Explore the vast range of titles available.

Multiple sclerosis (MS) is a common, complex neurological disease. The precise aetiology of MS is not yet known, although epidemiological data indicate that both genetic and environmental factors are important. The evidence that the environment acts long before MS becomes clinically evident is well established and suggests the existence of a prodromal phase for the disease. The increasing incidence of MS emphasises the need for strategies to prevent this chronic disorder, and the possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring endophenotypes that result from associated risk factors. However, our current knowledge of causal pathways and endophenotypes in MS is limited. Identifying and studying individuals with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease.

Background: Epstein-Barr virus (EBV) infection is widely considered to be a risk factor for multiple sclerosis (MS). A previous meta-analysis estimated an odds ratio (OR) for MS in individuals seronegative for EBV of 0.06. Given the potential importance of this finding, we aimed to establish a more precise OR for adult and paediatric onset MS in EBV seronegative individuals. Methods: PubMed and EMBASE searches were undertaken to identify studies investigating the association between MS and EBV. Twenty-two adult and three paediatric studies were included. ORs were calculated using a fixed effects model. A sub-group analysis based on the method of EBV detection was performed. Results: The OR for developing adult MS in EBV seronegatives was 0.18 (95% confidence interval (CI) 0.13–0.26)) and for paediatric MS was 0.18 (95% CI 0.11–0.30). Sub-group analysis on EBV detection method showed that studies which used immunofluoresence generated an OR=0.07 (95% CI 0.03–0.16); for those that used enzyme-linked immunosorbent assay (ELISA) OR=0.33 (95% CI 0.22–0.50) and for studies which used ELISA and immunofluoresence OR=0.00 (95% CI 0–0.43). Conclusion: The sensitivity and specificity of the assay used to measure EBV antibody titres have an influence on the association between MS and EBV. Looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. This has implications for future studies of EBV in MS. MS patients without EBV infection, if they truly exist, should be studied in more detail.

Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive–compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3–10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3–16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host’s immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders.

Several lines of evidence support a role for Epstein–Barr virus (EBV) in the aetiology of multiple sclerosis (MS). This includes the observation that nearly all MS patients show serological markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity also increases with distance from the equator. We found that the proportion of EBV positive individuals is positively associated with latitude independently of MS status (odds ratio = 1.06, 95% CI = 1.02–1.09, p = 0.002). Latitude-related factors may be implicated in the immune response to EBV and its role in MS aetiology.

Over the last few years, vitamin D deficiency has emerged as a risk factor for many diseases. Public awareness of the importance of the ‘sunshine vitamin’ is increasing, however deficiency remains an ongoing problem. Is an awareness of the importance of vitamin D enough to promote healthy people to take supplements or is a different approach required? In this article the importance of vitamin D is discussed and data showing that knowledge of this is not sufficient to encourage people to take supplements are presented.

The propensity of HIV-1 for genetic variation, a consequence of error-prone reverse transcription combined with high rates of replication, is thought to contribute to the establishment of persistent infection in the host despite the presence of a vigorous antiviral immune response. Protective immunity to viruses is mediated primarily by cytotoxic T lymphocytes, which recognize viral peptides of 8-11 amino acids bound to major histocompatibility complex class I molecules on the surface of infected cells. In this review we examine the mechanisms by which mutation within peptide antigen-encoding regions of the viral genome enables HIV-1 to evade recognition by virus-specific cytotoxic T lymphocytes. The discussion is relevant to other genetically unstable viruses and more generally to intracellular pathogens of variable antigenicity.

Background Plants are continuously exposed to changing environmental conditions and biotic attacks that affect plant growth. In crops, the inability to respond appropriately to stress has strong detrimental effects on agricultural production and yield. Ca 2+ signalling plays a fundamental role in the response of plants to most abiotic and biotic stresses. However, research on stimulus-specific Ca 2+ signals has mostly been pursued in Arabidopsis thaliana , while in other species these events are little investigated . Results In this study, we introduced the Ca 2+ reporter-encoding gene APOAEQUORIN into the crop species barley ( Hordeum vulgare ). Measurements of the dynamic changes in [Ca 2+ ] cyt in response to various stimuli such as NaCl, mannitol, H 2 O 2 , and flagellin 22 (flg22) revealed the occurrence of dose- as well as tissue-dependent [Ca 2+ ] cyt transients. Moreover, the Ca 2+ signatures were unique for each stimulus, suggesting the involvement of different Ca 2+ signalling components in the corresponding stress response. Alongside, the barley Ca 2+ signatures were compared to those produced by the phylogenetically distant model plant Arabidopsis. Notable differences in temporal kinetics and dose responses were observed, implying species-specific differences in stress response mechanisms. The plasma membrane Ca 2+ channel blocker La 3+ strongly inhibited the [Ca 2+ ] cyt response to all tested stimuli, indicating a critical role of extracellular Ca 2+ in the induction of stress-associated Ca 2+ signatures in barley. Moreover, by analysing spatio-temporal dynamics of the [Ca 2+ ] cyt transients along the developmental gradient of the barley leaf blade we demonstrate that different parts of the barley leaf show quantitative differences in [Ca 2+ ] cyt transients in response to NaCl and H 2 O 2 . There were only marginal differences in the response to flg22, indicative of developmental stage-dependent Ca 2+ responses specifically to NaCl and H 2 O 2 . Conclusion This study reveals tissue-specific Ca 2+ signals with stimulus-specific kinetics in the crop species barley, as well as quantitative differences along the barley leaf blade. A number of notable differences to the model plants Arabidopsis may be linked to different stimulus sensitivity. These transgenic barley reporter lines thus present a valuable tool to further analyse mechanisms of Ca 2+ signalling in this crop and to gain insights into the variation of Ca 2+ -dependent stress responses between stress-susceptible and -resistant species.

