stimulate cell growth and proliferation, inhibit apoptosis, and favour the occurrence of genetic mutations through increased oxidative stress. The key mechanisms that underlie these relationships of nutritional energy balance with cancer development may strongly depend, however, on tumour type.Prospective cohort studies have shown relationships of risks of various cancer types with blood levels of glucose and insulin, and insulin-like growth factor-l. Furthermore, increased levels of circulating androgens and estrogens and reduced levels of progesterone are strongly implicated especially in the development of cancers of the endometrium and breast, among women with excess weight. The implication of specific hormonal or metabolic factors in cancer development is further increased by a growing body of evidence from human intervention studies – e.g. using selective estrogen receptor modulators [SERMS] and aromatase inhibitors – and epidemiological studies on the effects of specific hormonal medications . Finally, several studies have shown increased risks of cancer, e.g. of the colorectum and endometrium, among subjects with higher than average serum levels of inflammation factors such as C-reactive protein, TNF-alpha or various interleukins.According to present estimates, excess weight and lack of physical activity are likely the most important risk factors after smoking for cancer occurrence overall in western countries, and better knowledge of the true magnitude of the problem and of physiologic mechanisms involved can help define guidelines for primary prevention. At the same time, the knowledge gained about the hormonal and other physiologic mechanisms that link nutritional energy balance to cancer increasingly is also informing translational research into cancer preventive and curative treatments.


The rhizosphere supports the development and activity of a huge and diversified microbial community, including microorganisms capable to promote plant growth. Among the latter, plant growth-promoting rhizobacteria (PGPR) colonize roots of monocots and dicots, and enhance plant growth by direct and indirect mechanisms. Modification of root system architecture by PGPR implicates the production of phytohormones and other signals that lead, mostly, to enhanced lateral root branching and development of root hairs. PGPR also modify root functioning, improve plant nutrition and influence the physiology of the whole plant. Recent results provided first clues as to how PGPR signals could trigger these plant responses. Whether local and/or systemic, the plant molecular pathways involved remain often unknown. From an ecological point of view, it emerged that PGPR form coherent functional groups, whose rhizosphere ecology is influenced by a myriad of abiotic and biotic factors in natural and agricultural soils, and these factors can in turn modulate PGPR effects on roots. In this paper, we address novel knowledge and gaps on PGPR modes of action and signals, and highlight recent progress on the links between plant morphological and physiological effects induced by PGPR. We also show the importance of taking into account the size, diversity, and gene expression patterns of PGPR assemblages in the rhizosphere to better understand their impact on plant growth and functioning. Integrating mechanistic and ecological knowledge on PGPR populations in soil will be a prerequisite to develop novel management strategies for sustainable agriculture. Photosynthetic terrestrial plants play key roles as ecosystem engineers . They co10 bacteria per gram of soil  and signals that attract microbial populations, especially those able to metabolize plant-exuded compounds and proliferate in this microbial habitat . Root ex of soil  and enco of soil . The cor of soil . Its com of soil . Since r of soil . Plant-d of soil .sine qua non for plant growth promotion .Most terrestrial plants develop their root system to explore soil and find nutrients to sustain growth. Root is a complex organ made of distinct regions such as the root tip, root meristem, differentiation and elongation zones, and emerging lateral roots . These rChanges in RSA may result from interferences of PGPR with the main hormonal pathways involved in regulating plant root development: auxin, cytokinin, ethylene, and to a lesser extend gibberellin, and abscisic acid (ABA) . The balFigure 1; ipdC/ppdC bacterial gene) is a key enzyme involved in the indolepyruvic acid pathway. Effects of ipdC mutants on plant root morphology are often altered in comparison to those of wild-type strains , and nitric oxide (NO). Indole-3-acetic acid (IAA) is the best-characterized auxin produced by many plant-associated bacteria, including PGPR . Exogeno strains .Azospirillum brasilense have a nitrite reductase activity and consequently are able to produce NO during root colonization . GUS staining appeared more intense on a wider region of the root tip as well as in the vasculature, suggesting that there was a change of auxin distribution in the root in response to STM196 inoculation, even though this strain is a low auxin producer  has been documented in various PGPR like polymyxa . Cytokinpolymyxa . Inoculapolymyxa . Bacterianalyses . ConsequAzospirillum brasilense  coding for an ACC deaminase, which degrades ACC into ammonium and α-ketobutyrate . Through the analysis of the infrared spectral characteristics of crude cell wall preparations of maize roots, Azospirillum lipoferum CRT1 had lower lignin content than uninoculated ones. This result contrasts with those aforementioned for biocontrol agents. Nevertheless, lower lignin content may facilitate cell elongation, and therefore overall root elongation. Similarly, Azospirillum irakense produces pectate lyases that are capable of degrading the pectate content of root cell wall and might allow its progression between root