Research in the last two decades has made clear that astrocytes play a crucial role in the brain beyond their functions in energy metabolism and homeostasis. Many studies have shown that astrocytes can dynamically modulate neuronal excitability and synaptic plasticity, and might participate in higher brain functions like learning and memory. With the plethora of astrocyte mediated signaling processes described in the literature today, the current challenge is to identify, which of these processes happen under what physiological condition, and how this shapes information processing and, ultimately, behavior. To answer these questions will require a combination of advanced physiological, genetical, and behavioral experiments. Additionally, mathematical modeling will prove crucial for testing predictions on the possible functions of astrocytes in neuronal networks, and to generate novel ideas as to how astrocytes can contribute to the complexity of the brain. Here, we aim to provide an outline of how astrocytes can interact with neurons. We do this by reviewing recent experimental literature on astrocyte-neuron interactions, discussing the dynamic effects of astrocytes on neuronal excitability and short- and long-term synaptic plasticity. Finally, we will outline the potential computational functions that astrocyte-neuron interactions can serve in the brain. We will discuss how astrocytes could govern metaplasticity in the brain, how they might organize the clustering of synaptic inputs, and how they could function as memory elements for neuronal activity. We conclude that astrocytes can enhance the computational power of neuronal networks in previously unexpected ways. Thanks to those receptors astrocytes are not only capable to respond to the classical neurotransmitters glutamate and γ-aminobutyric acid (GABA) released from synapses [through metabotropic glutamate receptors (mGluRs) mGluR1-5 and GABAB receptors respectively; Pasti et al., 2+ signals through the astrocytic syncytium . Their activation leads to the intracellular activation of phospholipase C (PLC), followed by the production of the messenger molecule inositol trisphosphate  transients mediated by channels, exchangers, and transporters  whole-cell Ca2+ transients have led to the idea that unlike neurons, astrocytes display exclusively particularly slow responses, and that their signals are not suited to be restricted to small cellular compartments, as happens for example, in dendritic spines. However, in vivo experiments have shown that faster local responses of astrocytes in the somatosensory cortex can occur upon hind limb stimulation  channel. TRPA1 mediated spotty Ca2+ signals seem to play an important role in setting the basal intracellular Ca2+ concentration of hippocampal astrocytes . But what is the impact of this on neuronal functioning? Numerous studies in different brain regions have uncovered a multitude of ways in which astrocytes can modulate neuronal excitability and synaptic transmission. In the following section we will review several of these different pathways.The excitability of neurons is one of their most fundamental properties. Dynamic modulation of excitability is a powerful way of implementing state-dependent changes in neuronal computation. Several studies have shown that astrocytes can regulate neuronal excitability. Astrocytes can achieve this through several mechanisms: by regulation of the extracellular ionic composition, by maintaining a tonic extracellular transmitter concentration, by regulation of basal synaptic transmission, and by the induction of phasic events in neighboring neurons. We will shortly discuss these different mechanisms.+. Both hippocampal astrocytes  receptor mediated current, and a decrease in neuronal excitability , or long-lasting (long-term plasticity). Short-term plasticity (a change in synaptic strength lasting up to 10s of seconds) is thought to underlie critical computational functions of neuronal networks  ions (Dingledine et al., 2+ into the postsynaptic neuron, which can activate second messenger cascades leading to either LTP or LTD (Malenka and Bear, d-serine is a more likely co-agonist for the NMDAR then glycine (Mothet et al., d-serine in the brain seems to be the astrocyte. Astrocytes release d-serine into the extracellular space through vesicular fusion, and this astrocytic d-serine release is necessary to obtain sufficient NMDAR activation for induction of LTP in hippocampus (Yang et al., d-serine release (Zhang et al., Most forms of long-term synaptic plasticity depend on activation of postsynaptic NMDARs. The NMDAR classically is described as a coincidence detector of pre- and post synaptic neuronal activity. This is because for activation it needs both binding of presynaptically released glutamate as well as a postsynaptic depolarization to relieve it from block by magnesium (Mgd-serine as shown in hippocampus was described in the hypothalamic supraoptic nucleus (SON; Panatier et al., d-serine for postsynaptic NMDARs is greatly reduced, leading to a shift in the activity dependence of LTP and LTD (Figure A similar dependence of NMDAR mediated long-term plasticity on astrocyte-derived D Figure .d-serine can actively gate LTP in the rat barrel cortex in vivo (Takata et al., d-serine release from the astrocytes upon activation. These findings highlight the importance of d-serine as a modulator of plasticity both in vitro and in vivo. Furthermore, since cholinergic input into the cortex has been suggested to gate cortical plasticity (Bakin and Weinberger, Interestingly, a recent study showed that astrocytic release of d-serine can also induce synaptic plasticity independent of its role at the NMDAR (Kakegawa et al., d-serine from Bergmann glia. This d-serine subsequently activated postsynaptic δ2 glutamate receptors, which in turn caused internalization of postsynaptic AMPARs. Interestingly, interfering with this form of LTD disrupted motor coordination in vivo, showing its relevance for cerebellar development. From the study by Kakegawa et al. (Apart from acting as a NMDAR co-agonist, a recent study has shown that astrocytic release of a et al.  it is noa et al. . Furthera et al. . Therefoa et al.  and hippin vivo (Navarrete et al., Another gliotransmitter that can mediate long-term plasticity is glutamate. Previously, we mentioned that astrocyte stimulation at hippocampal Schaffer collateral synapses can induce short-term potentiation through astrocytic glutamate release followed by activation of presynaptic mGluRs (Fiacco and McCarthy, in vivo, by application of the cannabinoid receptor agonist Δ9-THC, leads to LTD of Schaffer collateral synapses instead of LTP. This LTD also requires astrocytic glutamate release, but is mediated by activation of postsynaptic NMDARs, followed by endocytosis of postsynaptic AMPARs (Han et al., Additionally, a recent study showed that pharmacological activation of astrocytes 1Rs (Sjöström et al., 1Rs together governed the induction of t-LTD. We showed that activation of presynaptic NMDARs during induction of t-LTD is mediated by astrocytic glutamate release (Min and Nevian, 2+ signaling. This in turn leads to glutamate release from the astrocyte, which activates presynaptic NMDARs. Activation of the presynaptic NMDARs induces a long-lasting decrease in synaptic release probability, although the signaling cascade downstream from presynaptic NMDAR activation is still unclear (Figure In the neocortex, we have recently shown that astrocytic release of glutamate is necessary for the induction of spike-timing-dependent depression (t-LTD; Min and Nevian, r Figure .2+ signals, and therefore presumably the astrocytic glutamate release, is not correlated with respect to the pre- and post-synaptic action potentials (Min and Nevian, 2+ block of the presynaptic NMDARs to hamper their efficient recruitment. However, it was recently shown that presynaptic NMDARs in the developing sensory cortex incorporate the NR3A subunit, which renders the receptor insensitive to Mg2+ block (Larsen et al., One interesting question rising from these results is how the presynaptic NMDARs are efficiently activated. Because the timing of the astrocytic CaThese results show that astrocytes form a crucial part of the retrograde signaling cascade for induction of t-LTD. Since endocannabinoid mediated forms of LTD occur in numerous brain regions and serve important functions (Heifets and Castillo, 7 receptors. Activation of these postsynaptic receptors leads to insertion of AMPARs, and thereby to a long-lasting postsynaptic increase in the efficacy of excitatory synapses (Gordon et al., 2+ signaling and subsequent release of ATP through mGluR activation. This protocol can lead to a similar long-lasting postsynaptic upscaling of the synaptic efficacy (Gordon et al., Astrocytes also play a role in homeostatic control of synaptic transmission. This was first shown in cultured neurons, where glial release of the cytokine TNFα increases the synaptic expression of AMPARs, thereby controlling the weight of all excitatory synapses (Beattie et al., Finally, long-term synaptic plasticity is costly in terms of energy. As mentioned before, astrocytic supply of energy to neurons is essential for maintaining synaptic transmission (Rouach et al., d-serine, they can directly induce synaptic plasticity by releasing glutamate or other gliotransmitters, and they can mediate homeostatic plasticity. In addition, dynamic regulation of metabolic support by astrocytes is crucial for synaptic plasticity.In conclusion, astrocytes play a role in several forms of long-term plasticity. Astrocytes can either set the threshold for LTP/LTD induction by controlling