The interferon response circuit: Induction and suppression by pathogenic viruses

AbstractType I interferons (IFN-α/β) are potent antiviral cytokines and modulators of the adaptive immune system. They are induced by viral infection or by double-stranded RNA (dsRNA), a by-product of viral replication, and lead to the production of a broad range of antiviral proteins and immunoactive cytokines. Viruses, in turn, have evolved multiple strategies to counter the IFN system which would otherwise stop virus growth early in infection. Here we discuss the current view on the balancing act between virus-induced IFN responses and the viral counterplayers

A 40-nm 256-Kb Half-Select Resilient 8T SRAM with Sequential Writing Technique

The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored

Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor

Cataloged from PDF version of article.Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category. © 2014 UICC

Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice

The hypothalamus-pituitary-adrenal-axis is strongly controlled by the endocannabinoid system. The specific impact of enhanced 2-arachidonoylglycerol signaling on corticosterone plasma levels, however, was not investigated so far. Here we studied the effects of the recently developed monoacylglycerol lipase inhibitor JZL184 on basal and stress-induced corticosterone levels in male CD1 mice, and found that this compound dramatically increased basal levels without affecting stress responses. Since acute changes in corticosterone levels can affect behavior, JZL184 was administered concurrently with the corticosterone synthesis inhibitor metyrapone, to investigate whether the previously shown behavioral effects of JZL184 are dependent on corticosterone. We found that in the elevated plus-maze, the effects of JZL184 on "classical" anxiety-related measures were abolished by corticosterone synthesis blockade. By contrast, effects on the "ethological" measures of anxiety (i.e. risk assessment) were not affected by metyrapone. In the open-field, the locomotion-enhancing effects of the compound were not changed either. These findings show that monoacylglycerol lipase inhibition dramatically increases basal levels of corticosterone. This endocrine effect partly affects the anxiolytic, but not the locomotion-enhancing effects of monoacylglycerol lipase blockade

Retinal and choroidal thickness measurements using spectral domain optical coherence tomography in anterior and intermediate uveitis.

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Role of electron inertia and reconnection dynamics in a stressed X-point collapse with a guide-field

In previous simulations of collisionless 2D magnetic reconnection it was consistently found that the term in the generalised Ohm's law that breaks the frozen-in condition is the divergence of the electron pressure tensor's non-gyrotropic components. A fully relativistic particle-in-cell (PIC) code was used to model $X$-point collapse with a guide-field in two and three spatial dimensions. We show that in a 2D $X$-point collapse with a guide-field close to the strength of the in-plane field, the increased induced shear flows along the diffusion region lead to a new reconnection regime in which electron inertial terms play a dominant role at the $X$-point. This transition is marked by the emergence of a magnetic island - and hence a second reconnection site - as well as electron flow vortices moving along the current sheet. The reconnection electric field at the $X$-point is shown to exceed all lower guide-field cases for a brief period, indicating a strong burst in reconnection. By extending the simulation to three spatial dimensions it is shown that the locations of vortices along the current sheet (visualised by their $Q$-value) vary in the out-of-plane direction, producing tilted vortex tubes. The vortex tubes on opposite sides of the diffusion region are tilted in opposite directions, similarly to bifurcated current sheets in oblique tearing-mode reconnection. The tilt angles of vortex tubes were compared to a theoretical estimation and were found to be a good match. Particle velocity distribution functions for different guide-field runs, for 2.5D and 3D simulations, are analysed and compared.Comment: A&A, Forthcoming articl

Metabolites of milk intake: a metabolomic approach in UK twins with findings replicated in two European cohorts

