Investigating the breakdown of the nerve agent simulant methyl paraoxon and chemical warfare agents GB and VX using nitrogen containing bases.

A range of nitrogen containing bases was tested for the hydrolysis of a nerve agent simulant, methyl paraoxon (MP), and the chemical warfare agents, GB and VX. The product distribution was found to be highly dependant on the basicity of the base and the quantity of water used for the hydrolysis. This study is important in the design of decontamination technology, which often involve mimics of CWAs.

Detection and correction of artefacts in estimation of rare copy number variants and analysis of rare deletions in type 1 diabetes.

Copy number variants (CNVs) have been proposed as a possible source of 'missing heritability' in complex human diseases. Two studies of type 1 diabetes (T1D) found null associations with common copy number polymorphisms, but CNVs of low frequency and high penetrance could still play a role. We used the Log-R-ratio intensity data from a dense single nucleotide polymorphism (SNP) array, ImmunoChip, to detect rare CNV deletions (rDELs) and duplications (rDUPs) in 6808 T1D cases, 9954 controls and 2206 families with T1D-affected offspring. Initial analyses detected CNV associations. However, these were shown to be false-positive findings, failing replication with polymerase chain reaction. We developed a pipeline of quality control (QC) tests that were calibrated using systematic testing of sensitivity and specificity. The case-control odds ratios (OR) of CNV burden on T1D risk resulting from this QC pipeline converged on unity, suggesting no global frequency difference in rDELs or rDUPs. There was evidence that deletions could impact T1D risk for a small minority of cases, with enrichment for rDELs longer than 400 kb (OR = 1.57, P = 0.005). There were also 18 de novo rDELs detected in affected offspring but none for unaffected siblings (P = 0.03). No specific CNV regions showed robust evidence for association with T1D, although frequencies were lower than expected (most less than 0.1%), substantially reducing statistical power, which was examined in detail. We present an R-package, plumbCNV, which provides an automated approach for QC and detection of rare CNVs that can facilitate equivalent analyses of large-scale SNP array datasets.

The determination of the structure of Saturn's F ring by nearby moonlets.

Saturn's narrow F ring exhibits several unusual features that vary on timescales of hours to years. These include transient clumps, a central core surrounded by a multistranded structure and a regular series of longitudinal channels associated with Prometheus, one of the ring's two 'shepherding' satellites. Several smaller moonlets and clumps have been detected in the ring's immediate vicinity, and a population of embedded objects has been inferred. Here we report direct evidence of moonlets embedded in the ring's bright core, and show that most of the F ring's morphology results from the continual gravitational and collisional effects of small satellites, often combined with the perturbing effect of Prometheus. The F-ring region is perhaps the only location in the Solar System where large-scale collisional processes are occurring on an almost daily basis.

Saturn's F ring is intermittently shepherded by Prometheus.

One of the stranger planetary rings is Saturn's narrow, clumpy F ring, lying just outside the main rings, in a region disturbed by chaotic orbital dynamics. We show that the F ring has a stable "true core" that dominates its mass and is confined into discontinuous short arcs of particles larger than a few millimeters in radius. The more obvious micron-size particles seen in images, outlining and obscuring the true core, contribute only a small fraction of its mass. We found that these arcs of large particles orbit Saturn in a specific corotational resonance with the nearby 100-kilometer diameter ringmoon Prometheus, which stabilizes the F ring material and allows it to persist within the disturbed region for decades or longer. Toward the end of the observing period, a small chaotic glitch in the orbit of Prometheus temporarily disrupted the confinement, but the arcs seem to be able to adapt.

Swell and Destroy: A Metal-Organic Framework-Containing Polymer Sponge That Immobilizes and Catalytically Degrades Nerve Agents.