the extracellular concentration of In the previous section, we have discussed how astrocytes can modulate neuronal functioning. Based on the above described astrocyte-neuron interactions, we will summarize some possible roles that astrocytes could play in neuronal computation. We suggest that the functional role of astrocytes adds to the computational power of neuronal networks.d-serine, astrocytes are ideally positioned to mediate metaplasticity. The level of astrocytic d-serine release will determine the possible amount of NMDAR activation and therefore of NMDAR mediated postsynaptic Ca2+ influx upon synaptic activity. Since many forms of LTP and LTD require NMDAR mediated Ca2+ influx for their induction, astrocytes can shift the threshold for LTP and LTD induction (Figure d-serine and therefore, the induction threshold for LTP and LTD (Panatier et al., d-serine release upon astrocyte activation by cholinergic inputs opens the window for subsequent LTP induction in the in vivo neocortex (Figure d-serine release is a physiologically important metaplasticity signal in the brain. It can translate the activity state of the neuronal network into a modulatory signal that determines the corresponding learning rule: during a high activity state due to arousal or heightened attention the neuronal and astrocyte networks are highly active supporting the induction of LTP. Future behavioral studies should determine what the importance of this astrocyte mediated metaplasticity is for learning and memory formation.Metaplasticity is a higher-order form of synaptic plasticity, defined as a change in the ability to induce synaptic plasticity (Abraham and Bear, n Figure . A clearx Figure . Therefo2+ signaling spreads along an astrocytic process and results in the release of gliotransmitters at neighboring synapses. Heterosynaptic short-term plasticity could play a role in switching between synaptic ensembles during information processing. As described earlier, astrocytes mediate heterosynaptic short-term depression at excitatory synapses onto CA1 pyramidal neurons (Zhang et al., Single astrocytes form non-overlapping domains (Bushong et al., Heterosynaptic long-term plasticity has been implicated in the homeostatic control of synaptic inputs to a neuron (Chistiakova and Volgushev, 2+ signaling, directly translates into synaptic plasticity. For example, we found that astrocyte activation with a voltage-clamp depolarization protocol results in increased Ca2+ signaling in the astrocyte, but that this activity alone does not change synaptic transmission strength at excitatory cortical synapses. An additional activation of the presynaptic axon was necessary in order to induce LTD (Min and Nevian, It is important to note that not every activation of an astrocyte, manifested by increases in Ca2+ transients gradually increases during the induction of t-LTD (Min and Nevian, The induction of many forms of synaptic plasticity requires a repeated presentation of a certain stimulus pattern (Petersen et al., 2+ signals in the processes of astrocytes can be used to perform chemical computations similar to linear and non-linear Ca2+ signaling in neurons. Efficient Ca2+ buffering (Neher, 2+ microdomains that limit the release of gliotransmitters in space and time. Only certain patterns of Ca2+ signals might cause a high enough concentration of Ca2+ in the astrocyte processes to trigger vesicular release. This could be accomplished by local Ca2+ buffer saturation and a specific spatial relationship between Ca2+ release sites in the ER and the vesicular Ca2+ sensor triggering exocytosis (Marchaland et al., 2+ signaling in astrocytes is needed to understand their chemical computation.How can an astrocyte act as a thresholding unit? The sophisticated Cag Neher, , receptog Neher,  and extrin vivo. However, recent advances in genetics have made it possible to specifically alter astrocyte signaling in vivo while keeping neuronal signaling intact. This has led to some important insights into astrocyte involvement in information processing. For example, it is now clear that astrocyte derived adenosine modulates the build-up of sleep pressure as well as the cognitive effects of sleep deprivation (Halassa et al., 1 receptor, Han et al. (in vivo (Saab et al., in vivo experiments with the subcellular astrocyte-neuron signaling mechanisms as described in this review.As described above, there is ample experimental evidence for an active role of astrocytes in neuronal plasticity. The most important question remaining is the functional relevance of the above described astrocyte-neuron interactions. This has proven very hard to address, since experimental approaches until recently were unable to specifically modify and study the role of astrocytes in neuronal computation and behavior n et al.  showed tn et al. . Finallyin vitro experiments and behavioral readouts in vivo is the use of mathematical models. As mentioned earlier, progress has been made with mathematical models of astrocyte Ca2+ signaling. In addition, several models have included bidirectional signaling between astrocytes and neurons on the synaptic level, leading to new insights into the function of this bidirectional signaling. For example, a study by Nadkarni et al. (One possible way to bridge the gap between cellular mechanisms observed with high-resolution i et al.  suggestsi et al. . In anoti et al. . Such moAn example of a recently developed neuron-glia network model comes from a recent study by Wade et al. . Here, i2+ dynamics, thereby potentially enhancing the computational power of neuronal networks. The challenge for the future is to understand how and when astrocyte mediated signaling processes are involved in computation in the brain. To answer this fascinating question will require a combination of state-of-the-art experimental techniques with advanced computational modeling.In conclusion, research on the involvement of astrocytes in neuronal signaling in the last years has resulted in a rich array of possible astrocyte-neuron interactions. It is now evident that beyond their permissive role in synaptic and network function astrocytes can perform integration of neuronal signals by means of their CaThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To the Editor: Kaba et al. (We conducted a retrospective subanalysis of results from a multicenter therapeutic trial assessing HEV seroprevalence among HIV/hepatitis C co-infected patients in France (The difference between our study, which demonstrated low HEV IgG prevalence in IDU patients, even in southern France, and the results from Kaba et al. ( In Response: The letter of Larrat et al. (,–Seroprevalence studies of different populations, especially those with differing immune responses, cannot lead except by chance to the same result. Of note, we recently reported that HEV seroprevalence was 2.3% among injection drug users infected with HIV (


Dear Editor:et al. about the relationship between down-regulation of osteopontin and breast tumour progression in vivois highly interesting [The article by Chakraborty eresting . Recent et al. in a recent study have reported that nearly 67% of oral squamous cell carcinomas and nearly 54% of all oral carcinomas in situ lesions are immunoreactive for osteopontin [et al. suggests that osteo-pontin may be an important marker of early invasion in lingular squamous cell carcinomas [For instance, Devoll eopontin . Similarrcinomas . In factBesides oral malignancies, osteopontin has also been implicated in the etio-pathogenesis of numerous other systemic malignancies such as non-small cell lung cancers and breast cancers . Clearly


Dictyostelium discoideum) and plants  gene family, which is 70% identical to glycogen synthase kinase-3 from mammals,  and rice (LOC_Os05G33050) also possess homologous proteins comprising ARM repeats and a BTB/POZ domain  signaling (Samuel et al., AtPUB19 showed that it is upregulated in response to drought, salt, cold and ABA (Liu et al., ATPUB18 as a negative regulator has been put forward in ABA-mediated stomatal closure and drought responses (Seo et al., ATPUB22/23 in Capsicum annum known as CaPUB1 was found to be highly inducible in response to various abiotic stresses such as drought, cold and salt (Cho et al., A biological role for the U-box/ARM protein Nicotiana, two U-box/ARM proteins NtCMPG1 and tobacco ACRE276 and their functional homolog in Arabidopsis, AtPUB17 has been implicated as positive mediators of plant defense and stress signaling (Gonzalez-Lamothe et al., Another report suggested the role of AtCHIP, an Arabidopsis U-box/ARM protein in response to extreme temperature conditions. Subsequently, AtCHIP was reported to be involved in the ABA stress signaling pathway by mediating interaction with protein phosphatase 2A (Yan et al., On the basis of facts described above, it can be concluded that animal and plant ARM repeat proteins share many resemblances. Therefore, it is possible that at least some transcription effectors involved in Wnt signaling are evolutionary conserved. These elements include nuclear accumulation in response to extracellular signal, phosphorylation and degradation. Apart from the common response, plants possess specific signaling pathways mediated by ARM proteins. In plants, ubiquitination is critically involved in the function of ARM proteins. The proliferation of β-catenin-like ARM proteins in plants suggest their significance in the regulation of diverse biological fuctions in them. Further study of these proteins in plants would contribute to our understanding of the molecular factors involved in response to abiotic stress.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.