Background Ca 2+ and H 2 O 2 are second messengers that regulate a wide range of cellular events in response to different environmental and developmental cues. In plants, stress-induced H 2 O 2 has been shown to initiate characteristic Ca 2+ signatures; however, a clear picture of the molecular connection between H 2 O 2 -induced Ca 2+ signals and H 2 O 2 -induced cellular responses is missing, particularly in cereal crops such as barley. Here, we employed RNA-seq analyses to identify transcriptome changes in roots and leaves of barley after H 2 O 2 treatment under conditions that inhibited the formation of cytosolic Ca 2+ transients. To that end, plasma membrane Ca 2+ channels were blocked by LaCl 3 application prior to stimulation of barley tissues with H 2 O 2 . Results We examined the expression patterns of 4246 genes that had previously been shown to be differentially expressed upon H 2 O 2 application. Here, we further compared their expression between H 2 O 2 and LaCl 3  + H 2 O 2 treatment. Genes showing expression patterns different to the previous study were considered to be Ca 2+ -dependent H 2 O 2 -responsive genes. These genes, numbering 331 in leaves and 1320 in roots, could be classified in five and four clusters, respectively. Expression patterns of several genes from each cluster were confirmed by RT-qPCR. We furthermore performed a network analysis to identify potential regulatory paths from known Ca 2+ -related genes to the newly identified Ca 2+ -dependent H 2 O 2 responsive genes, using the recently described Stress Knowledge Map. This analysis indicated several transcription factors as key points of the responses mediated by the cross-talk between H 2 O 2 and Ca 2+ . Conclusion Our study indicates that about 70% of the H 2 O 2 -responsive genes in barley roots require a transient increase in cytosolic Ca 2+ concentrations for alteration in their transcript abundance, whereas in leaves, the Ca 2+ dependency was much lower at about 33%. Targeted gene analysis and pathway modeling identified not only known components of the Ca 2+ signaling cascade in plants but also genes that are not yet connected to stimuli-associated signaling. Potential key transcription factors identified in this study can be further analyzed in barley and other crops to ultimately disentangle the underlying mechanisms of H 2 O 2 -associated signal transduction mechanisms. This could aid breeding for improved stress resistance to optimize performance and productivity under increasing climate challenges.

In cereal crops, such as barley ( Hordeum vulgare L.), the ability to appropriately respond to environmental cues is an important factor for yield stability and thus for agricultural production. Reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ), are key components of signal transduction cascades involved in plant adaptation to changing environmental conditions. H 2 O 2 -mediated stress responses include the modulation of expression of stress-responsive genes required to cope with different abiotic and biotic stresses. Despite its importance, knowledge of the effects of H 2 O 2 on the barley transcriptome is still scarce. In this study, we identified global transcriptomic changes induced after application of 10 mM H 2 O 2 to five-day-old barley plants. In total, 1883 and 1001 differentially expressed genes (DEGs) were identified in roots and leaves, respectively. Most of these DEGs were organ-specific, with only 209 DEGs commonly regulated and 37 counter-regulated between both plant parts. A GO term analysis further confirmed that different processes were affected in roots and leaves. It revealed that DEGs in leaves mostly comprised genes associated with hormone signaling, response to H 2 O 2 and abiotic stresses. This includes many transcriptions factors and small heat shock proteins. DEGs in roots mostly comprised genes linked to crucial aspects of H 2 O 2 catabolism and oxidant detoxification, glutathione metabolism, as well as cell wall modulation. These categories include many peroxidases and glutathione transferases. As with leaves, the H 2 O 2 response category in roots contains small heat shock proteins, however, mostly different members of this family were affected and they were all regulated in the opposite direction in the two plant parts. Validation of the expression of the selected commonly regulated DEGs by qRT-PCR was consistent with the RNA-seq data. The data obtained in this study provide an insight into the molecular mechanisms of oxidative stress responses in barley, which might also play a role upon other stresses that induce oxidative bursts.

GABA B receptors (GABA BRs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA BR agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK ⁺ BCs), through enhanced inhibition of GABA release via presynaptic GABA BRs. We conclude that cell type–specific up-regulation of GABA BR-mediated autoinhibition in CCK ⁺ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.