Organophosphorus chemical warfare agents function as potent neurotoxins. Whilst the destruction of nerve agents is most readily achieved by hydrolysis, their storage and transport are hazardous and lethal in milligram doses, with any spillage resulting in fatalities. Furthermore, current decontamination and remediation measures are limited by a need for stoichiometric reagents, solvents, and buffered solutions, complicating the process for the treatment of bulk contaminants. Herein, we report a composite polymer material capable of rendering bulk VX unusable by immobilization within a porous polymer until a metal-organic framework (MOF) catalyst fully hydrolyzes the neurotoxin. This is an all-in-one capability that minimizes the use of multiple reagents, facilitated by a porous high internal phase emulsion-based polystyrene monolith housing an active zirconia MOF catalyst (MOF-808); the porous polymer absorbs and immobilizes the liquid agents, while the MOF enables hydrolysis. The dichotomous hierarchy of porous materials facilitates the containment and rapid hydrolysis of VX (>80% degradation in 8 h) in the presence of excess H2O. This composite can further enable the hydrolysis of neat VX with reliance on ambient humidity (>95% in 11 days). Potentially, 4.5 kg of the composite can absorb, immobilize, and degrade the contents of a standard chemical drum/barrel (208 L, 55 gal) of the chemical warfare agent (CWA). We believe that this composite is the first example of what will be the go-to approach for CWA immobilization and degradation in the future. Furthermore, we believe that this demonstration of a catalytically reusable absorbent sponge provides a signpost for the development of similar materials where immobilization of a substrate in a catalytically active environment is desirable.

Synthesis and µ-Opioid Activity of the Primary Metabolites of Carfentanil.

Carfentanil is a synthetic opioid significantly more potent than clinically prescribed fentanyl. The primary metabolites of carfentanil, generated from human liver microsomes, were structurally confirmed through chemical synthesis. The synthesized compounds were evaluated for µ-opioid receptor (MOR) functional activity. Of the six metabolites assayed, a major metabolite showed comparable activity to the parent opioid. Three other metabolites showed significant MOR functional activity. The availability of the metabolites could aid improvements in the analysis of biomedical samples obtained from suspected human exposures to carfentanil and development of treatment protocols.

Close-range remote sensing of Saturn's rings during Cassini's ring-grazing orbits and Grand Finale.

Saturn's rings are an accessible exemplar of an astrophysical disk, tracing the Saturn system's dynamical processes and history. We present close-range remote-sensing observations of the main rings from the Cassini spacecraft. We find detailed sculpting of the rings by embedded masses, and banded texture belts throughout the rings. Saturn-orbiting streams of material impact the F ring. There are fine-scaled correlations among optical depth, spectral properties, and temperature in the B ring, but anticorrelations within strong density waves in the A ring. There is no spectral distinction between plateaux and the rest of the C ring, whereas the region outward of the Keeler gap is spectrally distinct from nearby regions. These results likely indicate that radial stratification of particle physical properties, rather than compositional differences, is responsible for producing these ring structures.

The effects of a poor night sleep on mood, cognitive, autonomic and electrophysiological measures.

Sustained sleep problems such as insomnia have been shown to be detrimental to health. This study examines the less understood, finer grained effects of a single bad night's sleep on mood, cognitive, autonomic and electrophysiological functions. We assessed 338 individuals who had no symptoms of a clinical sleep disorder. Of these, 226 individuals had six or more hours sleep and 112 individuals had less than six hours sleep prior to an assessment of mood, cognition, autonomic and electrophysiological functioning. Individuals in the relatively "bad night" sleep group had higher depression, anxiety, and stress scores and reported significantly poorer overall wellbeing. They made more errors on simple cognitive tasks while more complex task components were unaffected. They also had an increase in heart rate and EEG alpha and beta power at rest. Participants in this study had no symptoms of a clinical sleep disorder, however the effects of a poor night sleep on measures of mood, cognition, autonomic and electrophysiological function were similar, but less severe than those reported in insomnia patients. The integrative profile of measures reported here point to an increase in physiological arousal and sub-optimal cognition, following a poor night's sleep.

An "integrative neuroscience" platform: application to profiles of negativity and positivity bias.

The aim of the paper is to describe a standardized "Integrative Neuroscience" Platform that can be applied to elucidate brain-body mechanisms. This infrastructure includes a theoretical integration (the INTEGRATE Model). To demonstrate this infrastructure, hypotheses from the INTEGRATE Model are applied in an example investigation of the cognitive, brain and body markers of individual differences in the trait characteristic of Negativity Bias (the tendency to see oneself and one's world as negative). A sample of 270 healthy participants (18-65 years old) were grouped into equal sized matched subsets of high "Negativity Bias" and high "Positivity Bias" (n = 135 in each group). Participants were assessed using a standardized battery of psychological traits, cognition and brain and body (autonomic) activity. Greater "Negativity Bias" relative to "Positivity Bias" was characterized by greater autonomic reactivity and early neural excitation to signals of potential danger, at the timescale of Emotion (< 200 ms). Concomitantly, there was a relatively lower level of "Thinking", reflected in cognitive dimensions and associated electrical brain measures of working memory and EEG Theta power. By contrast, Negativity and Positivity Bias did not differ in levels of emotional resilience and social skills at the longer time scale of Self Regulation. This paper provides a demonstration of how an Integrative Neuroscience infrastructure can be used to elucidate the brain-body basis of trait characteristics, such as Negativity Bias, that are key indicators of risk for poor well-being and psychopathology.

