Right ventromedial and dorsolateral prefrontal cortices mediate adaptive decisions under ambiguity by integrating choice utility and outcome evaluation.

The Iowa gambling task (IGT) is one of the most influential behavioral paradigms in reward-related decision making and has been, most notably, associated with ventromedial prefrontal cortex function. However, performance in the IGT relies on a complex set of cognitive subprocesses, in particular integrating information about the outcome of choices into a continuously updated decision strategy under ambiguous conditions. The complexity of the task has made it difficult for neuroimaging studies to disentangle the underlying neurocognitive processes. In this study, we used functional magnetic resonance imaging in combination with a novel adaptation of the task, which allowed us to examine separately activation associated with the moment of decision or the evaluation of decision outcomes. Importantly, using whole-brain regression analyses with individual performance, in combination with the choice/outcome history of individual subjects, we aimed to identify the neural overlap between areas that are involved in the evaluation of outcomes and in the progressive discrimination of the relative value of available choice options, thus mapping the two fundamental cognitive processes that lead to adaptive decision making. We show that activation in right ventromedial and dorsolateral prefrontal cortex was predictive of adaptive performance, in both discriminating disadvantageous from advantageous decisions and confirming negative decision outcomes. We propose that these two prefrontal areas mediate shifting away from disadvantageous choices through their sensitivity to accumulating negative outcomes. These findings provide functional evidence of the underlying processes by which these prefrontal subregions drive adaptive choice in the task, namely through contingency-sensitive outcome evaluation.

CD8+ T-cells mediate immunopathology in tick-borne encephalitis

Epidemics of tick-borne encephalitis involving thousands of humans occur annually in the forested regions of Europe and Asia. Despite the importance of this disease, the underlying basis for the development of encephalitis remains undefined. Here, we prove the key role of CD8(+) T-cells in the immunopathology of tick-borne encephalitis, as demonstrated by prolonged survival of SCID or CD8(-/-) mice, following infection, when compared with immunocompetent mice or mice with adoptively transferred CD8(+) T-cells. The results imply that tick-borne encephalitis is an immunopathological disease and that the inflammatory reaction significantly contributes to the fatal outcome of the infection. (C) 2008 Elsevier Inc. All rights reserved.

Hydrogen-bonded dimer can mediate supramolecular beta-sheet formation and subsequent amyloid-like fibril formation: a model study

FT-IR data of six terminally blocked tripeptides containing Acp (epsilon-aminocaproic acid) reveals that all of them form supramolecular beta-sheets in the solid state. Single crystal X-ray diffraction studies of two peptides not only support this data but also disclose the fact that the supramolecular beta-sheet formation is initiated via dimer formation. The Scanning Electron Microscopic images of all peptides exhibit amyloid-like fibrils that show green birefringence after binding with Congo red, which is a characteristic feature of many neurodegenerative disease causing amyloid fibrils. (C) 2004 Elsevier Ltd. All rights reserved.

Using artefacts to mediate understanding in design conversations

The journey from the concept of a building to the actual built form is mediated with the use of various artefacts, such as drawings, product samples and models. These artefacts are produced for different purposes and for people with different levels of understanding of the design and construction processes. This paper studies design practice as it occurs naturally in a real-world situation by observing the conversations that surround the use of artefacts at the early stages of a building's design. Drawing on ethnographic data, insights are given into how the use of artefacts can reveal a participant's understanding of the scheme. The appropriateness of the method of conversation analysis to reveal the users' understanding of a scheme is explored by observing spoken micro-interactional behaviours. It is shown that the users' understanding of the design was developed in the conversations around the use of artefacts, as well as the knowledge that is embedded in the artefacts themselves. The users' confidence in the appearance of the building was considered to be gained in conversation, rather than the ability of the artefacts to represent a future reality.

G protein ss gamma subunits mediate presynaptic inhibition of transmitter release from rat superior cervical ganglion neurones in culture

