Reduction of interference effect by low spatial frequency information priming in an emotional Stroop task.

The affective prediction hypothesis assumes that visual expectation allows fast and accurate processing of emotional stimuli. The prediction corresponds to what an object is likely to be. It therefore facilitates its identification by setting aside what the object is unlikely to be. It has then been suggested that prediction might be inevitably associated with the inhibition of irrelevant possibilities concerning the object to identify. Several studies highlighted that the facilitation of emotional perception depends on low spatial frequency (LSF) extraction. However, most of them used paradigms in which only the object to identify was present in the scene. As a consequence, there have yet been no studies investigating the efficiency of prediction in the visual perception of stimuli among irrelevant information. In this study, we designed a novel priming emotional Stroop task in which participants had to identify emotional facial expressions (EFEs) presented along with a congruent or incongruent word. To further investigate the role of early extraction of LSF information in top-down prediction during emotion recognition, the target EFE was primed with the same EFE filtered in LSF or high spatial frequency (HSF). Results reveal a reduction of the Stroop interference in the LSF compared to the HSF priming condition, which supports that visual expectation, depending on early LSF information extraction, facilitates the inhibition of irrelevant information during emotion recognition.

Overcoming matrix effects in the chemiluminescence determination of extracellular adenosine triphosphate in erythrocyte suspensions.

As erythrocyte-derived extracellular adenosine triphosphate (ATP) gains recognition as a key vasodilator, its accurate determination is critical. Erythrocytes' high hemoglobin content can act as an inner filter when measuring ATP concentrations by chemiluminescence. We evaluated two approaches to correct for this matrix effect: addition of cell-free hemoglobin to the ATP standards and standard addition of ATP to erythrocyte suspensions. In addition, we reduced sample hematocrit to minimize the absorbance. We conclude that extracellular ATP should be determined in erythrocyte suspensions at 0.06 to 0.004% hematocrit. This gives robust signals without matrix effects and requires only microliters of blood.

Catalysis of nitrite generation from nitroglycerin by glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Vascular relaxation to nitroglycerin (glyceryl trinitrate; GTN) requires its bioactivation by mechanisms that remain controversial. We report here that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzes the release of nitrite from GTN. In assays containing dithiothreitol (DTT) and NAD(+), the GTN reductase activity of purified GAPDH produces nitrite and 1,2-GDN as the major products. A vmax of 2.6nmolmin(-)(1)mg(-)(1) was measured for nitrite production by GAPDH from rabbit muscle and a GTN KM of 1.2mM. Reductive denitration of GTN in the absence of DTT results in dose- and time-dependent inhibition of GAPDH dehydrogenase activity. Disulfiram, a thiol-modifying drug, inhibits both the dehydrogenase and GTN reductase activity of GAPDH, while DTT or tris(2-carboxyethyl)phosphine reverse the GTN-induced inhibition. Incubation of intact human erythrocytes or hemolysates with 2mM GTN for 60min results in 50% inhibition of GAPDH's dehydrogenase activity, indicating that GTN is taken up by these cells and that the dehydrogenase is a target of GTN. Thus, erythrocyte GAPDH may contribute to GTN bioactivation.

Enhanced embodied response following ambiguous emotional processing.

It has generally been assumed that high-level cognitive and emotional processes are based on amodal conceptual information. In contrast, however, "embodied simulation" theory states that the perception of an emotional signal can trigger a simulation of the related state in the motor, somatosensory, and affective systems. To study the effect of social context on the mimicry effect predicted by the "embodied simulation" theory, we recorded the electromyographic (EMG) activity of participants when looking at emotional facial expressions. We observed an increase in embodied responses when the participants were exposed to a context involving social valence before seeing the emotional facial expressions. An examination of the dynamic EMG activity induced by two socially relevant emotional expressions (namely joy and anger) revealed enhanced EMG responses of the facial muscles associated with the related social prime (either positive or negative). These results are discussed within the general framework of embodiment theory.

Developing Resilience During the COVID-19 Pandemic: Yoga and Mindfulness for the Well-Being of Student Musicians in Spain.