The integrate model of emotion, thinking and self regulation: an application to the "paradox of aging".

This study was undertaken using the INTEGRATE Model of brain organization, which is based on a temporal continuum of emotion, thinking and self regulation. In this model, the key organizing principle of self adaption is the motivation to minimize danger and maximize reward. This principle drives brain organization across a temporal continuum spanning milliseconds to seconds, minutes and hours. The INTEGRATE Model comprises three distinct processes across this continuum. Emotion is defined by automatic action tendencies triggered by signals that are significant due to their relevance to minimizing danger-maximizing reward (such as abrupt, high contrast stimuli). Thinking represents cognitive functions and feelings that rely on brain and body feedback emerging from around 200 ms post-stimulus onwards. Self regulation is the modulation of emotion, thinking and feeling over time, according to more abstract adaptions to minimize danger-maximize reward. Here, we examined the impact of dispositional factors, age and genetic variation, on this temporal continuum. Brain Resource methodology provided a standardized platform for acquiring genetic, brain and behavioral data in the same 1000 healthy subjects. Results showed a "paradox" of declining function in the "thinking" time scale over the lifespan (6 to 80+ years), but a corresponding preservation or even increase in automatic functions of "emotion" and "self regulation". This paradox was paralleled by a greater loss of grey matter in cortical association areas (assessed using MRI) over age, but a relative preservation of subcortical grey matter. Genetic polymorphisms associated with both healthy function and susceptibility to disorder (including the BDNFVal(66)Met, COMTVal(158/108)Met, MAOA and DRD4 tandem repeat and 5HTT-LPR polymorphisms) made specific contributions to emotion, thinking and self regulatory functions, which also varied according to age.

Brain structure and function correlates of general and social cognition.

AIMS: To examine how general (e.g., memory, attention) and social (emotional and interpersonal processes) cognition relate to measures of brain function and structure. METHODS: PCA was used to identify general and social cognitive factors from Brain Resource International Database in 1,316 subjects. The identified factors were correlated with each subject's corresponding brain structure (MRI) and function (EEG/ERP) data. RESULTS: Seven core cognitive factors were identified for general and three for social. General cognition was correlated with global grey matter, while social cognition was negatively correlated with grey matter in fronto-temporal-somatosensory regions. Executive function, information processing speed and verbal memory performance were correlated with delta-theta qEEG, while most general cognitive factors negatively correlated with beta qEEG. Faster information processing speed was correlated with alpha qEEG. Executive function and information processing speed was correlated with negative-going ERP amplitude and slower ERP latency at frontal sites, but at posterior sites negative correlations were found. DISCUSSION: In contrast to general cognition, social cognition is identified by different functional (automated) activity and more localized neural structures. Only general cognition, requiring more effortful, controlled processing is related to brain function measures, particularly in frontal cortices. INTEGRATIVE SIGNIFICANCE: Recording measures from multiple modalities including MRI, EEG/ERP, social and general cognition within the same subject provides a method of brain profiling for use in cognitive-neurotherapy and pharmacological studies.

An integrative approach to determine the best behavioral and biological markers of methylphenidate.

AIMS: To distinguish the most sensitive markers of methylphenidate (MPH) effects on behavior and underlying biology using an integrated cognitive and brain function test battery. METHODS: A randomized placebo-controlled trial with 32 healthy adult males. Subjects were tested on MPH doses across 18 sessions with subjective mood, objective behavioral and biological endpoints. From a computerized battery of tests, behavioral measures were cognitive performance scores, while biological measures of brain function included electroencephalographs (EEG) and event-related potentials (ERPs) with complementary measures of autonomic arousal. Using mixed modeling analyses; we determined which measures were most affected by MPH dose and correlation analyses determined the associations among them. RESULTS: MPH dose had the most pronounced effect on cognitive performance (sustained attention/vigilance), baseline autonomic arousal (heart rate, blood pressure) and baseline brain activity (EEG theta power). The faster reaction time, reduced errors, increased autonomic arousal and reductions in theta showed strong to moderate inter-correlations. MPH least affected subjective mood measures and early sensory ERP components. DISCUSSION: These findings suggest that MPH increases cortical and autonomic arousal, facilitating vigilance. The combination of behavioral and biological measures may provide an objective set of markers of MPH response. INTEGRATIVE SIGNIFICANCE: This approach has provided additional insight into the mechanism of the stimulant medication, MPH, which would not be achieved by using such measures in isolation.