The activation of presynaptic G protein-coupled receptors (GPCRs) is widely reported to inhibit transmitter release; however, the lack of accessibility of many presynaptic terminals has limited direct analysis of signalling mediators. We studied GPCR-mediated inhibition of fast cholinergic transmission between superior cervical ganglion neurones (SCGNs) in culture. The adrenoceptor agonist noradrenaline (NA) caused a dose-related reduction in evoked excitatory postsynaptic potentials (EPSPs). NA-induced EPSP decrease was accompanied by effects on the presynaptic action potential (AP), reducing AP duration and amplitude of the after-hyperpolarization (AHP), without affecting the pre- and postsynaptic membrane potential. All effects of NA were blocked by yohimbine and synaptic transmission was reduced by clonidine, consistent with an action at presynaptic alpha 2-adrenoceptors. NA-induced inhibition of transmission was sensitive to pre-incubation of SCGNs with pertussis toxin (PTX), implicating the involvement of G alpha(i)/(o)beta y subunits. Expression of G alpha transducin, an agent which sequesters G protein beta gamma (G beta y) subunits, in the presynaptic neurone caused a time-dependent attenuation of NA-induced inhibition. Injection of purified G beta gamma subunits into the presynaptic neurone inhibited transmission, and also reduced the AHP amplitude. Furthermore, NA-induced inhibition was occluded by pre-injection of G beta gamma subunits. The Ca2+ channel blocker Cd2+ mimicked NA effects on transmitter release. Cd2+, NA and G beta gamma subunits also inhibited somatic Ca2+ current. In contrast to effects on AP-evoked transmitter release, NA had no clear action on AP-independent EPSPs induced by hypertonic solutions. These results demonstrate that G beta gamma subunits functionally mediate inhibition of transmitter release by alpha 2-adrenoceptors and represent important regulators of synaptic transmission at mammalian presynaptic terminals.

How does the brain mediate interpretation of incongruent auditory emotions? The neural response to prosody in the presence of conflicting lexico-semantic cues

We frequently encounter conflicting emotion cues. This study examined how the neural response to emotional prosody differed in the presence of congruent and incongruent lexico-semantic cues. Two hypotheses were assessed: (i) decoding emotional prosody with conflicting lexico-semantic cues would activate brain regions associated with cognitive conflict (anterior cingulate and dorsolateral prefrontal cortex) or (ii) the increased attentional load of incongruent cues would modulate the activity of regions that decode emotional prosody (right lateral temporal cortex). While the participants indicated the emotion conveyed by prosody, functional magnetic resonance imaging data were acquired on a 3T scanner using blood oxygenation level-dependent contrast. Using SPM5, the response to congruent cues was contrasted with that to emotional prosody alone, as was the response to incongruent lexico-semantic cues (for the 'cognitive conflict' hypothesis). The right lateral temporal lobe region of interest analyses examined modulation of activity in this brain region between these two contrasts (for the 'prosody cortex' hypothesis). Dorsolateral prefrontal and anterior cingulate cortex activity was not observed, and neither was attentional modulation of activity in right lateral temporal cortex activity. However, decoding emotional prosody with incongruent lexico-semantic cues was strongly associated with left inferior frontal gyrus activity. This specialist form of conflict is therefore not processed by the brain using the same neural resources as non-affective cognitive conflict and neither can it be handled by associated sensory cortex alone. The recruitment of inferior frontal cortex may indicate increased semantic processing demands but other contributory functions of this region should be explored.

Glycosyl transferases in family 61 mediate arabinofuranosyl transfer onto xylan in grasses

Xylan, a hemicellulosic component of the plant cell wall, is one of the most abundant polysaccharides in nature. In contrast to dicots, xylan in grasses is extensively modified by alpha-(1,2)- and alpha-(1,3)-linked arabinofuranose. Despite the importance of grass arabinoxylan in human and animal nutrition and for bioenergy, the enzymes adding the arabinosyl substitutions are unknown. Here we demonstrate that knocking-down glycosyltransferase (GT) 61 expression in wheat endosperm strongly decreases alpha-(1,3)-linked arabinosyl substitution of xylan. Moreover, heterologous expression of wheat and rice GT61s in Arabidopsis leads to arabinosylation of the xylan, and therefore provides gain-of-function evidence for alpha-(1,3)-arabinosyltransferase activity. Thus, GT61 proteins play a key role in arabinoxylan biosynthesis and therefore in the evolutionary divergence of grass cell walls.

Substance P released by TRPV1-expressing neurons produces reactive oxygen species that mediate ethanol-induced gastric injury

Although neurokinin 1 receptor antagonists prevent ethanol (EtOH)-induced gastric lesions, the mechanisms by which EtOH releases substance P (SP) and SP damages the mucosa are unknown. We hypothesized that EtOH activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to release SP, which stimulates epithelial neurokinin 1 receptors to generate damaging reactive oxygen species (ROS). SP release was assayed in the mouse stomach, ROS were detected using dichlorofluorescein diacetate, and neurokinin 1 receptors were localized by immunofluorescence. EtOH-induced SP release was prevented by TRPV1 antagonism. High dose EtOH caused lesions, and TRPV1 or neurokinin 1 receptor antagonism and neurokinin 1 receptor deletion inhibited lesion formation. Coadministration of low, innocuous doses of EtOH and SP caused lesions by a TRPV1-independent but neurokinin 1 receptor-dependent process. EtOH, capsaicin, and SP stimulated generation of ROS by superficial gastric epithelial cells expressing neurokinin 1 receptors by a neurokinin 1 receptor-dependent mechanism. ROS scavengers prevented lesions induced by a high EtOH dose or a low EtOH dose plus SP. Gastric lesions are caused by an initial detrimental effect of EtOH, which is damaging only if associated with TRPV1 activation, SP release from sensory nerves, stimulation of neurokinin 1 receptors on epithelial cells, and ROS generation.

Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis

BACKGROUND & AIMS: We studied the role of protease-activated receptor 2 (PAR(2)) and its activating enzymes, trypsins and tryptase, in Clostridium difficile toxin A (TxA)-induced enteritis. METHODS: We injected TxA into ileal loops in PAR(2) or dipeptidyl peptidase I (DPPI) knockout mice or in wild-type mice pretreated with tryptase inhibitors (FUT-175 or MPI-0442352) or soybean trypsin inhibitor. We examined the effect of TxA on expression and activity of PAR(2) and trypsin IV messenger RNA in the ileum and cultured colonocytes. We injected activating peptide (AP), trypsins, tryptase, and p23 in wild-type mice, some pretreated with the neurokinin 1 receptor antagonist SR140333. RESULTS: TxA increased fluid secretion, myeloperoxidase activity in fluid and tissue, and histologic damage. PAR(2) deletion decreased TxA-induced ileitis, reduced luminal fluid secretion by 20%, decreased tissue and fluid myeloperoxidase by 50%, and diminished epithelial damage, edema, and neutrophil infiltration. DPPI deletion reduced secretion by 20% and fluid myeloperoxidase by 55%. In wild-type mice, FUT-175 or MPI-0442352 inhibited secretion by 24%-28% and tissue and fluid myeloperoxidase by 31%-71%. Soybean trypsin inhibitor reduced secretion to background levels and tissue myeloperoxidase by up to 50%. TxA increased expression of PAR(2) and trypsin IV in enterocytes and colonocytes and caused a 2-fold increase in Ca(2+) responses to PAR(2) AP. AP, tryptase, and trypsin isozymes (trypsin I/II, trypsin IV, p23) caused ileitis. SR140333 prevented AP-induced ileitis. CONCLUSIONS: PAR(2) and its activators are proinflammatory in TxA-induced enteritis. TxA stimulates existing PAR(2) and up-regulates PAR(2) and activating proteases, and PAR(2) causes inflammation by neurogenic mechanisms.

Enhancement of ENSO variability by a weakened Atlantic thermohaline circulation in a coupled GCM

A coupled ocean–atmosphere general circulation model is used to investigate the modulation of El Niño–Southern Oscillation (ENSO) variability due to a weakened Atlantic thermohaline circulation (THC). The THC weakening is induced by freshwater perturbations in the North Atlantic, and leads to a well-known sea surface temperature dipole and a southward shift of the intertropical convergence zone (ITCZ) in the tropical Atlantic. Through atmospheric teleconnections and local coupled air–sea feedbacks, a meridionally asymmetric mean state change is generated in the eastern equatorial Pacific, corresponding to a weakened annual cycle, and westerly anomalies develop over the central Pacific. The westerly anomalies are associated with anomalous warming of SST, causing an eastward extension of the west Pacific warm pool particularly in August–February, and enhanced precipitation. These and other changes in the mean state lead in turn to an eastward shift of the zonal wind anomalies associated with El Niño events, and a significant increase in ENSO variability. In response to a 1-Sv (1 Sv ≡ 106 m3 s−1) freshwater input in the North Atlantic, the THC slows down rapidly and it weakens by 86% over years 50–100. The Niño-3 index standard deviation increases by 36% during the first 100-yr simulation relative to the control simulation. Further analysis indicates that the weakened THC not only leads to a stronger ENSO variability, but also leads to a stronger asymmetry between El Niño and La Niña events. This study suggests a role for an atmospheric bridge that rapidly conveys the influence of the Atlantic Ocean to the tropical Pacific and indicates that fluctuations of the THC can mediate not only mean climate globally but also modulate interannual variability. The results may contribute to understanding both the multidecadal variability of ENSO activity during the twentieth century and longer time-scale variability of ENSO, as suggested by some paleoclimate records.