Obesity is a major public health concern and there are increasing calls for policy intervention. As obesity and the related health conditions develop during childhood, schools are being seen as important locations for obesity prevention, including multifaceted interventions incorporating policy elements. The objective of this systematic review was to evaluate the effects of policies related to diet and physical activity in schools, either alone, or as part of an intervention programme on the weight status of children aged 4 to 11 years. A comprehensive and systematic search of medical, education, exercise science, and social science databases identified 21 studies which met the inclusion criteria. There were no date, location or language restrictions. The identified studies evaluated a range of either, or both, diet and physical activity related policies, or intervention programmes including such policies, using a variety of observational and experimental designs. The policies were clustered into those which sought to affect diet, those which sought to affect physical activity and those which sought to affect both diet and physical activity to undertake random effects meta-analysis. Within the diet cluster, studies of the United States of America National School Lunch and School Breakfast Programs were analysed separately; however there was significant heterogeneity in the pooled results. The pooled effects of the physical activity, and other diet related policies on BMI-SDS were non-significant. The multifaceted interventions tended to include policy elements related to both diet and physical activity (combined cluster), and although these interventions were too varied to pool their results, significant reductions in weight-related outcomes were demonstrated. The evidence from this review suggests that, when implemented alone, school diet and physical activity related policies appear insufficient to prevent or treat overweight or obesity in children, however, they do appear to have an effect when developed and implemented as part of a more extensive intervention programme. Additional evidence is required before recommendations regarding the focus of policies can be made and therefore, increased effort should be made to evaluate the effect of policies and policy containing intervention programmes upon weight status. Obesity among children is associated with significant psychological, social and health consequences including insulin resistance, cardiovascular disease, low self-esteem and poorer education and employment outcomes ,2. The rTo date the systematic reviews which have examined the effect of obesity related school policies have evaluated diet and physical activity outcomes rather than weight status -16. JaimGuidance from The Cochrane Collaboration and the National Health Service Centre for Reviews and Dissemination informed the development of the review protocol, which is available upon request ,18.Two search strategies were developed for this systematic review, one for diet related and one for physical activity related policies  [Dialog Datastar], British Education Index [Dialog Datastar], Australian Education Index [Dialog Datastar], Cumulative Index to Nursing and Allied Health Library (CINAHL Plus) [Ebscohost], and The Cochrane Library [Wiley Online]. The search strategy was developed in Medline ; source of funding; ethics approval; recruitment; summary characteristics of the study population; details of the intervention ; treatment of any control group; definition of obesity; duration of follow-up/exposure; and results. Standard tools were used to assess the quality of the studies -24. The d) in body mass index standard deviation score (BMI-SDS), were calculated for each study using standard calculations and the R package MAd ), where ‘m’ is the average number of participants in each school and ‘ICC’ is the intra-cluster correlation . An ICC et al.,31. Furt2 statistic [Random effects meta-analysis of each cluster was undertaken in Stata  to obtaitatistic .The study identification process and reasons for exclusion are illustrated in Figure Ten studies examined diet related policies, five physical activity related policies, and six examined policies with both diet and physical activity related components (henceforth known as combined policies) Table . Despiteet al.[All the included studies examined BMI as an outcome categorised as overweight or obese, or adjusted to standard deviation scores (BMI-SDS), percentiles (BMI%), growth rates or Healthy Fitness Zone (BMIHFZ) . The Heaet al.. One stuet al..Study quality is summarised in Table Due to the nature of policy interventions, the randomised controlled trials and controlled before and after studies could not meet some of the quality criteria generally applied to these study designs. Blinding of the outcome assessment may not always have been possible and, for some studies, loss to follow up was greater than 20%. However, each study employed a valid design, in terms of the use of second sites as controls, random allocation and protection from contamination.The demographics and baseline weight status of the participants of each study are listed in Table Fifteen studies utilised the Center for Disease Control and Prevention (CDC) 2000 BMI reference categories and an additional paper appears to have used this categorisation but did not report it . Two stuet al.[Key results from each study are presented in Table et al. and Thomet al.. Table 4Thirteen studies evaluated diet related policies, including five evaluating the NSLP ,44,47,50The pooled result of participation in the NSLP was a small non-significant rise in BMI-SDS  -0.193 to 0.269)  and the effects of these policies have not been combined. However, the individual results and effect sizes are detailed in Table et al.[et al.[et al.[Six studies evaluated policies with both diet and physical activity related components, one of which did not report the quantitative results just the direction and significance and therefore effect sizes could not be calculated -59,63,64le et al. reportedl.[et al.,64. The l.[et al., was siget al.[The aim of this systematic review was to examine the effect of school diet and physical activity related policies upon anthropometric outcomes among children aged 4–11 years. Twenty-one studies were identified which examined a range of policies which were clustered as either diet related or physical activity related or both (combined policies) for analysis. Within the diet related policies cluster, eight studies evaluated the NSLP and SBP and as these policies target a subset of the population they were analysed separately from the other diet related policies. The NSLP was associated with a non-significant rise in BMI-SDS results, whereas the SBP was associated with a significant decrease in BMI-SDS and the other diet related policies were associated with a non-significant decrease in BMI-SDS, however, significant heterogeneity remained in the NSLP and SBP sub-clusters reducing the validity of these results Figures , 3 and 4et al. as imporet al.,26,31. Get al.. Five ofet al.,47,55,632 = 65.6%. Millimet and Tchernis [A strength of this review was the broad search strategy. School policy evaluation may be reported by a variety of disciplines and inside and outside of peer-reviewed journals and therefore through the variety of databases searched, the grey literature search and the inclusion of literature such as dissertations all the relevant studies were sought. Primarily, this demonstrated that there is a paucity of scientific evaluations of school policies as only 21 eligible studies were identified from the 6,894 retrieved, yet among the eligible studies where were a variety of designs, quality and policies which impinge upon the review. Among the 21 studies reviewed only five utilised experimental study designs which prevented the consideration of causal pathways in this review Table . Loss toTchernis  and MillTchernis  used comet al.[et al.[et al.[et al.[et al.[et al.[et al.[et al.[In order to calculate effect sizes, assumptions about the outcome correlations in studies using independent and non-independent samples were made; these assumptions were relaxed in a sensitivity analysis, reported in Additional file et al. and Choml.[et al. both foul.[et al. found a l.[et al. found thl.[et al. argue thl.[et al. argue thl.[et al. recentlyl.[et al. using rol.[et al. with thol.[et al. did not l.[et al.,67.et al.[This review evaluated the effect of school policies upon an objective measure of weight status (BMI-SDS) unlike previous reviews which have evaluated physical activity and diet outcomes, which may be more subjective -16. Theret al. found siet al.. SubsequThe evidence from this systematic review suggests that diet and physical activity related policies need to be located within more complex approaches to preventing childhood obesity which focus on multiple factors  and at multiple levels of influence  as advocated by the Centers for Disease Control and Prevention guidelines . No poliThe complex web of factors which influence weight have been illustrated in the obesity systems map which also highlights the range of levels of influence from micro to macro . Within 95% CI: 95% confidence interval; AVHPSP: Annapolis valley health promoting schools program; BMI: Body mass index; BMI%: Body mass index percentile; BMIHFZ: Body mass index healthy fitness zone; BMI-SDS: Body mass index standard deviation score; CDC: Centers for disease control and prevention; ECLS-K: Early childhood longitudinal study – kindergarten cohort; FMI: Fat mass index; HAES: Health at every size; ICC: Intra-cluster correlation; IOTF: International obesity task force; MeSH: Medical subject headings; NSLP: National school lunch program; PE: Physical education; SBP: School breakfast program; UK: United Kingdom; USA: United States of America; USDA: United States Department of Agriculture.The authors declare that they have no competing interests.AJW was involved with the conception and design of the review, undertook the searches and participated in the study identification, data extraction and quality assessment, he then undertook the analysis and drafted the manuscript. WEH was involved with the conception and design of the review, advised on and supervised the analysis and assisted with drafting the manuscript. CAW was involved with the conception of the study and had input into the final manuscript. AJH participated in the study identification, data extraction and quality assessment and proofread the final manuscript. SL contributed to the drafting of the final manuscript and interpretation of the results. KMW was involved with the conception and design of the review, participated in the data extraction and quality assessment, assisted with the interpretation of results and drafting of the final manuscript. All authors read and approved the final manuscript.Search strategy.Click here for fileSensitivity analysis.Click here for fileEffect size calculations.Click here for fileDiet related policies meta-analysis with Rappaport, Daskalakis and Sendacki [ replacing Foster, et al. [.Sendacki  replacin, et al. .Click here for file


Exome sequencing now allows us to reliably identify these mutations using a single genomic test, and we have recently implemented exome sequencing in the diagnostic follow-up of these patients.Germline coding de novo mutations in genetic disease and the associated risk factors such as local genomic structure and paternal age. Next, I will describe our recent work using a diagnostic family-based exome sequencing approach to test this de novo mutation hypothesis in 100 patients with unexplained ID, as well as targeted follow-up studies of several candidate ID genes in 750 additional patients. A total of 79 unique coding de novo mutations were identified and validated in 52 patients. Damaging de novo (n = 10) as well as X-linked maternally-inherited (n = 3) mutations were detected in known ID genes, resulting in a minimal diagnostic yield of 13% in this cohort. In addition, potentially causative de novo mutations in novel candidate ID genes were detected in 22 patients. For three of these candidate genes, recurrent de novo mutations were identified in patients with similar phenotypes, confirming that they are true ID genes. To further expand the possibilities of exome sequencing for mutation detection, we have recently implemented automatic CNV detection on exome data, and compared its performance to that of high-resolution genomic microarrays. This analysis shows that exome sequencing can reliably detect the large majority of pathogenic de novo CNVs, responsible for approximately 15% of ID.In this presentation, I will first discuss the role of de novo mutations therefore represent an important cause of ID, and exome sequencing is an effective diagnostic strategy for their detection.In conclusion,