Here, we report on a quasi-experimental study to explore the applicability and perceived benefits of the CRAFT program, which is based on mindfulness, yoga, positive psychology, and emotional intelligence, to improve higher education student musicians' health and well-being during the lockdown. A subset of student musicians at a Higher Conservatory of Music in Spain followed the CRAFT program during the academic year 2019/2020, 1 h per week as part of their curriculum. Students enrolled in CRAFT-based elective subjects formed the CRAFT program group (n = 40), while other students represented the control group (n = 53). The onset of the national lockdown elicited by the COVID-19 pandemic occurred halfway through the program, which was subsequently delivered in an online format. We administered an online survey to explore the effect that the exposure to the CRAFT program had in terms of how participants dealt with various health and well-being concerns arising from the COVID-19 lockdown. There was a significantly higher proportion of proactive participants in the CRAFT program group, 92%, than in the control group, 58%, in terms of implementing practices to improve their health and well-being during the lockdown. Additionally, significantly more participants acknowledged perceived benefits from their practices in the CRAFT program group, 78%, than in the control group, 52%. Among proactive participants, yoga/meditation was the most implemented in the CRAFT program group, followed by exercise, and other yoga/meditation practices, whereas in the control group, exercise and Alexander technique-based practices were the most applied. In the CRAFT program group, the highest rate of perceived benefits was from yoga/meditation CRAFT-based practices, 51%, followed by exercise, 32%, and other yoga/meditation practices, 27%, whereas in the control group, benefits were reported by 29% of exercising participants and 16% for those having practiced the Alexander technique. A similar pattern was observed when excluding participants with previous yoga/meditation experience. This study revealed how participants can independently apply learned skills from the CRAFT program in response to a naturally occurring life event of unprecedented global impact, suggesting that previous exposure to mindfulness and yoga is likely to have a beneficial effect on how young adults react towards exceptionally stressful conditions.

Potent and selective 5-LO inhibitor bearing benzothiophene pharmacophore: discovery of MK-5286.

The strategy and SAR studies that led to the discovery of a novel potent and orally available 5-lipoxygenase (5-LO) inhibitor 3-(4-fluorophenyl)-6-({4-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-benzothiophene-2-carboxamide ((S)-2l or MK-5286) were described.

In hindsight, life flows from left to right.

Three experiments investigated the mental representation of meaningful event sequences. Experiment 1 used extended (5 min long) naturalistic scenes excerpted from commercial movies. Experiments 2 and 3 presented everyday activities by means of sequences of six photographs. All experiments found both left-right and distance effects in an order decision task, suggesting that when contemplated in hindsight, experienced events unfold along a left-to-right analogical mental line. Present results are discussed in the context of the mental representation of other kinds of ordinal sequences, and other left-right effects reported in non-ordinal domains.

Temporal focus and time spatialization across cultures.

The temporal focus hypothesis (TFH) proposes that whether the past or the future is conceptualized as being located in front depends on temporal focus: the balance of attention paid to the past (tradition) and the future (progress). How general is the TFH, and to what extent can cultures and subcultures be placed on a single line relating time spatialization and temporal focus in spite of stark differences in language, religion, history, and economic development? Data from 10 Western (sub)cultural groups (N = 1198,) were used to derive a linear model relating aggregated temporal focus and proportion of future-in-front responses. This model then successfully fitted 10 independently collected (sub)cultural groups in China and Vietnam (N = 899). Further analysis of the whole data set (N = 2,097) showed that the group-level relation arose at the individual level and allowed precise quantification of its influence. Finally, in an effort to apply the model to all relevant published data sets, we included recent data from Britain and South Africa: The former, but not the latter, fitted the model well. Temporal focus is a central factor that shapes how people around the world think of time in spatial terms.

Double-label expression studies of prostacyclin synthase, thromboxane synthase and COX isoforms in normal aortic endothelium.

We have performed double-label immunofluorescence microscopy studies to evaluate the extent of co-localization of prostacyclin synthase (PGIS) and thromboxane synthase (TXS) with cyclooxygenase (COX)-1 and COX-2 in normal aortic endothelium. In dogs, COX-2 expression was found to be restricted to small foci of endothelial cells while COX-1, PGIS and TXS were widely distributed throughout the endothelium. Quantification of the total cross-sectioned aortic endothelium revealed a 6- to 7-fold greater expression of COX-1 relative to COX-2 (55 vs. 8%) and greater co-distribution of PGIS with COX-1 compared to COX-2 (19 vs. 3%). These results are in contrast to the extensive co-localization of PGIS and COX-2 in bronchiolar epithelium. In rat and human aortas, immunofluorescence studies also showed significant COX-1 and PGIS co-localization in the endothelium. Only minor focal COX-2 expression was detected in rat endothelium, similar to the dog, while COX-2 was not detected in human specimens. Inhibition studies in rats showed that selective COX-1 inhibition caused a marked reduction of 6-keto-PGF(1alpha) and TXB(2) aortic tissue levels, while COX-2 inhibition had no significant effect, providing further evidence for a functionally larger contribution of COX-1 to the synthesis of prostacyclin and thromboxane in aortic tissue. The data suggest a major role for COX-1 in the production of both prostacyclin and thromboxane in normal aortic tissue. The extensive co-localization of PGIS and COX-2 in the lung also indicates significant tissue differences in the co-expression patterns of these two enzymes.