cortex cells and its functioning as an endophyte , and provide clues to understand the systemic effect of PGPR.In addition to their effects on root tissues, PGPR can modify the physiology and functioning of plant tissues located at a substantial distance from the colonized sites, such as shoots. Two types of mechanisms are involved. On the one hand, some PGPR can enhance nutrient availability/uptake for plant roots. Stimulation of plant nutrition will lead to modifications in primary metabolism and consequently will contribute to enhance growth. On the other hand, certain PGPR trigger specific systemic responses, mostly by unknown signaling mechanisms. High-throughput analyses of plant transcriptomic and metabolomic responses have evidenced the effects of PGPR on plant gene expression and metabolite accumulation, respectively. These results highlight the extensive effect of PGPR on whole plant physiology and functioning .The impact of PGPR on plant nutrition may result from effects on plant nutrient uptake and/or on plant growth rate . It is iPseudomonas, Bacillus, Rhizobium – are able to dissolve insoluble forms of phosphate  in leaves of Arabidopsis; upregulated genes were involved in maintenance of genome integrity, growth hormone and amino acid syntheses, ABA signaling and ethylene suppression, Ca2+ dependent signaling and induction of ISR . Some studies have shown that PGPR can elicit changes in the activities of root enzymes involved in the production of metabolites, especially flavonoids, leading to changes in the pattern of root exudation  in barley and wheat roots was increased when a rhizosphere bacterium was applied with the fungus  and biotic factors  that can lead to distinct expression patterns in space and time, possibly with different effects on host plant . In thisphlA, involved in DAPG biosynthesis, in Pseudomonas protegens (formely Pseudomonas fluorescens) CHA0 (phlA was increased fourfold in the rhizosphere of monocots (maize and wheat) compared to the rhizosphere of dicots (bean and cucumber). The analysis of six maize cultivars also revealed that phl expression and hence biocontrol activity could be affected by plant genotype  CHA0 . The expgenotype . Specifigenotype . Among 6ens CHA0 . No specpression . Umbellipression  whereas pression .acdS) is another bacterial function that may be differentially expressed according to plant genotypes. Indeed, in vitro experiments demonstrated that some compounds present in root exudates tightly control acdS expression. First, ACC, the precursor of ethylene that is metabolized by AcdS, can positively regulate acdS expression  indicated that this amino acid is abundant at the emergence of secondary roots  signals that allow bacteria to monitor their density and to coordinate gene expression only when a quorum of cells is achieved  and otheN-acyl-homoserine lactones (AHLs). In fluorescent pseudomonads, colonization properties and biosynthesis of antimicrobial metabolites, such as phenazines, is often subjected to an AHL-based QS regulation  but no effect is observed on cellulase activity and on the phytostimulatory effect , whereas others can intercept AHL or can act as a physical barrier preventing their diffusion  were upregulated on roots in the presence of Pseudomonas fluorescens F113 compared with its DAPG-negative mutant  and one mycorrhizal strain (Rhizophagus irregularis/Glomus intraradices JJ291) showed an increase of root surface, root volume and number of roots, although data were not statistically significant compared to the single Rhizophagus inoculation (Azospirillum strains were tested) could lead to significant modification of maize growth . When analysing plant growth-promoting effects, it is thus important to integrate the complexity of the interactions between PGPR populations within the rhizo-microbiome. To do so, functional ecology approaches are needed, in which the relations between the size, diversity and activities of PGPR assemblages in the rhizosphere are taken into account. This is of particular importance when assessing the effect of various environmental factors, including that of plant genotype.Many studies have deciphered the mechanisms of action of PGPR using one individual strain and one host plant. But in reality, as described above, PGPR strains are not acting individually in the rhizosphere but rather as part of bacterial communities, in which cell communication signals may coordinate the activities of all individual strains. Indeed, a vast array of PGPR populations displaying co-occurring plant-beneficial activities and that may share between each other antagonistic or synergistic effects are interacting with a same host plant , integrating competitive and inhibitory effects , both at plant species . Next-generation sequencing technologies have started to reveal their taxonomic and functional diversity. They have begun to bring new knowledge on the ecology of PGPR functional groups. In the near future, it is expected that metatranscriptomics and metaproteomics will develop drastically, and will allow further progress on the understanding of the activity and ecological behavior of natural PGPR populations within the rhizosphere. However, given the heterogeneity in space and time of the rhizosphere habitat, samplings at different times and locations within the plant rhizosphere and within fields will be essential to better understand the ecology and performance of PGPR at plant and field plot scales. Nevertheless, despite being very reductionist, mechanistic functional studies using one PGPR and one plant are still useful to investigate the ways PGPR exert beneficial effects on plants. We think that the most important advances on plant-PGPR cooperation will be brought in the future by combining both ecology and functional biology approaches.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.