PLoS Genetics, Joyce et al. report the first comprehensive RNAi screen of genes regulating somatic chromosome pairing in Drosophila Many generations of biologists have been intrigued by the myriad structures that eukaryotic chromosomes can adopt and have questioned how their form relates to function Drosophila presents a unique opportunity for identifying molecular regulators that establish, maintain, and antagonize homolog pairing because its homologous chromosomes are almost always paired in somatic cells. Metz described somatic cell homolog pairing in 1916 Suppressor of Hairy Wing (Su(Hw)) and Topoisomerase II as pairing promoting factors Cap-H2, was shown to be necessary and sufficient to antagonize pairing of homologs in the context of polytene chromosomes Cap-H2 mutant Drosophila males have chromosome unpairing defects in meiosis I, also providing evidence for a Cap-H2 anti-pairing activity Recent evidence has raised the exciting possibility that both pairing and anti-pairing forces may act on chromosomes to regulate the spatial juxtaposition of homologous sequences . Two preThe ability to perturb homolog pairing by RNAi depletion The pairing and anti-pairing genes code for cell cycle, protein turn-over machinery, and chromatin proteins, among others. Previous studies suggested that cell cycle regulation and chromosome pairing are related by showing that entry into S-phase and G2/M disrupt pairing Perhaps the most exciting broad conclusions from this study are that chromosome pairing is much more complicated and dynamic than anyone had anticipated, and that an abundance of “pairing promoting” and “anti-pairing” factors provide opposing forces. The authors suggest that the degree of homolog pairing in somatic cells, at the gene level and at the whole chromosome level, is likely determined by the relative activities of pairing and anti-pairing factors . It is n


Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs), a small subpopulation of tumor cells, can generate bulk populations of nontumorigenic cancer cell progeny through the self-renewal and differentiation processes. As CSCs are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors, development of CSC-targeted therapeutic strategies holds new hope for improving survival and quality of life in patients with cancer. Therapeutic innovations will emerge from a better understanding of the biology and environment of CSCs, which, however, are largely unexplored. This review summarizes the characteristics, evidences and development of CSCs, as well as implications and challenges for cancer treatment. The former can be divided into two progeny stem cells or differentiated progenitors and thus controlling the self-amplification of stem cells, whereas the latter produces one differentiated progenitor and another daughter [in vivo, and the microenvironment plays an important role in the function preservation of stem cells [Stem cells, which are rare in most tissues, are defined as cells with the ability to perpetuate themselves by self-renewing and to differentiate into a variety of specialized cells in a tissue or organ ,2. Both daughter . Generaldaughter . Stem ceem cells .CSCs are a small subpopulation of tumor cells with an infinitely proliferative potential existing in tumor tissues . They plCSCs and stem cells have a host of similar characteristics, such as self-renewal, indefinite self-replication, asymmetric cell division, generating a large number of differentiated cells and expressing specific molecules ,18. Addiet al.[+/CD38−) [+/CD38− cells can form tumors that phenotypically resemble the patient’s original tumor [Growing evidence has shown that tumors are derived from and maintained by a rare population of dysregulated stem cells. The CSC hypothesis was first raised by Mackillop et al. in 1983.+/CD38−) . After tal tumor ,24, indial tumor . This noal tumor , lung [2al tumor ,28, liveal tumor , ovary [al tumor , colon [al tumor , pancreaal tumor   [Further evidence of CSCs comes from histology and immunocytochemistry studies. For example, many tumors are very heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases, which implies that the cell that produced them had the capacity to generate multiple cell types. Ginestier et al. showed tl.[et al. confirmel.[et al., brain [l.[et al., and livl.[et al. were alsl.[et al., are botl.[et al.,48. In 2ma (NPC) . Furtheret al.[et al.[According to label-retaining cell (LRC) trial, adult stem cells can be identified based on their ability to retain nucleoside analog, such as bromodeoxyuridine. In accordance with this principle, Zhang et al. found thl.[et al. confirmeet al.[Growing evidences suggests the existence of a dynamic equilibrium and bidirectional conversion between CSCs and cancer progenitors . On the et al. demonstrin vivo, whereas most daughter cells exited from the cell cycle are not able to proliferate in vitro; (2) Differentiation to a limited extent in vitro, and the capacity can be analyzed by special surface markers at the different differentiation stages. During this process, the cellular morphology was often bizarre and maturation is incomplete. Another study [Cancer progenitor cells display low a self-renewal capacity and a higher probability of terminal differentiation compared with CSCs . Variouser study  showed t+ stem cells from CML patients were insensitive to STI571 in vitro, thereby these immature Ph+ progenitor cells can survive, while the overall sensitivity of CML CD34+ progenitor cells to STI571 is mainly determined by cell cycle status [Growing evidences indicated that drug-targeted therapies to control tumors either at CSCs or cancer progenitor cells level exhibited different sensitivity. Chronic myeloid leukemia (CML) stem cells were insensitive to tyrosine kinase inhibitors like imatinib, dasatinib and nilotinib, while sensitive to leukemia progenitor cells –62. The e status .high/+ CD24low/− expression was found in breast tumor-initiating stem-like cells. However, it was not clear whether CD44 and CD24 consistently distinguished tumorigenic from non-tumorigenic cells. Subsequently, these CSC-like cells were verified intrinsically resistant to conventional chemotherapy [et al.[et al.[+ stem and early progenitor cells lost their CD133 expression, giving rise to late progenitors and finally differentiated progeny. These lineage programs for cell fate determination can be restricted by PcG proteins, such as Bmi1, which regulates tumor initiation in CD133+ stem and early progenitor cells, while regulates tumor maintenance of proliferation, differentiation and cell fate determination in CD133− proliferative progenitors. Likewise, Stewart et al.[Increasing evidences showed that the surface protein markers expressed by CSCs and cancer progenitor cells were somewhat dissimilar. In 2003 , CD44higotherapy  and ioniotherapy . Jiang ey [et al. suggestel.[et al. showed trt et al. found th+/CD38− cells, in leukemia is similar to normal hematopoietic progenitor cells [To date, the cell of origin of CSCs remains to be a pendent and troubled problem around the world. There are two hypotheses for the origin of CSCs . One staor cells . The eviIt has been proposed that CSCs and normal stem cells can interconvert into each other. The more important consequence of this event is that normal stem cells can generate CSCs that ultimately induce a new tumor. Emerging evidence has supported this notion, as CSCs share many properties of normal stem cells. For examples, both have the capacity of self-renewal and non-directional differentiation potential, and many classic cancer related signal transduction pathways also regulate the development of normal stem cells. In this scenario, cancer cells could simply utilize the existing stem cell regulatory pathways to stimulate their self-renewal. In addition, both stem cells and CSCs have telomerase activity and amplified telomere repeats, while most adult human somatic cells lack detectable telomerase. Another theory associates stem cells with the formation of tumors, which is most often related with tissues with a high rate of cell turnover. In these tissues, it has long been expected that stem cells are responsible for tumor formation. Tissue with fast renewal, such as epithelial tissue and those of the hematopoietic system, are sites with high incidence of cancer. The faster tissues renew, the higher the rate of mutation that will occur during replication and transcription. Although it is not clear which target cells mutate and transform to tumors, experimental data obtained from a variety of tumors show that certain colon cancers and leukemia result from an accumulation of multiple mutations of stem cells . Due to Some researchers presume that CSCs may be obtained by the mutation of committed progenitor cells with an ability of self-renewal. For example, leukemia stem cells can be transformed from granulocyte-macrophage progenitors with the assistance of MLL-AF9 fusion protein . Anotheret al.[+ cells could generate additional lgr5+ cells as well as all other adenoma cell types, thus exhibiting activity of CSCs in mouse intestinal adenomas [et al. found that the yellow fluorescent protein (YFP) could been expressed in around 1% of basal papilloma epithelial cells in mice, and these YFP-labeled tumor cells were capable of generating all cell types that comprised the tumor [Despite the lack of direct experimental evidence, some studies show that CSCs may be the fusion of stem cells and other cells . These net al.. The CSCet al., which het al., A549 luet al., colon cet al. and glioet al.. Terminaet al.–83. Howeadenomas ; (2) theadenomas ; (3) usihe tumor .At present, the molecular mechanisms underlying regulating the development of CSCs remain to be unexplored. Various signaling pathways have been suggested, and some of them are reviewed as follows.The Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms, which regulates widely the development and homeostasis of vertebrate and invertebrate embryos and adult individuals through the local interaction between cells, and controls how cells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specific developmental programs . Notch aStudies indicate that Notch signaling is likely to be implicated in the pathogenesis of many human tumors, including leukemia  and pancWnt proteins are secreted signaling molecules of Wnt signaling, and nuclear β-catenin function as a key mediator. One indicator of Wnt pathway activation is the nuclear accumulation of its main effector β-catenin, which is one component of a transcriptional activation complex that includes members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of DNA binding proteins . In normet al.[et al.[Wnt signaling pathway regulates many developmental processes through transcriptional regulation  and its et al. demonstrl.[et al. documentl.[et al.,112.in vivo[+ glioma CSCs [et al.[in vitro (7). The signal transducer and activator of transcription 3 (STAT3) is a crucial transcriptional regulator involved in tumorigenesis. Inhibition of STAT3 with specific inhibitors or targeting STAT3 with specific shRNAs disrupts proliferation and maintenance of GSCs [Other molecular pathways or factors that play a critical role in the development of CSCs include following: (1) mTOR signaling pathway, which is frequently aberrantly activated in human cancers, and significantly correlated with biological cell behaviors . Recent in vivo. In addiin vivo; (2) Fibin vivo. In addiin vivo and gastin vivo. Studiesin vivo. Using toma CSCs . In addioma CSCs ; (4) Recoma CSCs  suggest oma CSCs ; (5) Epioma CSCs . This nooma CSCs ; (6) Baos [et al. in 2008  of GSCs ,125.Once a cancer has been diagnosed, treatments vary according to cancer type and severity. Surgery, radiation therapy, chemotherapy or hormonal therapy represents traditional approaches designed to remove or kill rapidly-dividing cancer cells. However, there has been hardly any substantial progress with new therapies regarding clinical endpoints, despite significant advances in molecular mechanisms of cancer. Cancer remains a major public health issue. Conventional anti-cancer treatments target the more mature cancer cells that form the bulk of the tumor, but do not target the CSCs, which are relatively quiescent and intrinsically resistant, thus possibly accounting for treatment failures . To target al.[Tumor metastasis is a complex process, and is also the main cause of the death of cancer patients in clinic. It is the key to improve the prognosis of patients by removing CSCs selectively with no significant toxicity . Severalet al. confirm et al.; (3) Somet al.. In breaet al.. Subsequet al.. Cell diet al., especiaet al.,140; (4)et al..et al.[Another way to control the tumor progression is to induce differentiation of CSCs. Study by Piccirillo et al. showed aet al.. The CSCet al.. The bioet al.[et al.[et al.[Recent studies have found that CSCs are the main reason for tumor growth, recurrence and metastasis . Dingli et al. in 2010 et al.. (3) Manet al.. (4) Meal.[et al. and Lianl.[et al. have obsl.[et al.,152,153,l.[et al..Despite recent clinical studies have begun to monitor the behavior of CSCs during chemotherapy, it is still an urgent requirement of more clinical studies to assess how responses to therapy correlate with CSC biomarkers. Development of new CSC-targeted strategies is currently hindered by the lack of reliable markers for the identification of CSCs and the poor understanding of their behavior and fate. Although cancers represent a major therapeutic challenge, with better understanding in the CSCs, the more specific markers to look for this lethal disease. There is no doubt that the application of CSC theory to study the tumorigenesis mechanisms will lead a paradigm shift in the cancer research and the understanding of the essence of cancer, supplying a new way to effectively diagnose tumor sites and find functional proteins as potential therapy targets.