Nerve terminal GABAA receptors activate Ca2+/calmodulin-dependent signaling to inhibit voltage-gated Ca2+ influx and glutamate release

-Aminobutyric acid type A (GABAA) receptors, a family of Cl-permeable ion channels, mediate fast synaptic inhibition as postsynaptically enriched receptors for -aminobutyric acid at GABAergic synapses. Here we describe an alternative type of inhibition mediated byGABAA receptors present on neocortical glutamatergic nerve terminals and examine the underlying signaling mechanism(s). By monitoring the activity of the presynaptic CaM kinase II/synapsin I signaling pathway in isolated nerve terminals, we demonstrate that GABAA receptor activation correlated with an increase in basal intraterminal [Ca2]i. Interestingly, this activation of GABAA receptors resulted in a reduction of subsequent depolarization-evoked Ca2 influx, which thereby led to an inhibition of glutamate release. To investigate how the observed GABAA receptor-mediated modulation operates, we determined the sensitivity of this process to the Na-K-2Cl cotransporter 1 antagonist bumetanide, as well as substitution of Ca2 with Ba2, or Ca2/calmodulin inhibition by W7. All of these treatments abolished the modulation by GABAA receptors. Application of selective antagonists of voltage-gated Ca2 channels (VGCCs) revealed that the GABAA receptor-mediated modulation of glutamate release required the specific activity of L- and R-type VGCCs. Crucially, the inhibition of release by these receptors was abolished in terminals isolated from R-type VGCC knock-out mice. Together, our results indicate that a functional coupling between nerve terminal GABAA receptors and L- or R-type VGCCs is mediated by Ca2/calmodulin-dependent signaling. This mechanism provides a GABA-mediated control of glutamatergic synaptic activity by a direct inhibition of glutamate release.

Platelet-mediated metabolism of the common dietary flavonoid, quercetin.

BACKGROUND: Flavonoid metabolites remain in blood for periods of time potentially long enough to allow interactions with cellular components of this tissue. It is well-established that flavonoids are metabolised within the intestine and liver into methylated, sulphated and glucuronidated counterparts, which inhibit platelet function. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate evidence suggesting platelets which contain metabolic enzymes, as an alternative location for flavonoid metabolism. Quercetin and a plasma metabolite of this compound, 4'-O-methyl quercetin (tamarixetin) were shown to gain access to the cytosolic compartment of platelets, using confocal microscopy. High performance liquid chromatography (HPLC) and mass spectrometry (MS) showed that quercetin was transformed into a compound with a mass identical to tamarixetin, suggesting that the flavonoid was methylated by catechol-O-methyl transferase (COMT) within platelets. CONCLUSIONS/SIGNIFICANCE: Platelets potentially mediate a third phase of flavonoid metabolism, which may impact on the regulation of the function of these cells by metabolites of these dietary compounds.

Sonogashira coupling on an extended gold surface in vacuo: reaction of phenylacetylene with iodobenzene on Au(111)

Temperature-programmed reaction measurements supported by scanning tunneling microscopy have shown that phenylacetylene and iodobenzene react on smooth Au(111) under vacuum conditions to yield biphenyl and diphenyldiacetylene, the result of homocoupling of the reactant molecules. They also produce diphenylacetylene, the result of Sonogashira cross-coupling, prototypical of a class of reactions that are of paramount importance in synthetic organic chemistry and whose mechanism remains controversial. Roughened Au(111) is completely inert toward all three reactions, indicating that the availability of crystallographically well-defined adsorption sites is crucially important. High-resolution X-ray photoelectron spectroscopy and near-edge X-ray absorption fine structure spectroscopy show that the reactants are initially present as intact, essentially flat-lying molecules and that the temperature threshold for Sonogashira coupling coincides with that for C−I bond scission in the iodobenzene reactant. The fractional-order kinetics and low temperature associated with desorption of the Sonogashira product suggest that the reaction occurs at the boundaries of islands of adsorbed reactants and that its appearance in the gas phase is rate-limited by the surface reaction. These findings demonstrate unambiguously and for the first time that this heterogeneous cross-coupling chemistry is an intrinsic property of extended, metallic pure gold surfaces: no other species, including solvent molecules, basic or charged (ionic) species are necessary to mediate the process.

Tweaking the gain on platelet regulation: The tachykinin connection

Soluble factors such as ADP and thromboxane (TX) A(2) that are secreted or released by platelets at sites of tissue injury, mediate autocrine and paracrine regulation of platelet function, resulting in rapid localised thrombus formation. The suppression of platelet function, particularly through targeting such secondary regulatory mechanisms, that serve to 'fine-tune' the platelet response, has proven effective in the prevention of inappropriate platelet activation that results in thrombosis. The most commonly used anti-platelet approaches (ADP receptor antagonism or inhibition of TXA(2) synthesis), however, lack efficacy in many patients, suggesting the existence of additional uncharacterised mechanisms for the regulation of platelet function. Recent data, which form a focus of this review, have identified peripheral tachykinin peptide family members, such as substance P and the newly identified endokinins, as physiologically important positive feedback regulators of platelet function. The actions of tachykinins that are released from platelets during activation are mediated by the neurokinin-1 receptor. Initial analysis of the role of this receptor in platelet thrombus formation, and thrombosis in the mouse, indicate this to be a promising new target for the development of anti-thrombotic drugs. (C) 2008 Elsevier Ireland Ltd. All rights reserved.