Yoga is an ancient mind/body practice, which originated in the Indian subcontinent, that promotes overall health and well-being. Yoga's ultimate goal is the achievement of a state of unified consciousness. Historically, the practice of yoga included eight steps towards spiritual emancipation and included practices involving physical postures, breathing techniques, and meditation. Today, yoga is very popular in the West amongst the general public. Numerous modern schools or styles of yoga exist , most of which are forms of traditional Hatha yoga, each with their own distinct priorities in terms of the balance of inclusion of spiritual and physical practices, with some styles focusing more exclusively on physical postures despite the historical focus of yoga on inner development. Research on the psychophysiological benefits of yoga and meditation practice has revealed benefits in physical, mental, and emotional self-regulation. Demonstrated improvements in stress, anxiety, mood, and physical health and well-being have proven useful for therapeutic purposes, and this has led to the popular implementation of yoga as a primary or adjunctive therapy.Despite several clinical studies and systematic reviews on the effects of the different yoga styles, further research is required to clarify yoga's value as an intervention. With respect to yoga's value for specific indications and disorders, most studies report positive effects in favor of yoga interventions, although there are a variety of effect sizes observed. The degree of clinical benefit of yoga in any specific research trial may depend on a variety of factors including participant characteristics , diagnoses and study entry criteria, yoga intervention characteristics , compliance and attrition effects, and so forth. Moreover, as a relatively new field of research, most of the research trials are pilot studies, with typically small samples sizes, moderate methodological quality, and often inadequate control groups rendering the general findings tentative and in need of further research validation. For this special issue, we have invited investigators to submit original research articles and systematic reviews/meta-analyses on the clinical effects of yoga intervention programs. The special issue starts with a summarizing overview of published literature reviews on the clinical effects of yoga interventions on physical and mental health, and it continues with a wide range of scientific contributions, addressing specific aspects of a colorful field of research. Of course we are aware of the many unanswered questions and the methodological flaws and limitations of several of these studies, yet we believe that the papers of this special issue will shed light on a fascinating and expanding field within mind-body medicine that is rich with promising findings.Arndt BüssingArndt BüssingSat Bir S. KhalsaSat Bir S. KhalsaAndreas MichalsenAndreas MichalsenKaren J. ShermanKaren J. ShermanShirley TellesShirley Telles


Alcoholic liver disease (ALD) encompasses hepatic steatosis, which may progress to alcoholic hepatitis, fibrosis, and cirrhosis. It remains a leading cause of morbidity and mortality in the US and worldwide. The severity of liver disease correlates with plasma levels of bacterial products in patients, and experimental ALD depends on the level of gut derived bacterial products in rodents. Since intestinal decontamination and deficiency of bacterial product receptors or their downstream signaling molecules protect from alcohol-induced liver disease, bacterial translocation (BT), qualitative, and quantitative changes of the enteric microbiome are considered as being of fundamental importance in the pathogenesis of ALD. Recent enhancements in diagnostic technologies provide a better insight into these shifts. This review highlights vital events in ALD such as BT, the importance of Toll-like receptor (TLR) signaling, intestinal bacterial overgrowth (IBO), and changes in the intestinal microbiome. Furthermore, a treatment trial section of patients reviews possible future options of therapy for ALD modifying the enteric microbiome. Liver cirrhosis is the 12th leading cause of death in the United States, and 48% of all cirrhotic deaths are alcohol-related , Toll-like receptor (TLR) stimulation via bacterial ligands and consequent steps, intestinal bacterial overgrowth (IBO), and dysbiosis, as well as clinical trials of various treatment modalities of patients with ALD. It additionally refers to other etiologies of liver disease and the implication of the microbiome/bacteria therein.BT is defined as migration of viable bacteria or bacterial products from the gastrointestinal tract through the epithelium to mesenteric lymph nodes or other extraintestinal organs  or viable bacteria can be measured in the portal or systemic circulation. Plasma LPS levels were elevated in patients with alcoholic steatohepatitis and alcoholic cirrhosis  pathways are activated. TLR4 mutant C3H/Hej mice and TLR4 knock-out mice had mitigated hepatic steatosis, inflammation and necrosis in ALD compared to wild type mice -3b and Reg3g, two of the bactericidal proteins, have been found to be suppressed in murine and human small intestine after ethanol feeding and chronic alcohol abuse, respectively  displayed