VSG by RNA polymerase I (Pol-I), with silencing of other VSGs, and periodic switching of the expressed gene, typically via DNA recombination with duplicative translocation of a new VSG to the active site. Thus, telomeric location, epigenetic controls and monoallelic transcription by Pol-I at an extranucleolar site are prominent features of VSGs and their expression, with telomeres, chromatin structure and nuclear organization all making vitally important contributions to monoallelic VSG expression control and switching. We discuss VSG transcription, recombination and replication control within this chromosomal and sub-nuclear context.African trypanosomes are lethal human and animal parasites that use antigenic variation for evasion of host adaptive immunity. To facilitate antigenic variation, trypanosomes dedicate approximately one third of their nuclear genome, including many minichromosomes, and possibly all sub-telomeres, to variant surface glycoprotein (VSG) genes and associated sequences. Antigenic variation requires transcription of a single  Given the important role of tracts of imperfect 70 bp repeats in VSG recombination reactions (Fig. VSG switching (Glover et al., Although RAD51-dependent mechanisms of T. brucei nuclear DNA replication and suggest a link with antigenic variation. The first link between the DNA replication machinery and VSG transcriptional control was based on studies of T. brucei ORC1/CDC6 (Godoy et al., VSGs in insect-stage cells (Tiengwe et al., et al., et al., procyclin loci in bloodstream-form cells following knockdown of MCM-binding protein (Kim et al., T. brucei replication has yet to be demonstrated. These findings implicate DNA replication in VSG transcriptional control, but the basis of this, and in particular whether there is a common mechanistic action of ORC1/CDC6 and MCM-binding protein, remains unclear. Association of ORC1/CDC6 with telomeres (Benmerzouga et al., P. falciparum and other organisms, both at telomeres and elsewhere (Sasaki and Gilbert, T. brucei ORC1/CDC6 is remarkably small relative to Orc1 orthologues and lacks the N-terminal bromo-adjacent homology domain involved in binding HP1, which acts in heterochromatin-mediated silencing in other organisms (Flueck et al., et al., A number of studies are providing insights into the machinery, co-ordination and regulation of VSG expression are also possible. Loss of ORC1/CDC6 is likely to reduce the number of replication origins and hence replication efficiency, which in turn is likely signalled by the cell-cycle checkpoint machinery; in other eukaryotes ORC mutations trigger a Rad9-dependent checkpoint, arresting cells in S-phase (Ide et al., T. brucei, the equivalent histone residue, H3K76, is di-or tri-methylated by two enzymes, DOT1A and DOT1B, respectively (Janzen et al., et al., VSG transcriptional control and VSG switching dynamics present in dot1b mutants, may be due to a link between replication and checkpoint signalling (Stockdale et al., VSG expression and switching may relate to chromosome dynamics after replication. ORC in other eukaryotes is implicated in sister chromatid cohesion; pre-replication complexes can direct loading of cohesin, and ORC provides a cohesin-independent route for sister chromatid association in budding yeast (Diaz-Martinez et al., T. brucei cohesin knockdown, which also causes elevated BES switching (Landeira et al., Two less direct explanations for the roles of ORC1/CDC6 and perhaps MCM-binding protein in VSG BESs (Boothroyd et al., et al., VSGs in their previously transcribed or silent states clearly depends upon the replication process. However, mechanistic data are currently lacking here, and we do not yet know the timing, rate or direction of replication through BESs or other VSG loci.Other studies also suggest that DNA replication acts in antigenic variation. The DNA DSBs found within the VSG allelic exclusion and recombination, both essential aspects of antigenic variation in T. brucei, are critically dependent upon the telomeric environment. Emerging evidence also reinforces the importance of distinct chromatin territories within the nuclear space, although cause or consequence is less certain here. The sub-telomeric context likely provides an environment that experiences more frequent breaks, which allowed T. brucei to effectively co-opt and potentially modify a natural response to DNA breaks to achieve efficient antigenic variation. These typically heterochromatic loci also facilitated the massive expansion of the VSG gene family without multi-gene expression. Modifications have been achieved through exploiting minichromosomes to increase the maximum telomeric VSG-count by approximately 10-fold, by expansion of recombinogenic 70 bp repeats flanking VSG genes and, potentially, through BRC-repeat expansions within BRCA2. Clusters of large numbers of silent telomeric VSGs likely now facilitate the homology search and improve access to templates for repair. T. brucei has also co-opted the Pol-I machinery for VSG expression, leading to the formation of a novel extranucleolar, telomere-associated Pol-I compartment.The available evidence indicates that VSG loci, and it will be important to determine the cis-regulatory sequences, the trans-acting factors and how they interact to drive VSG exclusion and switching. An approach focussed on T. brucei homologues of DNA repair, transcription regulatory and chromatin-associated factors identified in other systems has been fruitful. However, an important goal for the future is to seek factors that play more direct and specific roles in VSG expression control, some of which may represent exploitable drug-targets. Such factors should further illuminate the mechanisms underlying monotelomeric VSG expression and recombination, the processes that make T. brucei such a persistent parasite.There are a complex variety of chromatin states that could impact transcription, recombination and replication at


Digestive malignancies remain one of the leading causes of cancer-related death worldwide despite the fact that increasing clinical and biological knowledge has emerged. Among all the newly discovered cancer cases, colorectal cancer, stomach cancer, liver cancer, and esophagus cancer rank in the front and the mortality rate for them also tops the list. The poor prognosis of digestive tumors is partially due to late diagnosis, delayed initiation of treatment, and unsatisfactory reaction to cancer therapies. Many molecular markers have been discovered for early diagnosis and better therapeutic outcomes from which we do benefit a lot. However, diagnosis and treatment of alimentary cancers require further optimization. We believe further study of novel molecular targets for early detection and better treatment would be helpful to reduce mortality rate and to improve the prognosis of malignant diseases of digestive system.In this current issue, we focus on recent advances in the research of novel molecular targets which would help reveal the possible mechanism of tumorigenesis, progression, metastasis, and recurrence of digestive malignancies. The potential value of these molecular targets in cancer therapy is also highlighted. We present 10 articles on novel molecular targets in digestive system of which six articles discuss the molecular markers in hepatocellular carcinoma, three articles discuss the molecular makers in gastric carcinoma, and one makes a comprehensive review on one anticancer target in digestive system cancer therapy.In the paper entitled “H-Ras oncogene expression and angiogenesis in experimental liver cirrhosis,” by G. Ö. Elpek et al. evaluated the relation between H-Ras expression and angiogenesis in liver cirrhosis which can progress to liver carcinoma. The oncogene H-Ras is elevated in liver cirrhosis and correlates significantly with angiogenesis.“LEPREL1 expression in human hepatocellular carcinoma and its suppressor role on cell proliferation” by J. Wang et al. found that LEPREL1 was downregulated in hepatocellular carcinoma (HCC) tissues both in mRNA and protein levels, and the down-regulation was not associated with conventional clinical parameters of HCC. LEPREL1 could serve as a potential tumor suppressor gene by inhibiting HCC cell proliferation.The research paper “Expression of potential cancer stem cell marker ABCG2 is associated with malignant behaviors of hepatocellular carcinoma” by G. Zhang et al. found that ABCG2 could probably function as a liver cancer stem cell marker because of its close relationship with tumorigenesis and also because it could promote cell proliferation, drug resistance, and metastasis. This molecule may represent an attractive target for the innovation of cancer stem cell-directed therapy for HCC.in vitro and in vivo,” S. He et al. found that the interference of NET-1 could enhance the anticancer effect of sorafenib. The interference of NET-1 could lead to impaired ability of proliferation and migration and could induce apoptosis in HCC cell line. NET-1 may be a promising molecular target to develop adjuvant therapy in combination with the only effective targeted drug, sorafenib for HCC.In “Study of RNA interference targeting NET-1 combination with sorafenib for hepatocellular carcinoma therapy Another two articles talked about the function of microRNA in HCC. X.-Y. Huang et al. showed that miR-29 was upregulated in HCC and correlated with poor outcomes of HCC. It might function by promoting cell proliferation and inhibiting cell apoptosis. The work by Z. Wang et al. clarified the association of miR-499 and miR-34b/c polymorphisms with susceptibility to HCC and got to the final conclusion that rs3746444 was not associated with susceptibility to HCC while rs4938723 was associated with increased HCC risk.“Mast cells positive to tryptase and c-kit receptor expressing cells correlates with angiogenesis in gastric cancer patients surgically treated” by M. Ammendola et al. studied the angiogenesis in gastric cancer and found that MCTP and c-kitR-EC correlated positively with microvascular density. Drugs against c-kitR and tryptase could be promising agents in antiangiogenic therapy.“Significance of glutathione peroxidase 1 and caudal-related homeodomain transcription factor in human gastric adenocarcinoma,” J. J. Han et al. demonstrated GPX1 and CDX2 might participate in the carcinogenesis, differentiation, and progression of gastric adenocarcinoma, and CDX2 might be an independent prognostic factor.“Indirect comparison showed survival benefit from adjuvant chemoradiotherapy in completely resected gastric cancer with D2 lymphadenectomy” by Q. Yang et al. confirmed the role of adjuvant chemoradiotherapy in D2-resected gastric cancer patients with discussion of underlying molecular mechanism of this benefit.The review article “PP2A-mediated anticancer therapy” by W. Chen et al. made a general review of the tumor suppressor PP2A by focusing on PP2A structure and the possible mechanism of its participation in anticancer therapy.In summary, this special issue presents several intriguing achievements in the field of novel molecular targets in digestive malignancies which we hope could be utilized in the future for early diagnosis and treatment.


