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Inhalation of low concentrations of carbon dioxide (CO2) triggers anxious behaviours in rodents via chemosensors in the amygdala, and increases anxiety, autonomic arousal and hypervigilance in healthy humans. However, it is not known whether CO2 inhalation modulates defensive behaviours coordinated by this network in humans. We examined the effect of 7.5% CO2 challenge on the defensive eye-blink startle response. A total of 27 healthy volunteers completed an affective startle task during inhalation of 7.5% CO2 and air. The magnitude and latency of startle eye-blinks were recorded whilst participants viewed aversive and neutral pictures. We found that 7.5% CO2 increased state anxiety and raised concurrent measures of skin conductance and heart rate (HR). CO2 challenge did not increase startle magnitude, but slowed the onset of startle eye-blinks. The effect of CO2 challenge on HR covaried with its effects on both subjective anxiety and startle latency. Our findings are discussed with reference to startle profiles during conditions of interoceptive threat, increased cognitive load and in populations characterised by anxiety, compared with acute fear and panic., (© The Author(s) 2014.)

Emulating the input-output functions performed by a brain structure opens the possibility for developing neuroprosthetic systems that replace damaged neuronal circuits. Here, we demonstrate the feasibility of this approach by replacing the cerebellar circuit responsible for the acquisition and extinction of motor memories. Specifically, we show that a rat can undergo acquisition, retention, and extinction of the eye-blink reflex even though the biological circuit responsible for this task has been chemically inactivated via anesthesia. This is achieved by first developing a computational model of the cerebellar microcircuit involved in the acquisition of conditioned reflexes and training it with synthetic data generated based on physiological recordings. Secondly, the cerebellar model is interfaced with the brain of an anesthetized rat, connecting the model's inputs and outputs to afferent and efferent cerebellar structures. As a result, we show that the anesthetized rat, equipped with our neuroprosthetic system, can be classically conditioned to the acquisition of an eye-blink response. However, non-stationarities in the recorded biological signals limit the performance of the cerebellar model. Thus, we introduce an updated cerebellar model and validate it with physiological recordings showing that learning becomes stable and reliable. The resulting system represents an important step toward replacing lost functions of the central nervous system via neuroprosthetics, obtained by integrating a synthetic circuit with the afferent and efferent pathways of a damaged brain region. These results also embody an early example of science-based medicine, where on the one hand the neuroprosthetic system directly validates a theory of cerebellar learning that informed the design of the system, and on the other one it takes a step toward the development of neuro-prostheses that could recover lost learning functions in animals and, in the longer term, humans.

Convenient syntheses of mono- and bis-imidazolium 1,3,5-triazine derivatives bearing piperidine and morpholine substituents are reported. In situ deprotonation of the mono-imidazolium salts and reaction with Ag2O or Au(tht)Cl (tht = tetrahydrothiophene) precursors affords the corresponding Ag(NHC)Cl and Au(NHC)Cl carbene complexes. In the presence of Ag(I) or Au(I) salts the bis-imidazolium pincers eliminate the imidazolium group to afford -OMe or -NMe2 substituted triazines depending on the solvent used. In solution, the Ag(I) and Au(I) complexes show a barrier to rotation about the Ctriazine-Namine bonds, with calculated ΔG(≠) barriers in the region of 70 kJ mol(-1). Single crystal X-ray structures of several of the proligands and their corresponding Ag(I) and Au(I) complexes were obtained. These universally reveal an extended, rigidly planar π-conjugated network between the triazine core, imidazolium/imidazolylidene substituents and exocyclic amine functions, to which the origin of the rotational barrier observed in solution is attributed. Only very weak Ntriazine-metal interactions are observed in the solid state, as indicated by small deviations of the CNHC-Ag-Cl bond angles from 180° and also supported by DFT calculations on the Ag(NHC)Cl complex (NHC = 4,6-dipiperidinyl-2-methylimidazolylidene triazine). Preliminary antimicrobial susceptibility studies against five microorganisms (methicillin resistant Staphylococcus aureus NCTC 13277, S. aureus NCTC 6571, Pseudomonas aeruginosa NCTC 10662, Proteus mirabilis NCTC 11938 and Candida albicans ATCC 90028) show that the above triazine-based Ag-NHC complexes are active antimicrobial and antifungal agents.