significantly diminished endotoxemia, BT, and liver damage in the course of acute pancreatitis and simultaneous heavy alcohol consumption  as opposed to the placebo-controlled group in which no change was observed  to L. acidophilus (probiotic) and inulin (prebiotic) alone, respectively, in Salmonella typhimurium-induced liver injury (Rishi et al., Synbiotics are mixtures of pre- and pro-biotics. Rats fed with synbiotics (ALD remains a leading cause of morbidity and mortality in the United States and worldwide. Since progression of ALD is partly driven by inflammatory responses to bacteria and their products, BT is a central event in the pathogenesis of ALD. This review highlights several mechanisms which facilitate BT, i.e., impaired bile flow, intestinal dysmotility, altered gastric pH, impaired intestinal immunity, and oxidative stress at the intestinal mucosa that increases intestinal permeability. Translocated bacterial PAMPs, in particular LPS, leads to TLR signaling and secretion of pro-inflammatory cytokines and chemokines, and this ultimately enhances alcoholic liver injury and steatohepatitis. Linked to BT and crucial in ALD are quantitative changes in the intestinal microflora. IBO is a driving force in the etiology of ALD. Given a leaky gut, overgrowth leads to increased luminal burden of bacterial products and toxins that can now traverse the gut barrier and encounter the liver as first organ in the body. This can be considered a second hit for hepatocytes that already encounter and metabolize ethanol. Recent advances in diagnostic technologies such as deep pyrosequencing have enabled a meticulous investigation of qualitative changes of the enteric microbiome. By means of these tools, dysbiosis has been described in preclinical and clinical ALD. Further studies are necessary to elucidate more clearly the exact impact of qualitative changes in the enteric flora on disease progression. Using metagenomics, transcriptomics, and metabolomics, future investigations need to focus on the identification of metabolites that mediate the effect of orally ingested alcohol to extraintestinal organs. Although there is promising but limited evidence that modulation of the microbiome using—biotics mitigate disease activity in patients, additional clinical studies on perhaps novel targets are still required before routine use of these agents is advisable.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.


Polymer science is a so pervasive and relevant discipline in the contemporary scenario that it is unnecessary to spend much words to emphasize its role. As a matter of fact, it has been proposed to designate our time as the polymer age, to mark its distinction from previous mankind eras dominated by a series of diverse materials  and to remark that our lifestyle would be hardly conceivable without polymers. The advent and the global scale establishment of the polymer technology has shaped the world around us and has profoundly changed its perspectives, as it occurs for any revolutionary technology. Despite the astonishing achievements we have witnessed along the years, many exciting challenges remain to be faced; these are well worth to tackle because of their impact on our everyday life: examples include green polymer chemistry, environmental pollution issues, polymers for energy storage and delivery, polymers for the human health.In the following, the research subjects considered most challenging and richer of promise will be touched upon; these will form the main focus of the Specialty Section Frontiers in Polymer Chemistry.time-resolved FTIR and solid-state NMR has contributed to check and refine the theoretical approaches. Improvements are expected in the near future along the directions of classical lattice fluid theories  and on the side of the available schemes to treat non-equilibrium glassy polymers . The extensive knowledge accumulated so far makes it a mature subject, but areas in rapid evolution still exist. Thus, although classical thermodynamic approaches are considered to be well established, major refinements are being proposed on the theme of H-bonding systems. Technologically relevant fields such as membranes for gas mixtures separation, drug delivery materials, barrier structures for food packaging, durability, and aging issues in polymers and polymer-composites, are all impacted by the ubiquitous occurrence of H-bonding interactions between the substrate and low molecular weight penetrants, especially water. Theories describing the transport properties of these systems by extending available mean-field models to include self- and cross-interactions are being actively investigated  chain-packing in the crystalline and liquid-crystalline states, rotational isomeric state theory, and in the simulation of the solid state, both crystalline and amorphous.A further physical-chemistry area in turbulent evolution is computational polymer science. The fast progress in terms of computing resources, coupled with the advent of powerful, less computationally intensive methodologies  provided the theoreticians  with a tool to tackle large chemical systems, well exceeding 100 atoms. This has opened up new opportunities, especially in regard to the interpretation of spectroscopic observables  in terms of electronic