Pichia anomala, Acinetobacter spp. and Pseudomonas putida; specialists such as Dunaliella salina, Saccharomyces cerevisiae, Lactobacillus spp. and other lactic acid bacteria; freshwater autotrophs Gonyostomum semen and Microcystis aeruginosa; obligate anaerobes such as Clostridium acetobutylicum; facultative pathogens such as Rhodotorula mucilaginosa, Pantoea ananatis and Pseudomonas aeruginosa; and other extremotolerant and extremophilic microbes such as Aspergillus spp., Salinibacter ruber and Haloquadratum walsbyi. Some microbes, such as Escherichia coli, Mycobacterium smegmatis and Pseudoxylaria spp., exhibit characteristics of both weed and non-weed species. We propose that the concept of nonweeds represents a ‘dustbin’ group that includes species such as Synodropsis spp., Polypaecilum pisce, Metschnikowia orientalis, Salmonella spp., and Caulobacter crescentus. We show that microbial weeds are conceptually distinct from plant weeds, microbial copiotrophs, r-strategists, and other ecophysiological groups of microorganism. Microbial weed species are unlikely to emerge from stationary-phase or other types of closed communities; it is open habitats that select for weed phenotypes. Specific characteristics that are common to diverse types of open habitat are identified, and implications of weed biology and open-habitat ecology are discussed in the context of further studies needed in the fields of environmental and applied microbiology.Competition between microbial species is a product of, yet can lead to a reduction in, the microbial diversity of specific habitats. Microbial habitats can resemble ecological battlefields where microbial cells struggle to dominate and/or annihilate each other and we explore the hypothesis that (like plant weeds) some microbes are genetically hard-wired to behave in a vigorous and ecologically aggressive manner. These ‘microbial weeds’ are able to dominate the communities that develop in fertile but uncolonized – or at least partially vacant – habitats via traits enabling them to out-grow competitors; robust tolerances to habitat-relevant stress parameters and highly efficient energy-generation systems; avoidance of or resistance to viral infection, predation and grazers; potent antimicrobial systems; and exceptional abilities to sequester and store resources. In addition, those associated with nutritionally complex habitats are extraordinarily versatile in their utilization of diverse substrates. Weed species typically deploy multiple types of antimicrobial including toxins; volatile organic compounds that act as either hydrophobic or highly chaotropic stressors; biosurfactants; organic acids; and moderately chaotropic solutes that are produced in bulk quantities . Whereas ability to dominate communities is habitat-specific we suggest that some microbial species are archetypal weeds including generalists such as:  As the collective metabolism and ecological activities of microorganisms determine the health and sustainability of life on Earth it is essential to understand the function of both individual microbes and in their communities. The cellular systems of an insignificant portion of microbial species have been intensively characterized at the levels of biochemistry, cell biology, genomics and systems biology; and a substantial body of (top-down) studies has been published in the field of microbial ecology in relation to species interactions, community succession and environmental metagenomics. There are, however, some fundamental questions that remain unanswered in relation to the behaviour of microbial species within communities: what type of biology, for instance, enables microbes to dominate entire communities and their habitats and thereby determine levels of biodiversity in specific environments?et al., et al., et al., et al., dominate their respective communities. In the field of plant ecology it is open habitats (such as freshly exposed fertile soil) that facilitate the emergence of weed species both within specific ecosystems and across evolutionary timescales. We propose that weed behaviour is equally prevalent in some microbial habitats, that open microbial habitats promote the emergence of microbial weed species, and that microbial weed biology represents a potent ecological and evolutionary mechanism of change for some microbial species and their communities.Plant species that primarily inhabit freshly disturbed habitats – known as weeds – are characterized by vigorous growth; tolerance to multiple stresses; exceptional reproduction, dispersal and survival mechanisms; a lack of specific environmental requirements; production of phytotoxic chemicals; and/or other competitive strategies . The bioThis article focuses on the following questions: (i) what types of substrate or environment facilitate the emergence of dominant microbial species, (ii) are there archetypal weed species that can consistently dominate microbial communities, (iii) what are the stress biology, nutritional strategies, energy-generating capabilities, antimicrobial activities and other competitive strategies of microbial weeds, (iv) which components and characteristics of microbial cells form the mechanics of weed biology, (v) what are the properties of open  habitats that promote the emergence of weed species, and (vi) how are microbial weeds conceptually distinct from plant weeds, and other ecophysiological groups of microorganism?et al., et al., et al., et al., Aureobasidium pullulans, Candida spp., Debaryomyces hansenii, Metschnikowia pulcherrima, Pichia guilliermondii, Pichia manshurica, Rhodotorula mucilaginosa and Zygowilliopsis californica  and generalists such as Aspergillus, Pichia and Pseudomonas species , Haloquadratum walsbyi , and Gonyostomum semen and Microcystis aeruginosa (eutrophic freshwater) ability to dominate can be restricted to a specific type of habitat. Most of these microbes do not populate their respective habitat as a one-off or chance event; they can consistently dominate their microbial communities and do so regardless of their initial cell number . Furthermore dominating species span the Kingdoms of life and, collectively, can be observed in most segments of the biosphere; from bioaerosols to solar salterns, oceans and freshwater to sediments and soils, the phyllosphere and rhizosphere, to those with molar concentrations of salts or sugars (see Table S1). The phenomenon can also be observed during food-production, food-spoilage and waste-decomposition processes where resource-rich habitats are available for colonization (see Table S1). The materials present in and the microbes living on these substrates are ultimately derived from the natural environment so community successions resulting in single-species dominance are likely to be commonplace in comparable open habitats within natural ecosystems . Environments in which P. putida is a major ecological player (Table S1) typically contain an array of chemically diverse aromatics and hydrocarbons that induce chaotropicity-mediated stresses  environments including soils, plant necromass, saline and very high-sugar habitats (Table S1). At least 20 species of Aspergillus and the closely related genus Eurotium are xerotolerant  strains are capable of reasonable growth rates close to 0°C  may be attributed, in part, from enhanced energy-generating capability. Aspergillus species (like many fungi) can utilize a range of polyols – as well as trehalose – as compatible solutes based on their individual strengths as protectants against osmotic stress, desiccation rehydration, chaotropes etc.  accumulates carotenoids in response to light which can protect against oxidative stress that is a potential hazard in salterns exposed to high levels of ultraviolet , also uses the ‘salt-in’ compatible-solute strategy, and – along with S. ruber – has light-activated protein pumps that generate proton-motive force and thereby boost energy generation  can successfully compete with the multitude of halophilic Archaea found in 5 M NaCl environments . This alga preferentially utilizes glycerol as a compatible solute, is able to accumulate glycerol to molar concentrations  either primarily use glycerol as a compatible solute or preferentially accumulate this chaotrope at low temperature , the acidic surface-film of sphagnum moss (as well as other plant tissues) and various surfaces within the human body and other animals  a polyextremophile that is psychrophilic, highly salt-tolerant, and can growth over the majority of the pH range known to support microbial life  ohmeri and Pichia sydowiorum that exhibited the greatest tolerance to the widest range of solute-imposed stresses (Table D. hansenii and Hortaea werneckii), and/or otherwise lacked the capacity for vigorous growth on the high-sugar substrate at 30°C  of the parent plant have a favourable water activity and high nutrient availability and are therefore potentially habitable by a wide range of microbes , accumulate a compatible solute (glycerol) that affords protection against this chaotrope (see below), and at the same time generate energy without any loss of ATP-generation efficiency  – which is activated under cellular stress. This regulatory system enables the coordination of an array of stress responses in an energy-efficient manner (Table S. cerevisiae responses to osmotic stress [via the high-osmolarity glycerol-response (HOG) pathway], oxidative stress, and challenges to protein and membrane stability are exceptionally efficient  which can be prevalent in relatively low-nutrient aquatic and non-aquatic habitats . Despite their copiotrophic phenotype, pseudomonads utilize a number of strategies to maintain growth and metabolism under phosphate-, iron- or nitrogen-depleted conditions  metabolic versatility in nutrient utilization can enhance the competitive ability of microbes , and polysaccharides . In order to out-compete other