Photo-crosslinking of proteins in intact cells reveals a dimeric structure of cyclooxygenase-2 and an inhibitor-sensitive oligomeric structure of microsomal prostaglandin E2 synthase-1.

We have characterized the structures of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) in intact cells using bifunctional and photo-activatable crosslinking agents. A dimeric complex was detected for COX-2 by both crosslinking approaches, consistent with the crystal structure of the enzyme. For mPGES-1, treatment of A549 cells with disuccinimidyl suberate yielded immunoreactive protein bands corresponding to a dimer (33 kDa) and a trimer (45 kDa), as observed for the isolated enzyme. Photo-crosslinking with photoactivatable methionine in intact cells generated complexes with molecular weights corresponding to the dimer (33 kDa) and two putative trimer forms (50 and 55 kDa). Treatment with the selective mPGES-1 inhibitor MF63 prevented the formation of the 50 and 55 kDa crosslinked complexes, while an inactive structural analogue had no effect. Our data indicate that COX-2 forms a dimer in intact cells and that mPGES-1 has an oligomeric structure that can be disrupted by a selective inhibitor.

Parallel processing of objects in a naming task.

The authors investigated whether speakers who named several objects processed them sequentially or in parallel. Speakers named object triplets, arranged in a triangle, in the order left, right, and bottom object. The left object was easy or difficult to identify and name. During the saccade from the left to the right object, the right object shown at trial onset (the interloper) was replaced by a new object (the target), which the speakers named. Interloper and target were identical or unrelated objects, or they were conceptually unrelated objects with the same name (e.g., bat [animal] and [baseball] bat). The mean duration of the gazes to the target was shorter when interloper and target were identical or had the same name than when they were unrelated. The facilitatory effects of identical and homophonous interlopers were significantly larger when the left object was easy to process than when it was difficult to process. This interaction demonstrates that the speakers processed the left and right objects in parallel.

When the Sad Past Is Left: The Mental Metaphors Between Time, Valence, and Space.

A mental metaphor is a strategy that consists of completing the representation of a concept with structural components of a correlating concept. Three issues were addressed here to deepen our understanding of this mechanism: the use of mental metaphors between abstract concepts, the simultaneous activation of multiple mental metaphors and the importance of the focus of attention on the relevant dimensions of a mental metaphor. In two experiments, participants made temporal or valence judgments (with their left or right hand) on verbs with a negative or positive meaning and conjugated in the past or future form, allowing for the simultaneous activation of the "time is space", "valence is space," and "time is valence" mental metaphors. Left-past/right-future and left-negative/right-positive congruency effects were found, and these effects were greater in the temporal and valence judgment tasks, respectively, demonstrating the importance of attentional cuing. Simultaneously, a congruency effect between the abstract concepts of time and valence (past-negative/future-positive) was observed, revealing that a mental metaphor can occur between abstract concepts and that multiple metaphors can be processed simultaneously. These results are discussed in terms of different theories within the field of mental metaphors.

Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K.

A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.

Detergents profoundly affect inhibitor potencies against both cyclo-oxygenase isoforms.

The sensitivity of Coxs (cyclo-oxygenases) to inhibition is known to be highly dependent on assay conditions. In the present study, the inhibitor sensitivities of purified Cox-1 and -2 were determined in a colorimetric assay using the reducing agent N, N, N ', N '-tetramethyl- p -phenylenediamine. With the detergent genapol X-100 (2 mM) present, the potencies of nimesulide, ibuprofen, flufenamic acid, niflumic acid and naproxen were increased over 100-fold against Cox-2 and titration curve shapes changed, so that maximal inhibition now approached 100%. Indomethacin, diclofenac and flosulide were not changed in potency. Similar effects of genapol were observed with inhibitors of Cox-1. DuP-697 and two analogues became more than 10-fold less potent against Cox-2 with genapol present. Tween-20, Triton X-100 and phosphatidylcholine, but not octylglucoside, gave qualitatively similar effects as genapol. Similar detergent-dependent changes in inhibitor potency were also observed using a [(14)C]arachidonic acid HPLC assay. The increases in potency of ibuprofen, flufenamic acid, isoxicam and niflumic acid towards Cox-2 and ibuprofen towards Cox-1 were accompanied by a change from time-independent to time-dependent inhibition. The interactions of Cox inhibitors has been described in terms of multiple binding step mechanisms. The genapol-dependent increase in inhibitor potency for ketoprofen was associated with an increase in the rate constant for the conversion of the initial enzyme-inhibitor complex to a second, more tightly bound form. The loss of potency for some inhibitors is probably due to inhibitor partitioning into detergent micelles. The present study identifies detergents as another factor that must be considered when determining inhibitor potencies against both Cox isoforms.

Mechanism of horseradish peroxidase inactivation by benzhydrazide: a critical evaluation of arylhydrazides as peroxidase inhibitors.