structure methods (Castiglioni, Synthesis and chemical modification of polymers is another area of exceptional progress. Fueled by the development of the controlled-synthesis routes [Radical Addition Fragmentation Transfer polymerization (RAFT, Barner-Kowollik, Two issues are driving worldwide research toward polymers from natural and renewable sources: the growing concern about environmental deterioration caused by the increasing production and disposal of conventional synthetic polymers, and the will to reduce the dependence of western economies from petrochemical products. Vegetable oils are one of the most readily available alternatives: they are cheap, renewable resources and the functional groups present therein can be suitably activated for polymerization (Yu et al., Polymers from renewable sources suffer two major drawbacks: the lesser mechanical properties and the sensible price compared to their conventional counterparts. To alleviate both these disadvantages, various blends and composites have been developed along the years: in this field improvements are required in connection to the synthesis of compatibilizers, which ensure optimum dispersion and better interfacial adhesion between the components. Furthermore, the technology of reactive extrusion, a complex and challenging area of polymer rheology, is actively investigated as a means to optimize the current products (Yu et al., Energy conversion, storage and delivery is a further sector where polymer chemistry is playing a major role Rabek, . Analysiin-situ formation of the inorganic phase, modified sol-gel routes whose chemistry can be tailored so as to be compatible with the presence of the polymeric matrix are being actively explored (Kickelbick, Enormous research efforts have been devoted during the last decade toward the development of nanocomposites. These were introduced in the 1990s as an extension of the classical polymer-composite concept (Pavlidou and Papaspyrides, From the considerations enumerated so far emerges a discipline rich of opportunities and challenges, whose development is likely to produce significant advancements in our society. The Specialty Section Frontiers in Polymer Chemistry was born to witness, disseminate, and foster these advancements.


The primary purpose of this topic is to collect scientific contributions providing novel insights in the cellular and molecular mechanisms of epileptogenesis as potential targets for innovative therapeutic approaches aimed at preventing the chronic epileptic disorder.Prevention of chronic epileptic disorder with an appropriate intervention might represent the most ambitious goal in the clinical treatment of this epileptic disorder, but has been largely unsuccessful to this point. Clinical trials aimed at prevention of chronic epilepsy have often produced negative, disappointing results. However, in most cases, these studies ultimately evaluated the downstream clinical manifestations, failing to monitor early, specific molecular epileptogenic events. Therefore, elucidation of the underlying mechanisms of epileptogenesis, are essential.Several types of brain injuries are causes of acquired epilepsy, including brain trauma, one of the most common causes of idiopathic epilepsy  is the most common form of refractory epileptic disorder often related to childhood seizures. The symptomatic manifestations of TLE appear only after a widespread irreversible damage of entorhinal cortex  receptors activity can contribute to spread of seizures in the limbic system. Recent evidences on the identification of intracellular signaling pathways activated by DA receptors activity are leading to promising studies aimed at the identification of novel targets for the treatment of epilepsy  integrity. ECM plays a critical role in the modulation of AMPA receptor mobility, paired-pulse depression, L-type voltage-dependent CaNeuronal cell death has been implicated as a causal factor leading to the development of the epileptic disorder. The findings reported in this topic support the idea that repeated seizures mediate neuronal necrosis and apoptosis prevalently associated to the activation of certain distinct anti/pro-apoptotic Bcl-2 family factors. Thus, epileptogenesis elicits apoptotic events by means of a specific pattern of Bcl-2 family proteins, which might represent a possible target of intervention to protect against the epileptic damage (Henshall and Engel, Hormones play an important role in the epileptic disorders. Corticosteroids, progesterone, estrogens, and neurosteroids have been shown to affect seizure activity in animal models and in human. However, the impact of hormones on epileptogenesis is still underexplored and controversial. Further studies are required in the field to generate evidences on the therapeutic potential of hormonal agents in epileptogenesis Reddy, .The circadian pattern of seizures is one of the first phenomena described in the epileptic disorders. However, due to the lack of promising hypotheses, has not attracted enough scientific attention. Recent findings provide novel insights in the implication of circadian rhythm in modulating transcription factors governing clock genes expression, and the mTOR signaling pathway, one of the most relevant signaling pathway in epilepsy Cho, .