species in such habitats, microbes must utilize these macromolecular substrates that typically have a low bioavailability, require specialist enzymes to degrade, can be toxic, and/or are energy-expensive to catabolize. Facultatively saprotrophic microbes such as Aspergillus, Pichia, Rhodotorula and Acinetobacter species are able to access and catabolize recalcitrant polysaccharides; some weed species can produce exceptional amounts, or high-affinity versions, of inducible saprotrophic enzymes, such as xylanases  can retain activity over a wide range of environmental stresses  high chaotropicity  weeds are able to dominate their habitats due largely to the production of phytotoxic inhibitors that can be exuded from leaves, roots and plant necromass and which inhibit the germination and/or growth of other plant species  is unique to microbial weed species Tables  and 2. Wet al., et al., et al., et al., et al., octanol-water < 1.95 typically partition into the aqueous phase of cellular macromolecules and can act as potent chaotropic stressors  also inhibits the growth of competing species by acidifying the environment which it achieves via the production of a number of organic acids , including efflux pumps  is conferred by an array of mechanisms : killer toxins, hydrolytic enzymes and volatile substances  have an unusually high resistance to the net chaotropicity of the ammonia, ethanol, butanol, acetone and other chaotropic substances in their habitat  that are highly effective at expulsion of hydrocarbons such as toluene as well as many other stressors and toxins  are inhibitory to competing species  gives an insight into the complexity of the microbial warefare that takes place in open habitats: 57 compounds were detected including terpenes, alcohols, ketones and esters . This is a product of its metabolic versatility, exceptional tolerance to hydrocarbons and other solutes, and antimicrobial activities  that emerges as a dominant genus; and in the green layer at lower pH (2–2.5), R. mucilaginosa has the competitive advantage (Table S1). Phyllosphere, rhizosphere and other habitats can also remain continuously open if they are replenished with organic substances from ions released from soil particles, extracellular polymeric substances and compatible solutes from microbial cells, root diffusates, animal wastes, diverse sources of necromass, etc.The concept of an open habitat is a fundamental, well-established principle in the fields of plant and animal ecology. For microorganisms, open habitats can be defined according to the diversity, interactions and community succession of their inhabitants in contrast to other types of microbial habitat that are defined by physicochemical characteristics, substrate type or nutrient concentration Table . Hydrocas Tables  and 6. O−1 mole−1 chaotropic activity, < pH 11 or > −15°C  or Aspergillus species . The stress biology, energy-generating capabilities and antimicrobial activities of these species undoubtedly contribute to their success . Several ecophysiological classification systems that are based on microbial growth-phenotype and/or substrate utilization (Table S2). Microbial generalists can occupy a wide range of ecological niches, and typically achieve this via the ability to utilize a wide range of nutrients and substrates (Table S2). Conversely microbial specialists, such as S. cerevisiae, H. werneckii and many basidiomycetes have specific nutritional and/or physicochemical requirements . By contrast P. putida appears to be an exceptional example of a microbial weed both in terms of its cellular biology and its ability to dominate diverse types of open habitat.Microorganisms have been previously categorized based on the way in which their phenotype impacts ecological behaviour: as autotrophs and heterotrophs; generalists and specialists; Saccharomyces cerevisiae supports global industries in fermented products, biofuel, biocides (ethanol is also an important disinfectant; McDonnell and Russell, P. anomala produces a substantial catalogue of biotechnologically useful substances and is employed in production of foodstuffs (see Walker, et al., et al., et al., et al., et al., P. putida is used for the commercial production of bulk and fine chemicals, industrial biocatalysis, and as the basis of many other industrial and environmental biotechnologies (Kruijt et al., et al., et al., et al., Aspergillus spp., P. putida and Clostridium spp. play primary roles in the treatment or decomposition of plant matter, oil and hydrocarbons, xenobiotics in polluted soils, sludge and slurry treatments, and other organic wastes (Tables S2 andAspergillus species are used for production of foods (Rose, et al., S. cerevisiae, Rhodotorula spp., P. anomala, P. putida, lactic acid bacteria and other weed species invaluable as agents of biological control, for preventing spoilage of drinks, foodstuffs and animal feeds (see Calvente et al., et al., et al., It is irrefutable that a small minority of microbial species recurrently appear as the dominant members of microbial communities; and we suggest here that these microbes have shared phenotypic traits. This implies that open-habitat ecology has impacted the evolutionary trajectories of these microbes, and that the activities of weeds determine microbial diversity in many localities within the biosphere. Whereas microbial weed species are not always useful to humankind see , they mads Rose, , fine chMicrobial weeds are also used as model systems for research, yet key aspects of their biology remain enigmatic. Many plant weeds have exceptional reproduction and dispersal systems  and it rCrop plants such as sunflowers, potatoes, wheat and barley are known to have weedy ancestors (Anderson,


However, in humans there is limited evidence of endocrine disruption caused by EDCs. EDCs are a large group of persistent organic pollutants (POPs), such as polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and polybrominated ethers (PBDEs), chloronaphtalenes (PCNs), and bisphenol A (BPA), stable, lipophilic pollutants that affect fertility and cause serious reproductive problems. Xenoestrogens are synthetic compounds, but there are also numerous natural molecules in food that exhibit estrogen-mimetic activities. These natural molecules are mainly phytoestrogens isoflavones, and the most consumed are genistein and daidzein. Additionally, certain mushrooms or fungi can contain estrogen-like compounds called mycoestrogens.The potential effect of the so-called endocrine disruptors (EDCs) or xenoestrogens on human health and the proven effect on wildlife have got considerable attention in the scientific community. Endocrine disruption represents one of the most controversial environmental issues despite the fact that many substances, both natural and artificial, have been recognized to interfere with endocrine signaling pathways. Such interactions have been documented both in laboratory animal studies as well as Endocrine-disrupting chemicals: some actions of POPs on female reproduction.”Xenoestrogens activities in oocyte, ovary, placenta, and mammary gland and in the consequent serious reproductive problems, including ototoxic action, lack of ovulation, premature ovarian failure (POF), or polycystic ovarian syndrome (PCOS) are discussed in the review E. Gregoraszczuk and A. Ptak “Assessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways” discuss different molecular actions of some of the major xenoestrogens found in food or the environment and summarize the current models used to evaluate environmental estrogens. This paper is accompanied by clinical study of Caserta et al. “Correlation of endocrine disrupting chemicals serum levels and white blood cells gene expression of nuclear receptors in a population of infertile women” compares the internal exposure to bisphenol A (BPA), perfluorooctane sulphonate (PFOS), perfluorooctanoic acid (PFOA), monoethylhexyl phthalate (MEHP), and di(2-ethylhexyl) phthalate (DEHP) in serum samples of 111 infertile women and 44 fertile women and analyses levels of gene expression of nuclear receptors  as biomarkers of effective dose.G. Kerdivel et al., in their paper “Two of the papers deal with aspects of alkylphenols action as endocrine disruptors. Association between endocrine disrupting phenols in colostrums and maternal and infant health” showed that most neonates who are exposed to BPA rather than NP or OP via colostrum are recommended continuous biomonitoring of the phenols to clarify their suspected health risk on neonates and pregnant or gestation mothers. Furthermore, A. Hejmej in their paper “Photoperiod-dependent effects of 4-tert-octylphenol on adherens and gap junction proteins in bank vole seminiferous tubules” evaluating in vivo and in vitro effects of 4-tert-octylphenol (OP) on the expression and distribution of adherens and gap junction proteins, N-cadherin, β-catenin, and connexin 43 (Cx43), in testes showed that long-term treatment with OP resulted in the reduction of junction proteins expressions independent of FSH indicating that OP acts directly on adherens and gap junction proteins in the testes.The paper by B. Yi et al. “Diverse effects of phytoestrogens on the reproductive performance: cow as a model” review how exposure of soybean-derived phytoestrogens can have adverse effects on reproductive performance in female adults. Authors suggest that these findings should be specially taken into consideration when recommendations are made regarding dietary or therapeutic phytoestrogen intake in humans. Particularly that they are commonly recognized as therapeutic compounds.I. Wocławek-Potocka et al. in their paper “Action of halowax 1051 on enzymes of phase I (CYP1A1) and phase II (SULT1A and COMT) metabolism in the pig ovary” describe local ovarian metabolism of PCNs in ovarian tissue and suggest that fast activation of phase I enzymes with simultaneous inhibition of phase II enzymes indicates that androgenic action of PCNs on follicular steroidogenesis may partially result from metabolite action occurring locally in ovarian follicles.Polychlorinated naphthalenes (PCNs) are new player as endocrine disruptors. Data concerning their potency and action on ovarian function are scarce. Dr J. Barc et al. in their paper “To complete the issue, B. Ayala-García et al. revise current knowledge about the epigenetic mechanisms that underlie the effects of EDs on phenotypic variability and plasticity to stress the value of using the information derived from experiments with EDs to unveil the mechanisms that underlie phenotypic variability and speciation through epigenetic phenotypic plasticity.Taking into account that in this special issue have been published review articles, research articles and clinical studies, we hope that the information published in this special issue enriches the knowledge of our readers and scholars interested in the influence of xenobiotics on human health.Ewa L. GregoraszczukEwa L. GregoraszczukRadmila KovacevicRadmila Kovacevic