Many compounds are oxidized by haem enzymes, such as peroxidases and cytochromes P450, to highly reactive intermediates that function as enzyme inactivators. To evaluate the potential of arylhydrazides as selective metabolically activated peroxidase inhibitors, the mechanism of HRPC (horseradish peroxidase isoenzyme C) inhibition by BZH (benzhydrazide) was investigated in detail. No oxygen consumption was detected in BZH solutions at pH 7.0-12.0, but addition of HRPC resulted in significant O2 uptake above pH 8.0, indicating that the enzyme catalyses BZH oxidation. Addition of H2O2 to HRPC plus BZH activates the latter as an inhibitor. This involves the three-electron oxidation of BZH in one-electron steps by the peroxidase catalytic intermediates, Compounds I and II, to produce a benzoyl radical that covalently alters the active site and inhibits peroxidase activity. Alternatively, the benzoyl radical could be produced by di-imide (NH=NH) elimination from the BZH radical. Production of Compound III (oxyperoxidase) followed by p-670 (m/z =583, biliverdin-like derivative) was observed for HRPC incubated with excess H2O2, and the addition of BZH resulted in an increase in the rate of p-670 production. BZH is an inefficient inhibitor of HRPC with a K(I) of 80 muM, an apparent inactivation rate constant (k(inact)) of 0.035 min(-1), and an IC50 of 1.0 mM. This prompted the investigation of HRPC inactivation by a series of related arylhydrazides with known binding affinities for HRPC. The hydrazide with the highest affinity (2-naphthoichydrazide; K(d)=5.2 muM) was also found to be the most effective inhibitor with K(I), k(inact) and IC50 values of 14 muM, 0.14 min(-1) and 35 muM, respectively.

A multisensory interaction effect in the conceptual realm of time.

Recent studies on the conceptualization of abstract concepts suggest that the concept of time is represented along a left-right horizontal axis, such that left-to-right readers represent past on the left and future on the right. Although it has been demonstrated with strong consistency that the localization (left or right) of visual stimuli could modulate temporal judgments, results obtained with auditory stimuli are more puzzling, with both failures and successes at finding the effect in the literature. The present study supports an account based on the relative relevance of visual versus auditory-spatial information in the creation of a frame of reference to map time: The auditory location of words interacted with their temporal meaning only when auditory information was made more relevant than visual spatial information by blindfolding participants.

Attentional factors in conceptual congruency.

Conceptual congruency effects are biases induced by an irrelevant conceptual dimension of a task (e.g., location in vertical space) on the processing of another, relevant dimension (e.g., judging words' emotional evaluation). Such effects are a central empirical pillar for recent views about how the mind/brain represents concepts. In the present paper, we show how attentional cueing (both exogenous and endogenous) to each conceptual dimension succeeds in modifying both the manifestation and the symmetry of the effect. The theoretical implications of this finding are discussed.

Resorufin butyrate as a soluble and monomeric high-throughput substrate for a triglyceride lipase.

Triglyceride lipases such as lipoprotein lipase, endothelial lipase, and hepatic lipase play key roles in controlling the levels of plasma lipoprotein. Accordingly, small-molecule modulation of these species could alter patient lipid profiles with corresponding health effects. Screening of these enzymes for small-molecule therapeutics has historically involved the use of lipid-based particles to mimic native substrates. However, particle-based artifacts can complicate the discovery of therapeutic molecules. As a simplifying solution, the authors sought to develop an approach involving a soluble and monomeric lipase substrate. Using purified bovine lipoprotein lipase as a model system, they show that the hydrolysis of resorufin butyrate can be fluorescently monitored to give a robust assay (Z' > 0.8). Critically, using parallel approaches, they show that resorufin butyrate is soluble and monomeric under assay conditions. The presented assay should be useful as a simple and inexpensive primary or secondary screen for the discovery of therapeutic lipase modulators.

Thinking about the future moves attention to the right.

Previous studies have shown that past and future temporal concepts are spatially represented (past being located to the left and future to the right in a mental time line). This study aims at further investigating the nature of this space-time conceptual metaphor, by testing whether the temporal reference of words orient spatial attention or rather prime a congruent left/right response. A modified version of the spatial cuing paradigm was used in which a word's temporal reference must be kept in working memory whilst participants carry out a spatial localization (Experiment 1) or a direction discrimination, spatial Stroop task (Experiment 2). The results showed that the mere activation of the past or future concepts both oriented attention and primed motor responses to left or right space, respectively, and these effects were independent. Moreover, in spite of the fact that such time-reference cues were nonpredictive, the use of a short and a long stimulus onset asynchrony in Experiment 3 showed that these cues modulated spatial attention as typical central cues like arrows do, suggesting a common mechanism for these two types of cuing.