Escherichia coli represents the most facile approach for the preparation of non-glycosylated proteins for analytical and preparative purposes. So far, the optimization of recombinant expression has largely remained a matter of trial and error and has relied upon varying parameters, such as expression vector, media composition, growth temperature and chaperone co-expression. Recently several new approaches for the genome-scale engineering of E. coli to enhance recombinant protein expression have been developed. These methodologies now enable the generation of optimized E. coli expression strains in a manner analogous to metabolic engineering for the synthesis of low-molecular-weight compounds. In this review, we provide an overview of strain engineering approaches useful for enhancing the expression of hard-to-produce proteins, including heterologous membrane proteins.Protein expression in  Escherichia coli has been used extensively for protein overexpression due to its rapid growth rate, ease of high-cell-density fermentation, low cost and, most importantly, the availability of excellent genetic tools. The optimization of recombinant protein expression in E. coli has been carried out largely by trial and error by varying simple parameters such as expression vectors, host strains, media composition, and growth temperature.Since the beginning of the modern biotechnology era in the late 70s, During the past years, extensive studies have shown that the replacement of codons within a heterologous gene with synonymous ones used preferentially in the expression host (codon optimization), and the manipulation of the nucleotide sequence of the translational initiation region can have a profound effect on recombinant protein yields -4. mRNA Directed evolution of the polypeptide sequence for improved synthesis and folding in a prokaryotic host, also termed as "expression maturation", has been employed successfully for a variety of complex heterologous proteins including mammalian G protein-coupled receptors (GPCR), hemoglobin, antibody fragments and other proteins -15. In eOne alternative to expression maturation is to engineer host strains that are suitable for the expression of particular classes of proteins, such as proteins with complex disulfide topologies, membrane proteins, or proteins with intrinsically slow folding kinetics, which, in general, are more prone to misfolding and aggregation. The advantage of this approach is its broader generality since it leads to the generation of high-expression strains for a variety of polypeptides that share some common features. Furthermore, analysis of the chromosomal or vector mutations that confer enhanced expression can provide a better understanding of the rate limiting steps in protein expression and perhaps be of general utility for the production of other similar proteins.E. coli through genetic and genome-scale engineering. Relevant technologies for the creation and isolation of overexpressing mutants and successful examples of increased protein yields are presented. The terms "genetic engineering" and "strain engineering" are used interchangeably throughout this text.Here, we will provide a review of current efforts to enhance recombinant protein production in Chromosomal lesions such as nucleotide substitutions, gene deletions or insertions and, alternatively, overexpression of homologous or heterologous genes can all influence the expression of target proteins. Genetic modifications can be introduced into DNA in a targeted manner within a specific cellular pathway known to be involved in protein biogenesis. Alternatively, when the causes of poor expression are not known, a library of random chromosomal gene fragments can be cloned and co-expressed with the target protein or, the entire genome may be subjected to random mutagenesis, followed by screening to isolate clones that confer increased protein production.Targeted strain engineering focuses on the introduction of mutations in DNA sequences known to affect protein synthesis, degradation, secretion or folding. Several excellent reviews describing the strategies for improving protein secretion or for limiting protein degradation have already been published -19. TherE. coli. Mutations, such as the well characterized rne131 allele, that attenuate the activity of this essential protein, confer increased mRNA stability, which can in turn result in higher protein expression levels . Th. ThE. coeriplasm . FurtherE. coli strains with markedly enhanced capacities for recombinant protein production. Several unique and powerful methods have emerged recently that allow the generation of large libraries of bacterial mutants carrying different types of genetic profiles. Furthermore, advances in high-throughput screening have enabled the monitoring of the overexpression phenotype at the single-cell level and the rapid isolation of the rare clones with the desired overexpression profiles. The information obtained from the analysis of the genetic profiles in the isolated strains can provide invaluable and fundamental understanding about the biology of protein biogenesis, folding, stability and homeostasis in bacteria. These pieces of information can subsequently be combined and utilized to generate specialized protein expression bacterial "cell factories" for uses in research as well as in the industrial field.Recent studies have demonstrated that strain/genetic engineering is a very promising approach for evolving engineered The authors declare that they have no competing interests.All authors defined the topic of the review and wrote, read and approved the manuscript.