Poly High Internal Phase Emulsion for the Immobilization of Chemical Warfare Agents.

We report a facile method for the absorption (characterized by the weight/weight swelling degree, Q) of a variety of chemical warfare agents (CWAs); including sulfur mustard (HD) (Q = 40) and V-series (VM, VX, i-Bu-VX, n-Bu-VX) of nerve agents (Q ≥ 45) and a simulant, methyl benzoate (Q = 55), through the use of a poly(styrene-co-vinyl benzyl chloride-co-divinylbenzene) lightly cross-linked poly high internal phase emulsion (polyHIPE). By varying the vinyl benzyl chloride (VBC) content and the volume of the internal phase of the precursor emulsion it is demonstrated that absorption is facilitated both by the swelling of the polymer and the uptake of liquid in the pores. In particular the sample prepared from a 95% internal emulsion water content showed rapid swelling (<5 min to total absorption) and the ability to swell both from a monolithic state and from a compressed state, making these systems ideal practical candidates for the rapid immobilization of CWAs.

Chromosome contacts in activated T cells identify autoimmune disease candidate genes.

BACKGROUND: Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. RESULTS: Within 4 h, activation of CD4+ T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases, we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach. CONCLUSIONS: Our systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.

Predicting stimulant medication response in ADHD: evidence from an integrated profile of neuropsychological, psychophysiological and clinical factors.

There have been significant advances in understanding the neurobiology of Attention-Deficit/Hyperactivity Disorder (ADHD) and it is timely to examine the ability of biological and psychological markers to predict medication response in this disorder. We evaluated prediction of medication response in adolescent ADHD using neuropsychological testing and psychophysiological measures of central and autonomic function. Fifty ADHD adolescents participated in pre- and post-stimulant medication testing. Separately ranked performance in auditory oddball and visual Working Memory (WM) tasks determined 20 "responders" and 20 "non-responders" with 10 "neutrals" excluded from the discriminant function analyses (DFA). For both oddball and WM performance rankings, the two groups did not differ in age, sex, or handedness. However, responders did have higher levels of symptomatology than non-responders at baseline. Pre-stimulant medication psychophysiology variables were used as predictors in each DFA. Oddball performance correctly classified 85.0% of responders and 95.0% of non-responders. Better response was associated with increased resting beta power (left posteriorly), delayed oddball target N1 (frontally), decreased oddball target P2 (left posteriorly) and decreased WM distractor P3 (right frontally). Working memory performance classified 80.0% of responders and 90.0% of non-responders, with a broadly similar profile of psychophysiological predictors. These finding indicate the value of integrating neuropsychological and psychophysiological data in predicting medication response in ADHD.

Toward an integrated profile of emotional intelligence: introducing a brief measure.

Over the last decade, an increasing number of research studies have focused on the construct of Emotional Intelligence (EI), which may be broadly defined as the capacity to perceive and regulate emotions in oneself as well as those of others. Researchers have generally adopted an organizational or management focus to the study of EI, however studies which adopt a more integrated perspective by combining psychological with biological measures, may help in further elucidating this relatively abstract construct. The first objective of this paper was to report on the psychometric properties of a brief, self-report measure of EI (Brain Resource Inventory for Emotional intelligence Factors or BRIEF), comprising internal emotional capacity (IEC), external emotional capacity (EEC) and self concept (SELF). Second, we further explored the validity of the measure by assessing the relationships between the BRIEF and variables considered relevant to the understanding of EI (including gender, age, personality, cognitive intelligence and resting state electroencephalography, EEG). The BRIEF possessed sound psychometric properties (internal consistency, r=0.68-0.81; test-retest reliability, r=0.92; construct validity with the Self Report Emotional Intelligence Test, r=0.70). As hypothesized, females were found to score higher than males on EI. EI was associated more with personality than with cognitive ability, and EEG was found to explain a significant portion of the variance in EI scores. The finding that low EI is related to underarousal of the left-frontal cortex (increased theta EEG) is consistent with research on patients with depression, as well as attention deficit hyperactivity disorder. Although EI did not display age-related increases, this might relate to the exclusion of adolescents from our sample. In conclusion, examination of the way in which EI measures relate to a complementary range of psychological and biological measures may help to further elucidate this construct.