Background: The ability to anticipate and then secure future rewards and avoid future punishments by responding effectively to environmental demands is at the core of successful decision making. Disruptions to these processes have been shown to be implicated in a number of psychiatric conditions. In the current paper we use the electrophysiological monetary incentive delay task (e-MID) to decompose the neural response to (i) reinforcement anticipation, (ii) reinforcement-contingent target processing and (iii) reinforcement-related feedback., Methods: Thirty-eight adolescents and young adults performed an ERP-based analogue of the monetary incentive delay task. ERP components previously associated with motivationally salient cue (cue-P3 and contingent negative variation, CNV), target (P3) and feedback (success vs. failure; feedback-related negativity; FRN and the late positive potential; LPP) stimuli were examined., Results: Response times were shorter and less variable in the monetary gain and loss conditions. Distinctive ERP components were observed for each phase of reinforcement processing. First, cue-P3 was enhanced to monetary gain cues. Predicted alterations in cue-P3 following monetary loss cues and the CNV following cues of either monetary loss or gain were not observed. Target P3 was enhanced in both incentive conditions. The FRN was greater following monetary loss feedback. LPP amplitude was enhanced following feedback denoting monetary gain and the avoidance of monetary loss., Conclusion: Although behaviourally the effects of monetary loss and gain were similar, the e-MID task differentiated neural processing in terms of anticipation and feedback-related brain potentials. The e-MID task and the results of the current study provide a valuable complement to fMRI-based approaches to studying normal and abnormal brain correlates of reinforcement processing., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: The ubiquitous tendency to choose immediate over delayed rewards can, in extremis, lead to maladaptive preferences for smaller sooner over larger later rewards (i.e., impulsive choice) in certain pathological groups. The delay aversion hypothesis provides one possible account of impulsive choice and argues that this tendency is motivated by the avoidance of the negative affective states associated with delay imposed prior to the delivery of a large reward. This model also predicts that on non-choice tasks individuals will be motivated to work harder and more efficiently, when given the opportunity to avoid delay. In the current paper we studied the neural markers of the motivational salience of the imposition and escape from delay using a simple reaction time task under two conditions: First where fast responses were expected to lead to delay escape and second where delay was inescapable., Methods: Forty participants performed the Escape Delay Incentive (EDI) task during which they were asked to respond as quickly as they could to a target stimulus. The EDI task included two conditions: first, a Delay Escape condition where fast responses led to the avoidance of delay and a Delay No-Escape condition in which a delay was presented on every trial irrespective of response speed. EEG was recorded from 66 equidistant electrode sites across the scalp. The neural response in these two conditions was compared in terms of contingent negative variation (CNV; preparation of motivated responses) and late positive potential, LPP; evaluation of performance feedback)., Results: As predicted individuals responded more quickly and showed enhanced CNV amplitude to Delay Escape compared with Delay No-Escape trials. Enhanced LPP amplitude was also observed when participants were not able to avoid the delay in the Delay Escape condition. ADHD symptoms were associated with larger CNV differences between Delay Escape and Delay No-Escape conditions. An association between ADHD symptoms and the LPP in the Delay Escape condition did not reach significance., Conclusion: The results of the current study suggest that delay escape is a potent reinforcer at both behavioural and neural levels. Future research should extend this analysis to clinical samples using a broader range of delays and across imaging modalities., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Catalogue of Somatic Mutations in Cancer (COSMIC) (http://www.sanger.ac.uk/cosmic) is a publicly available resource providing information on somatic mutations implicated in human cancer. Release v51 (January 2011) includes data from just over 19,000 genes, 161,787 coding mutations and 5573 gene fusions, described in more than 577,000 tumour samples. COSMICMart (COSMIC BioMart) provides a flexible way to mine these data and combine somatic mutations with other biological relevant data sets. This article describes the data available in COSMIC along with examples of how to successfully mine and integrate data sets using COSMICMart. DATABASE URL: http://www.sanger.ac.uk/genetics/CGP/cosmic/biomart/martview/.