Malaria continues to be a global public health challenge, particularly in developing countries. Delivery of prompt and effective diagnosis and treatment of malaria cases, detection of malaria epidemics within one week of onset and control them in less than a month, regular disease monitoring and operational classification of malaria are among the major responsibilities of the national malaria programme. The study was conducted to determine these indicators at the different level of primary health care facilities in malaria-affected provinces of IranIn this survey, data was collected from 223 health facilities including health centres, malaria posts, health houses and hospitals as well as the profile of all 5, 836 recorded malaria cases in these facilities during the year preceding the survey. Descriptive statistics  were used to summarize the results and Chi square test was used to analyse data.All but one percent of uncomplicated cases took appropriate and correctly-dosed of anti-malarial drugs in accordance to the national treatment guideline. A larger proportion of patients  were also given complete treatment including anti-relapse course, in line with national guidelines. About one third  of uncomplicated malaria cases were treated more than 48 hours after first symptoms onset. Correspondingly, half of severe malaria cases took recommended anti-malarial drugs for severe or complicated disease more than 48 hours of onset of first symptoms. The latter cases had given regular anti-malarial drugs promptly.The majority of malaria epidemics  in study areas were detected within one week of onset, but only half of epidemics were controlled within four weeks of detection. Just half of target districts had at least one health facility/emergency site with adequate supply and equipment stocks. Nevertheless, only one-third of them [33% (95% CI: 0.00 - 67.8)] had updated inventory of malaria foci on quarterly basis.To sum up, malaria case management still constitutes a public health problem in Iran. Additionally, data suggest scarcity in management and evaluation of malaria foci, detection and control of malaria epidemics as well as assignment of emergency sites across different regions of the country. Consequently, massive and substantial investments need to be made at the Ministry of Health to coordinate national malaria control programmes towards achieving determined goals and targets. Malaria is a global public health challenge, with about one million deaths each year and a further 250 million new cases of malaria diagnosed annually -3. InterThe Ministry of Health and Medical Education in Iran has focused its effort on recommended guidelines by World Health Organization (WHO) -9. TheseHowever, to date no comprehensive national malaria survey has been conducted to identify the coverage of these strategies in Iran. Additionally, the existing evidence about malaria indicators in the country, which has come mainly from routine surveillance data, is not sufficient to measure progress towards achieving national and regional goals and targets properly. Therefore, the present study was conducted to determine malaria indicators at the levels of health-treatment units and district health facilities and to investigate the quality of treatment of malaria cases in 20 malaria-affected districts in the three above-mentioned regions.Details of sampling methods have been described elsewhere . BrieflyIn a multistage random sampling, 125 clusters with an average size of 40 households were selected randomly from the study population. Firstly, sample size was divided based on the proportion of population in the three target provinces. Furthermore, since each province is, in turn, administratively subdivided into several districts and each district includes several rural and urban areas, the sample size of each province was divided based on the proportion of population in rural and urban areas. Secondly, all the health centers/units in the target districts in the three mentioned provinces were listed based on geographical regions and separately for urban and rural and then the populations were calculated cumulatively. At this stage, clusters and head-clusters (the first selected household as opening point for survey) were determined using systematic random sampling method. After that, trained personnel referred to the first household in every cluster and moved on their right side to cover the entire forty households in every cluster. Household information has been reported in a previously published article on malaria indicators at household level .The survey also collected information from all health facilities in which at least one household had been selected for this study. Consequently, the profile of 5, 836 recorded malaria cases within included health facilities during the year preceding the survey were reviewed and data were extracted to evaluate malaria diagnosis and treatment. Furthermore, all the target district health centres were censuses to estimate malaria indicators at district level or health centres. Having this approach, data were collected from 223 health facilities in both rural and urban area of malaria endemic regions in Iran distributed in S & B, Hormozgan and Kerman provinces.Three questionnaires were used for this part of survey: the health-caring units, patients' information in the health care services, and malaria indicators in district health centres. After investigating similar studies in other parts of the world -15 and aData for malaria cases, health-treatment services and district health centres were gathered by teams of well-qualified data collectors through direct referring to the selected health facilities and filling in questionnaires, and checklists. Each team of data collectors comprised one health professional, one laboratory technician and team supervisor who were experienced and familiar with the basic concepts, objectives and technical terms of the project as well as one driver. Once all the information was collected and entered to the software of SPSS (Version 15) by trained