The dose-dependent effect of methylphenidate on performance, cognition and psychophysiology.

The effects of methylphenidate (MPH) on 32 healthy human male volunteers (aged 18 to 25 years, mean age=22.26) were examined using a within-subject design. Each participant attended six testing periods, held once per week. Within each testing period, three repeat testing sessions were undertaken: pre-medication, on-medication and two hours post-medication. In these sessions, dose was manipulated (placebo, 5 mg, 15 mg or 45 mg) according a double-blind placebo design. In this report, we focus on behavioral, autonomic arousal (heart rate, skin conductance) and psychophysiological (ERP) data acquired during the working memory task. We found increased autonomic arousal (heart rate, skin conductance and blood pressure) with MPH. A linear reduction in reaction time, omission errors and target P3 latency, and a corresponding increase in background P3 amplitude was observed with increased MPH dose. The relationship between these measures supported an increase in performance and underlying brain function with MPH. To our knowledge, this is the first paper to use behavioral, arousal and electrophysiological measures in an integrative approach to study the effects of MPH on healthy adults.

Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci.

Genome-wide association studies have been tremendously successful in identifying genetic variants associated with complex diseases. The majority of association signals are intergenic and evidence is accumulating that a high proportion of signals lie in enhancer regions. We use Capture Hi-C to investigate, for the first time, the interactions between associated variants for four autoimmune diseases and their functional targets in B- and T-cell lines. Here we report numerous looping interactions and provide evidence that only a minority of interactions are common to both B- and T-cell lines, suggesting interactions may be highly cell-type specific; some disease-associated SNPs do not interact with the nearest gene but with more compelling candidate genes (for example, FOXO1, AZI2) often situated several megabases away; and finally, regions associated with different autoimmune diseases interact with each other and the same promoter suggesting common autoimmune gene targets (for example, PTPRC, DEXI and ZFP36L1).

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have examined IL-2 sensitivity in CD4+ T-cell subsets in 70 individuals with long-standing T1D, allowing us to investigate the effect of low IL-2 sensitivity on Treg frequency and function. IL-2 responsiveness, measured by STAT5a phosphorylation, was a very stable phenotype within individuals but exhibited considerable interindividual variation and was influenced by T1D-associated PTPN2 gene polymorphisms. Tregs from individuals with lower IL-2 signaling were reduced in frequency, were less able to maintain expression of FOXP3 under limiting concentrations of IL-2, and displayed reduced suppressor function. These results suggest that reduced IL-2 signaling may be used to identify patients with the highest Treg dysfunction and who may benefit most from IL-2 immunotherapy.

Mapping inter-regional connectivity of the entire cortex to characterize major depressive disorder: a whole-brain diffusion tensor imaging tractography study.

Diffusion tensor imaging (DTI) can be used to study the organization of brain white matter noninvasively. The aim of this study was to present a proof of concept for integrating DTI with high-resolution anatomical (T1) images to map and assess inter-regional connectivity across the entire cortex in a cohort of healthy participants and compared with patients with major depressive disorder. We used MRI data of 23 patients and 23 matched controls, assessed as part of baseline testing in the International Study to Predict Optimized Treatment in Depression (iSPOT-D). Freesurfer was used to analyze the T1 images to automatically label 35 gyral-based areas for each hemisphere. DTI tractography was performed to parcellate intercortical tracts using each of these areas in seed-target combinations. We quantified fractional anisotropy, number-of-fiber connections, and fiber path length for each DTI connection, with the goal of identifying the best measure or combination of measures to characterize major depression. The best classification accuracy for the individual measures was achieved using the number-of-fibers data, whereas the combination model provided a slight improvement. The most discriminant features between the two groups were for white matter associated with the limbic, frontal, and thalamic projection fibers and as part of cortical connections between the left inferior temporal and the postcentral cortex; the left parstriangularis and the left superior frontal; the left cuneus and the corpus callosum; the left lingual and the right lateral occipital, the right superior parietal and the right superior temporal cortices; and the right inferior parietal and the right insula and postcentral cortices.