In heart failure (HF), exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac β-adrenergic receptor (β-AR) dysfunction. It has been demonstrated that exercise reverses β-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G-protein coupled receptor kinase-2 (GRK2) which is known to be involved in both β1-AR and β2-AR dysregulation in HF. Similar alterations of β-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/α-2AR/catecholamine (CA) production axis. At vascular level, exercise shows a therapeutic effect on age-related impairment of vascular reactivity to adrenergic stimulation and restores β-AR-dependent vasodilatation by increasing vascular β-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50% of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favorable effects of exercise on blood pressure control. It has been generally accepted that regular physical activity is associated with beneficial effects on the cardiovascular system  are associated with adverse outcome (Kaye et al., Since it has been demonstrated that myocardial GRK2 levels and activity mirror those measured in peripheral lymphocytes in HF patients (Iaccarino et al., Exercise training in patients with stable HF, can relieve symptoms, improve exercise capacity and quality of life, and reduce disability, hospitalization, and mortality (Piepoli et al., The crucial role of β-AR dysregulation in the pathophysiology of HF is well established. GRK2, which plays a key role in the regulation of β-AR, is significantly elevated in human and experimental HF (Ungerer et al., As mentioned above, exercise training appears to reduce autonomic derangement and neurohumoral excitation at rest in HF. The effects of exercise training on adrenergic hyperactivation in HF patients have not been completely clarified. Recently, an important molecular mechanism has been identified that contributes to the sympathetic overdrive of the failing heart. This mechanism involves the upregulation of GRK2 in adrenal medulla of HF animals, which leads to downregulation and G protein uncoupling of the α2-ARs present in the chromaffin cell membranes of the adrenal gland that normally exert negative feedback control on CA turnover (Lymperopoulos et al., Noteworthy, alterations of β-AR system, similar to those observed in HF, have been described also in the senescent heart (Davies et al., Exercise has been shown to modulate GRK2 levels/activity by reducing levels of this kinase in the heart and, consequently, inducing β-AR “resensitization.” It has been previously demonstrated in rats that both exercise and β-blockers reverse β-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation (Leosco et al., At vascular level, studies conducted in the aorta and carotid arteries of old rats have shown a reduced β-AR-dependent vasorelaxation (Chapman et al., In old healthy subjects, it has been demonstrated that physical training ameliorates age-related deterioration of cardiac function in terms of enhanced LV inotropic response to CA (Ehsani et al., The most common form of hypertension is neurogenic hypertension that is associated with sympathetic overdrive, loss of parasympathetically mediated cardiac variability, and excessive angiotensin II activity Esler, . EvidencClinical interventions showing impressive blood pressure lowering effects by targeting reductions in SNS activation (Krum et al., Exercise training could elicit adaptations in the adrenergic system, since SNS is activated during each bout of exercise and repeated activation of SNS may result in an attenuation of sympathetic activity (Grassi et al., SNS overactivity is common in many cardiovascular disease states and is related to a higher incidence of morbidity and mortality. It is widely accepted that exercise training is associated with reductions in SNS activity, whether at rest or during conditions that produced sympathoexcitation, and this effect may represent an important mechanism by which exercise may contribute to long term cardiovascular health. Future studies are needed to further identify the molecular mechanisms that are involved in physical activity dependent changes in the control of SNS activity.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The objective of this article was to review the effects of xenobiotics on total antioxidant capacity (TAC). Measurement of TAC is appropriate for evaluation of the total antioxidant defenses of blood, cells, and different kinds of tissues and organs. TAC is reduced by alcoholism, smoking, and exposure to radiation, herbicides, carbon monoxide, carbon tetrachloride, lead, arsenic, mercury, cadmium, aluminum, and other toxic elements. The test is also an important tool in evaluating environmental and occupational exposure. The involvement of unstable free radicals and reactive species from oxygen (ROS), nitrogen (RNS), and chlorine in cell and tissue damage is well established , hydroxyl radical (•OH), nitric oxide (NO•), peroxynitrite (ONOO–), though others are not   is any molecule that has one or more incomplete orbitals. A FR can gain electrons, oxidizing another atom/molecule or lose them, thus reducing an element. Some reactive oxygen species (ROS) are FR [superoxide anion , proteins (protein peroxidation), nucleic acids (DNA or RNA oxidation), and carbohydrates (glycosilation) (Vladimirov & Proskurnina 2•–) by mitochondria. As a further step, SOD and GPx convert O2•– into hydrogen peroxide (H2O2). However, as H2O2 is also a toxic reactive oxygen species, it should also be modified to inocuous water and atomic oxygen by the enzyme CAT.Since the 1960's, many research groups have been evaluating oxidative and nitrosative stress and the antioxidant defenses by measuring the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione redutase (GSH) and glutathione peroxidase (GPx). As a consequence of oxidative phosphorylation, 3–5% of oxygen in converted to the free radical superoxide anion  of a biological sample , food or vegetable extract or of living tissues and organs . Many xenobiotics can be toxic to cells, tissues and organs, constituting environemntal and occupational health problems.et al., et al., et al., et al., et al., In order to know if a therapeutic drug can preserve or consume the antioxidants of a patient, TAC determination is done in medicinal drugs. Thus the perioperative anesthetics dopamine (1080±162 mmolET/L), propofol (100±18 mmolET/L), dobutamine (80±16 mmol ET/L), and noradrenaline (62±16 mmolET/L) were found to present higher TAC values , one of the most potent liver toxins, presents a toxicological dose-response effect characterized by oxidative stress and lipid peroxidation events that induce reduction of liver TAC, liver degeneration, necrosis and fibrosis  are important metal-scavenging proteins protecting cells against cadmium, mercury, zinc and copper cytotoxicity  can also reduce plasma TAC by 20%  and activating the nuclear antioxidant response element which is further responsible for the increase in TAC levels. This could explain why exposure to magnetic fields has been correlated to increased TAC levels in male workers (Sirmatel et al., et al., Exposure to eletromagnetic radiation of 900MHz from mobile phones induced lipid peroxidation in the hippocampus and brain cortex of rats as well as oxidative stress and histopathological changes in the rats’ endometrium, effects which were reversed by antioxidants (Köylü et al., et al., et al., (It should be noted that the tecniques for determination of TAC in blood and biological fluids are still very recent. Thus potential clinical correlations between TAC and disease are yet in progress. Similarly, in many pathophysiological conditions the relationship with TAC levels has yet to be established. In a study with different degrees of injury, there was no correlation between plasma TAC levels and severity of lesions in patients with burns (Farriol  et al.,  revealedAlcohol, smoking, heavy metals and toxic elements, some pesticides, some occupational exposures, and eletromagnetic and nuclear radiations can decrease TAC, rendering subjects less resistant to oxidative and nitrosative injuries and subsequent diseases. More research is needed to address the role of antioxidant supplementation in xenobiotic exposure and disease prevention.


To the Editor: Anthrax is a global zoonotic disease, but human infections are rare in countries of Western Europe. During 2009–2010, a total of 119 (47 laboratory-confirmed) drug-abuse–related cases of anthrax were reported in the United Kingdom and Germany  user; the disease was described in 1 person who died in Norway in 2000  plnthracis  (7). TheB. anthracis into Western Europe (This reemergence of drug-related anthrax in Europe strengthens the view that heroin may provide a continuing route of entry for