data operators, analysis was done and descriptive statistics  were used to estimate malaria indicators. Point estimates and 95% confidence intervals were estimated for all indicators. Relevant parametric or non-parametric statistical test, such as Pearson's Chi square test was used to determine association with a probability of committing a type 1 error (a) was set at 0.05.The quality of data collection was supervised and monitored daily by main investigators, provincial and district focal points during implementation of the project to ensure the quality and quantity of data collected by data collectors. Additionally, the quality of data entering was also monitored in two stages: in the primary stage, data file and its manual was prepared by skilled experts in statistics (MM & AAM). Then, data was entered by a team of trained data entry operators under the direct supervision of specialists in statistics and epidemiology . In the final stage, as data was analysed the information about every variable was controlled once more and if necessary was corrected by referring to the questionnaires.This study was approved by the research ethics committee of Zahedan University of Medical Sciences, Iran.Data were collected from all 223 health facilities located in the selected districts to estimate health facility-based indicators, including detection and control of epidemics, management and evaluation of malaria foci and service delivery. Additionally, data were extracted from the profile of 5, 836 recorded malaria cases in aforementioned health centres during the year preceding the survey.Generally, all but one percent of uncomplicated cases took appropriate and correctly-dosed of anti-malarial drugs in accordance to the national treatment guidelines. There is also evidence that a larger proportion of patients  were given complete treatment including anti-relapse course, in line with national guidelines whereas the remaining cases 14.2%) did not take anti-relapse course because either of immigration, or being less than five years of age or pregnancy that is primaquine is contraindicated. However, approximately two-third of uncomplicated ] in target districts detected within one week of onset by health staff. However, only half of them were controlled within four weeks of detection ] had at least one assigned small emergency site with adequate supply and equipment stock to be used in outbreaks Figure . Just inOnly one-third of target districts [33% (95% CI: 0.00 - 67.8)] had updated inventory of malaria foci on quarterly basis .One of the specific measures to be applied in order to achieve malaria elimination is reducing the parasite reservoir through early diagnosis and treatment and use of efficacious medicines. Based on GMP targets -9, 80% oFurthermore, data suggests striking differences in time interval between onset of symptoms and lab diagnosis/treatment of malaria patients across three surveyed provinces, which is consistent with the previous studies -15,19-21Prior studies  have alsOn the other hand, an interventional study in Tanzania  illustraFurthermore, the operational classification of malaria foci is one of the key components of GMP at the stage of malaria elimination. The transition of the functional status of malaria focus depending on the local situation and it might change constantly. According to the WHO classification , four caMoreover, the centre for disease control and prevention in Iran aims to detect malaria epidemics  within one week of onset and control them in less than a month, as advised by RBM programme -9. Approet al [In comparison, Coleman et al  examinedFurthermore, health centres have proposed to assign and equip some of their health facilities with adequate supply  for emergency situation such as outbreaks. The current findings showed that less than half of sampled health centres had at least one assigned small emergency site with adequate supply and equipment stock to be used in outbreak. Importantly, there was inconsistency in assignment of emergency sites across three provinces. Therefore, the present study indicates shortage and inconsistency in management and evaluation of malaria foci, detection and control of malaria epidemics as well as assignment of emergency sites across different regions of Iran.In conclusion, massive and substantial investments are needed to coordinate national malaria control programmes in Iran towards achieving determined goals and targets set by WHO. The first requirement is improving the quality of malaria case management. Secondly, health policy makers have to strength the epidemic preparedness and response capacity at the national level. More importantly, Ministry of Health should be ensured about the availability of nationally recommended anti-malarial drugs as well as other equipments stocks in all health facilities.The national malaria control programme of Iran should also put an emphasis on robustness and activeness of surveillance systems coupled with vigorous community recruitment as the driving force to ensure increased access to treatment. Finally, future research should focus on examination of health worker practices regarding case management as well as epidemic identification and response.The authors declare that they have no competing interests.The overall implementation of the first malaria indicator survey in Iran including survey design, drafting the questionnaires, data management and analysis, report writing and manuscript preparation were the results of joint efforts by multiple individuals who are listed as co-authors of this paper. AR, AAM, FR, MM, MR, AH, FN and RTA made a substantial contribution on conception, design of study, coordination and supervision of data collection. MS, RS and MS gave a major contribution on preparing study questionnaires and data collection. MM and AAM analysed and interpreted data. AR, AAM and FN drafted the first version of manuscript. All authors have made extensive contribution into the review and finalization of this manuscript; they have all read and approved the final manuscript.