COSMIC (http://www.sanger.ac.uk/cosmic) curates comprehensive information on somatic mutations in human cancer. Release v48 (July 2010) describes over 136,000 coding mutations in almost 542,000 tumour samples; of the 18,490 genes documented, 4803 (26%) have one or more mutations. Full scientific literature curations are available on 83 major cancer genes and 49 fusion gene pairs (19 new cancer genes and 30 new fusion pairs this year) and this number is continually increasing. Key amongst these is TP53, now available through a collaboration with the IARC p53 database. In addition to data from the Cancer Genome Project (CGP) at the Sanger Institute, UK, and The Cancer Genome Atlas project (TCGA), large systematic screens are also now curated. Major website upgrades now make these data much more mineable, with many new selection filters and graphics. A Biomart is now available allowing more automated data mining and integration with other biological databases. Annotation of genomic features has become a significant focus; COSMIC has begun curating full-genome resequencing experiments, developing new web pages, export formats and graphics styles. With all genomic information recently updated to GRCh37, COSMIC integrates many diverse types of mutation information and is making much closer links with Ensembl and other data resources.

A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented., (2010 Elsevier Ltd. All rights reserved.)

The catalogue of Somatic Mutations in Cancer (COSMIC) (http://www.sanger.ac.uk/cosmic/) is the largest public resource for information on somatically acquired mutations in human cancer and is available freely without restrictions. Currently (v43, August 2009), COSMIC contains details of 1.5-million experiments performed through 13,423 genes in almost 370,000 tumours, describing over 90,000 individual mutations. Data are gathered from two sources, publications in the scientific literature, (v43 contains 7797 curated articles) and the full output of the genome-wide screens from the Cancer Genome Project (CGP) at the Sanger Institute, UK. Most of the world's literature on point mutations in human cancer has now been curated into COSMIC and while this is continually updated, a greater emphasis on curating fusion gene mutations is driving the expansion of this information; over 2700 fusion gene mutations are now described. Whole-genome sequencing screens are now identifying large numbers of genomic rearrangements in cancer and COSMIC is now displaying details of these analyses also. Examination of COSMIC's data is primarily web-driven, focused on providing mutation range and frequency statistics based upon a choice of gene and/or cancer phenotype. Graphical views provide easily interpretable summaries of large quantities of data, and export functions can provide precise details of user-selected data.

Studies on emotion and its neurobiology have been far more focused on the recognition of emotion than on actions that are caused by emotional states. We investigate the performance of a patient, HS, with a unilateral lesion to the left temporal pole and orbito-frontal cortex (OFC) (including left amygdala), on a well-established approach/avoid task that taps into emotion-driven action. The striking finding of the present study is a remarkable, and selective, slowing of HS's avoidance of unpleasant items in her (impaired) contralesional field. This finding suggests that the left temporal lobe and OFC structures, including the amygdala, appear to be involved in the action component of emotion, specifically in avoiding negative items.

COSMIC is currently the most comprehensive global resource for information on somatic mutations in human cancer, combining curation of the scientific literature with tumor resequencing data from the Cancer Genome Project at the Sanger Institute, U.K. Almost 4800 genes and 250000 tumors have been examined, resulting in over 50000 mutations available for investigation. This information can be accessed in a number of ways, the most convenient being the Web-based system which allows detailed data mining, presenting the results in easily interpretable formats. This unit describes the graphical system in detail, elaborating an example walkthrough and the many ways that the resulting information can be thoroughly investigated by combining data, respecializing the query, or viewing the results in different ways. Alternate protocols overview the available precompiled data files available for download., (Copyright 2008 by John Wiley & Sons, Inc.)

The authors show that predispositions to approach and avoid do not consist simply of specific motor patterns but are more abstract functions that produce a desired environmental effect. It has been claimed that evaluating a visual stimulus as positive or negative evokes a specific motor response, extending the arm to negative stimuli, and contracting to positive stimuli. The authors showed that a large congruency effect (participants were faster to approach pleasant and avoid unpleasant stimuli, than to approach unpleasant and avoid pleasant stimuli) could be produced on a novel touchscreen paradigm (Experiment 1), and that the congruency effect could be reversed by spatial (Experiment 2) and nonspatial (Experiment 3) response effects. Thus, involuntary approach and avoid response activations are not fixed, but sensitive to context, and are specifically based on the desired goal., ((Copyright) 2008 APA.)

Background: PNH is an acquired hematopoietic stem cell disorder leading to a partial or absolute deficiency of all glycophosphatidyl-inositol (GPI)-linked proteins. The classical approach to diagnosis of PNH by cytometry involves the loss of at least two GPI-linked antigens on RBCs and neutrophils. While flow assays are more sensitive and specific than complement-mediated lysis or the Hams test, they suffer from several drawbacks. Bacterial aerolysin binds to the GPI moiety of cell surface GPI-linked molecules and causes lysis of normal but not GPI-deficient PNH cells. FLAER is an Alexa488-labeled inactive variant of aerolysin that does not cause lysis of cells. Our goals were to develop a FLAER-based assay to diagnose and monitor patients with PNH and to improve detection of minor populations of PNH clones in other hematologic disorders., Methods: In a single tube assay, we combined FLAER with CD45, CD33, and CD14 allowing the simultaneous analysis of FLAER and the GPI-linked CD14 structure on neutrophil and monocyte lineages., Results: Comparison to standard CD55 and CD59 analysis showed excellent agreement. Because of the higher signal to noise ratio, the method shows increased sensitivity in our hands over single (CD55 or CD59) parameter analysis. Using this assay, we were able to detect as few as 1% PNH monocytes and neutrophils in aplastic anemia, that were otherwise undetectable using CD55 and CD59 on RBC's. We also observed abnormal FLAER staining of blast populations in acute leukemia. In these cases, the neutrophils stained normally with FLAER, while the gated CD33bright cells failed to express normal levels of CD14 and additionally showed aberrant CD45 staining and bound lower levels of FLAER., Conclusion: FLAER combined with multiparameter flow cytometry offers an improved assay for diagnosis and monitoring of PNH clones and may have utility in detection of unsuspected myeloproliferative disorders., (Copyright 2007 Clinical Cytometry Society.)

In cystic fibrosis (CF), bacteria of the Burkholderia cepacia complex (Bcc) can induce a fulminant inflammation with pneumonitis and sepsis. Lipopolysaccharide (LPS) may be an important virulence factor associated with this decline but little is known about the molecular pathogenesis of Bcc LPS. In this study we have investigated the inflammatory response to highly purified LPS from different Bcc clinical isolates and the cellular signalling pathways employed. The inflammatory response (TNFalpha, IL-6) was measured in human MonoMac 6 monocytes and inhibition experiments were used to investigate the Toll-like receptors and associated adaptor molecules and pathways utilized. LPS from all clinical Bcc isolates induced significant pro-inflammatory cytokines and utilized TLR4 and CD14 to mediate activation of mitogen-activated protein kinase pathways, IkappaB-alpha degradation and NFkappaB activation. However, LPS from different clinical isolates of the same clonal strain of Burkholderia cenocepacia were found to induce a varied inflammatory response. LPS from clinical isolates of Burkholderia multivorans was found to activate the inflammatory response via MyD88-independent pathways. This study suggests that LPS alone from clinical isolates of Bcc is an important virulence factor in CF and utilizes TLR4-mediated signalling pathways to induce a significant inflammatory response.

The Catalogue Of Somatic Mutations In Cancer (COSMIC) database and web site was developed to preserve somatic mutation data and share it with the community. Over the past 25 years, approximately 350 cancer genes have been identified, of which 311 are somatically mutated. COSMIC has been expanded and now holds data previously reported in the scientific literature for 28 known cancer genes. In addition, there is data from the systematic sequencing of 518 protein kinase genes. The total gene count in COSMIC stands at 538; 25 have a mutation frequency above 5% in one or more tumour type, no mutations were found in 333 genes and 180 are rarely mutated with frequencies <5% in any tumour set. The COSMIC web site has been expanded to give more views and summaries of the data and provide faster query routes and downloads. In addition, there is a new section describing mutations found through a screen of known cancer genes in 728 cancer cell lines including the NCI-60 set of cancer cell lines.

We present a unique case demonstrating contributions of the pulvinar in response to visual threat. Substantial evidence demonstrates that the amygdala contributes to the emotion of fear and the response to threat. Traditionally, two routes to amygdala activation have been distinguished: a "slow cortical" route through visual and association cortex and a "fast subcortical" route through the thalamus. The pulvinar nucleus of the thalamus is well connected to the amygdala, suggesting that pulvinar damage might interfere with amygdala activation and response to threat. We tested this possibility in patient SM, who suffered complete loss of the left pulvinar. We measured interference from threatening images on goal-directed behavior. In SM's ipsilesional field, threatening images slowed responses more than pleasant images did. This interference decreased rapidly over time. In contrast, in SM's contralesional field, interference from threatening images was initially absent and then increased rather than decreased over time. Processing through the pulvinar therefore plays a significant role in generating response to visual threat. We suggest that, with disruption of the subcortical route to the amygdala, briefly presented images were not fully processed for threat. The reemergence of interference over time may reflect contributions of a slower route.

The discovery of mutations in cancer genes has advanced our understanding of cancer. These results are dispersed across the scientific literature and with the availability of the human genome sequence will continue to accrue. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website have been developed to store somatic mutation data in a single location and display the data and other information related to human cancer. To populate this resource, data has currently been extracted from reports in the scientific literature for somatic mutations in four genes, BRAF, HRAS, KRAS2 and NRAS. At present, the database holds information on 66 634 samples and reports a total of 10 647 mutations. Through the web pages, these data can be queried, displayed as figures or tables and exported in a number of formats. COSMIC is an ongoing project that will continue to curate somatic mutation data and release it through the website.

In the course of investigations on the possible involvement of the CIEEL (chemically initiated electron-exchange luminescence) mechanism in firefly bioluminescence, we have synthesized two novel firefly luciferin substrate analogues. D-Naphthylluciferin and D-quinolylluciferin were prepared by condensing D-cysteine with 2-cyano-6-hydroxynaphthalene and 2-cyano-6-hydroxyquinoline, respectively. These analogues are the first examples of bioluminescent substrates for firefly luciferase that do not contain a benzothiazole moiety. Firefly luciferase-catalyzed bioluminescence emission spectra revealed that compared to the normal yellow-green light of luciferin (lambda max = 559 nm), the emission from naphthylluciferin is significantly blue-shifted (lambda max = 524 nm); whereas quinolylluciferin emits orange-red light (lambda max = 608 nm). The fluorescence emission spectra, reaction pH optima, relative light yields, light emission kinetics and KM values of the analogues also were measured and compared to those of luciferin. Neither of the analogues produced the characteristic flash kinetics observed for the natural substrate. Instead, slower rise times to peak emission intensity were recorded. It appears that the formation of an intermediate from the analogue adenylates prior to the addition of oxygen is responsible for the slow rise times. The synthetic substrate analogues described here should be useful for future mechanistic studies.