Purpose: Milk provides a significant source of calcium, protein, vitamins and other minerals to Western populations throughout life. Due to its widespread use, the metabolic and health impact of milk consumption warrants further investigation and biomarkers would aid epidemiological studies.  Methods: Milk intake assessed by a validated food frequency questionnaire was analyzed against fasting blood metabolomic profiles from two metabolomic platforms in females from the TwinsUK cohort (n = 3559). The top metabolites were then replicated in two independent populations (EGCUT, n = 1109 and KORA, n = 1593), and the results from all cohorts were meta-analyzed.  Results: Four metabolites were significantly associated with milk intake in the TwinsUK cohort after adjustment for multiple testing (P < 8.08 × 10−5) and covariates (BMI, age, batch effects, family relatedness and dietary covariates) and replicated in the independent cohorts. Among the metabolites identified, the carnitine metabolite trimethyl-N-aminovalerate (β = 0.012, SE = 0.002, P = 2.98 × 10−12) and the nucleotide uridine (β = 0.004, SE = 0.001, P = 9.86 × 10−6) were the strongest novel predictive biomarkers from the non-targeted platform. Notably, the association between trimethyl-N-aminovalerate and milk intake was significant in a group of MZ twins discordant for milk intake (β = 0.050, SE = 0.015, P = 7.53 × 10−4) and validated in the urine of 236 UK twins (β = 0.091, SE = 0.032, P = 0.004). Two metabolites from the targeted platform, hydroxysphingomyelin C14:1 (β = 0.034, SE = 0.005, P = 9.75 × 10−14) and diacylphosphatidylcholine C28:1 (β = 0.034, SE = 0.004, P = 4.53 × 10−16), were also replicated.  Conclusions: We identified and replicated in independent populations four novel biomarkers of milk intake: trimethyl-N-aminovalerate, uridine, hydroxysphingomyelin C14:1 and diacylphosphatidylcholine C28:1. Together, these metabolites have potential to objectively examine and refine milk-disease associations

Muscle Sympathetic Nerve Activity Is Related to a Surrogate Marker of Endothelial Function in Healthy Individuals

BACKGROUND: Evidence from animal studies indicates the importance of an interaction between the sympathetic nervous system and the endothelium for cardiovascular regulation. However the interaction between these two systems remains largely unexplored in humans. The aim of this study was to investigate whether directly recorded sympathetic vasoconstrictor outflow is related to a surrogate marker of endothelial function in healthy individuals. METHODS AND RESULTS: In 10 healthy normotensive subjects (3 f/7 m), (age 37+/-11 yrs), (BMI 24+/-3 kg/m(2)) direct recordings of sympathetic action potentials to the muscle vascular bed (MSNA) were performed and endothelial function estimated with the Reactive Hyperaemia- Peripheral Arterial Tonometry (RH-PAT) technique. Blood samples were taken and time spent on leisure-time physical activities was estimated. In all subjects the rate between resting flow and the maximum flow, the Reactive Hyperemic index (RH-PAT index), was within the normal range (1.9-3.3) and MSNA was as expected for age and gender (13-44 burst/minute). RH-PAT index was inversely related to MSNA (r = -0.8, p = 0.005). RH-PAT index and MSNA were reciprocally related to time (h/week) spent on physical activity (p = 0.005 and p = 0.006 respectively) and platelet concentration (PLT) (p = 0.02 and p = 0.004 respectively). CONCLUSIONS: Our results show that sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy normotensive individuals, indicating that sympathetic outflow may be modulated by changes in endothelial function. In this study time spent on physical activity is identified as a predictor of sympathetic nerve activity and endothelial function in a group of healthy individuals. The results are of importance in understanding mechanisms underlying sympathetic activation in conditions associated with endothelial dysfunction and emphasise the importance of a daily exercise routine for maintenance of cardiovascular health

Computational Modelling Folate Metabolism and DNA Methylation: Implications for Understanding Health and Ageing

This is a pre-copyedited, author-produced PDF of an article accepted for publication in 'Briefings in Bioinformatics' following peer review. The version of record Mc Auley, M. T., Mooney, K. M., & Salcedo-Sora, J. E. (2016). Computational Modelling Folate Metabolism and DNA Methylation: Implications for Understanding Health and Ageing. Briefings in Bioinformatics. DOI: 10.1093/bib/bbw116 is available online at: https://academic.oup.com/bib/article-abstract/doi/10.1093/bib/bbw116/2606065/Computational-modelling-folate-metabolism-and-DNADietary folates have a key role to play in health as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methionine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests DNA methylation status could be a central modulator of the ageing process. This has important health implications because the methylation status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and ageing. The biochemical and molecular mechanisms which underpin these processes are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date no model has represented the full scope of the interaction between the folate cycle and the reactions which govern the DNA methylation cycle. In this review we will discuss several of the models which have been developed to represent these systems. In addition we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe