LC-HRMS screening of per- and polyfluorinated alkyl substances (PFAS) in impregnated paper samples and contaminated soils.

High per- and polyfluorinated alkyl substance (PFAS) concentrations have been detected in agricultural soils in Southwest Germany. Discharges of PFAS-contaminated paper sludge and compost are suspected to be the cause of the contamination. Perfluorinated carboxylic acids (PFCAs) have been detected also in groundwater, drinking water, and plants in this area. Recently, previously unknown compounds have been identified by high-resolution mass spectrometry (HRMS). Major contaminants were polyfluorinated dialkylated phosphate esters (diPAPs) and N-ethyl perfluorooctane sulfonamide ethanol-based phosphate diester (diSAmPAP). In this study, HRMS screening for PFAS was applied to 14 soil samples from the contaminated area and 14 impregnated paper samples which were from a similar period than the contamination. The paper samples were characterized by diPAPs (from 4:2/6:2 to 12:2/12:2), fluorotelomer mercapto alkyl phosphates (FTMAPs; 6:2/6:2 to 10:2/10:2), and diSAmPAP. In soil samples, diPAPs and their transformation products (TPs) were the major contaminants, but also FTMAPs, diSAmPAP, and their TPs occurred. The distribution patterns of the carbon chain lengths of the precursor PFAS in soil samples were shown to resemble those in paper samples. This supports the hypothesis that paper sludge is a major source of contamination. The presence of major degradation products like PFCAs, FTSAs, or PFOS and their distribution of carbon chain lengths indicate the activity of biotic or abiotic degradation processes and selective leaching processes from the upper soil horizons.

Cognitive modelling reveals distinct electrophysiological markers of decision confidence and error monitoring.

Is confidence in perceptual decisions generated by the same brain processes as decision itself, or does confidence require metacognitive processes following up on the decision? In a masked orientation task with varying stimulus-onset-asynchrony, we used EEG and cognitive modelling to trace the timing of the neural correlates of confidence. Confidence reported by human observers increased with stimulus-onset-asynchrony in correct and to a lesser degree in incorrect trials, a pattern incompatible with established models of confidence. Electrophysiological activity was associated with confidence in two different time periods, namely 350-500 â€‹ms after stimulus onset and 250-350 â€‹ms after the response. Cognitive modelling revealed that only the activity following on the stimulus exhibited the same statistical regularities as confidence, while the statistical pattern of the activity following the response was incompatible with confidence. It is argued that electrophysiological markers of confidence and error awareness are at least in parts distinct.

Total Synthesis of the Plant Growth Promoter Auxofuran Featuring a Gold(I) Catalyzed Furan Formation.

A concise synthesis of auxofuran (1) was developed. Starting with a Sonogashira cross-coupling reaction, enynol (10) was prepared. A gold(I) catalyzed cycloisomerization led to disubstituted furan 12. Via an intramolecular Friedel-Crafts cyclization, a dihydrobenzofuranone was obtained. Functional group manipulations, including benzylic oxidation, led to the target molecule.

Are errors detected before they occur? Early error sensations revealed by metacognitive judgments on the timing of error awareness.

Errors in choice tasks are not only detected fast and reliably, participants often report that they knew that an error occurred already before a response was produced. These early error sensations stand in contrast with evidence suggesting that the earliest neural correlates of error awareness emerge around 300 ms after erroneous responses. The present study aimed to investigate whether anecdotal evidence for early error sensations can be corroborated in a controlled study in which participants provide metacognitive judgments on the subjective timing of error awareness. In Experiment 1, participants had to report whether they became aware of their errors before or after the response. In Experiment 2, wemeasured confidence in these metacognitive judgments. Our data show that participants report early error sensations with high confidence in the majority of error trials across paradigms and experiments. These results provide first evidence for early error sensations, informing theories of error awareness.

Errors can elicit an error positivity in the absence of an error negativity: Evidence for independent systems of human error monitoring.

Errors in human behavior elicit a cascade of brain activity related to performance monitoring and error detection. Whereas the early error-related negativity (Ne/ERN) has been assumed to reflect a fast mismatch or prediction error signal in the medial frontal cortex, the later error positivity (Pe) is viewed as a correlate of conscious error processing. A still open question is whether these components represent two independent systems of error monitoring that rely on different types of information to detect an error. Here, we investigated the prediction that the Ne/ERN but not the Pe requires a representation of the correct response to emerge. To this end, we created a condition in which no information about the correct response was available while error detection was still possible. We hypothesized that a Pe, but no Ne/ERN should be obtained in this case. Participants had to classify targets but ignore flankers that were always associated with an incorrect response. Targets but not flankers were masked with varying target-masking intervals. Crucially, on some trials no target at all was presented, thus preventing the representation of a correct response and the emergence of an Ne/ERN. However, because flankers were easily visible and responses to the flankers were always incorrect, detection of these flanker errors was still possible. In line with predictions of a multiple-systems account, we observed a robust Pe in the absence of an Ne/ERN for these errors. Moreover, this Pe relied on the same neural activity as that on trials with a visible target, as revealed by multivariate pattern analysis. These findings demonstrate that the mechanisms reflected by the two components use different types of information to detect errors, providing evidence for independent systems of human error monitoring.

Rhodomyrtone (Rom) is a membrane-active compound.

Particularly in Asia medicinal plants with antimicrobial activity are used for therapeutic purpose. One such plant-derived antibiotic is rhodomyrtone (Rom) isolated from Rhodomyrtus tomentosa leaves. Rom shows high antibacterial activity against a wide range of Gram-positive bacteria, however, its mode of action is still unclear. Reporter gene assays and proteomic profiling experiments in Bacillus subtilis indicate that Rom does not address classical antibiotic targets like translation, transcription or DNA replication, but acts at the cytoplasmic membrane. In Staphylococcus aureus, Rom decreases the membrane potential within seconds and at low doses, causes release of ATP and even the excretion of cytoplasmic proteins (ECP), but does not induce pore-formation as for example nisin. Lipid staining revealed that Rom induces local membrane damage. Rom's antimicrobial activity can be antagonized in the presence of a very narrow spectrum of saturated fatty acids (C15:0, C16:0, or C18:0) that most likely contribute to counteract the membrane damage. Gram-negative bacteria are resistant to Rom, presumably due to reduced penetration through the outer membrane and its neutralization by LPS. Rom is cytotoxic for many eukaryotic cells and studies with human erythrocytes showed that Rom induces eryptosis accompanied by erythrocyte shrinkage, cell membrane blebbing, and membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Rom's distinctive interaction with the cytoplasmic membrane reminds on the amphipathic, alpha-helical peptides, the phenol-soluble modulins (PSMs), and renders Rom an important tool for the investigation of membrane physiology.

Total Synthesis of Biselyngbyolide B and Its C21-C22 Z-Isomer.

Investigations toward the synthesis of the 18-membered macrolactone biselyngbyolide B (2) from a C1-C13 and a C14-C23 fragment are described. As a key reaction in the synthesis of the C1-C13 fragment, we used an asymmetric propargylation of chiral vinylketene silyl N, O-acetal 12. Access to a C14-C23 fragment featuring a skipped diene and a sensitive allyl alcohol function was initially attempted via reductive fragmentation of a pyran template. However, this ring opening on iodide 32 with t-BuLi led to dienynol 33 with a 21 Z double bond. With a silyl protecting group at 3-OH and by implementing an intramolecular Stille coupling for macrolactonization, the 21 Z-isomer of biselyngbyolide B (47) was obtained. For preparation of a C14-C23 fragment with the 21 E-configuration, a cross-coupling of vinylstannane 48 with 4-bromocrotonate (49) set the configuration of the two double bonds. Biselyngbyolide B (2) was then accessed by an intramolecular Heck coupling. In preliminary biological cytotoxicity assays, 2 turned out to be active, whereas the 21 Z-isomer 47 was much less active. The 3-OMEM analogue 40 was devoid of activity. These results support the notion that the side chain with the correct configuration is relevant for binding to the Ca2+-ATPase and the biological activity.

Mediofrontal Negativity Signals Unexpected Timing of Salient Outcomes.

The medial prefrontal cortex (mPFC) and ACC have been consistently implicated in learning predictions of future outcomes and signaling prediction errors (i.e., unexpected deviations from such predictions). A computational model of ACC/mPFC posits that these prediction errors should be modulated by outcomes occurring at unexpected times, even if the outcomes themselves are predicted. However, unexpectedness per se is not the only variable that modulates ACC/mPFC activity, as studies reported its sensitivity to the salience of outcomes. In this study, mediofrontal negativity, a component of the event-related brain potential generated in ACC/mPFC and coding for prediction errors, was measured in 48 participants performing a Pavlovian aversive conditioning task, during which aversive (thus salient) and neutral outcomes were unexpectedly shifted (i.e., anticipated or delayed) in time. Mediofrontal ERP signals of prediction error were observed for outcomes occurring at unexpected times but were specific for salient (shock-associated), as compared with neutral, outcomes. These findings have important implications for the theoretical accounts of ACC/mPFC and suggest a critical role of timing and salience information in prediction error signaling.

Neural signatures of adaptive post-error adjustments in visual search.

Errors in speeded choice tasks can lead to post-error adjustments both on the behavioral and on the neural level. There is an ongoing debate whether such adjustments result from adaptive processes that serve to optimize performance or whether they reflect interference from error monitoring or attentional orientation. The present study aimed at identifying adaptive adjustments in a two-stage visual search task, in which participants had to select and subsequently identify a target stimulus presented to the left or right visual hemifield. Target selection and identification can be measured by two distinct event-related potentials, the N2pc and the SPCN. Using a decoder analysis based on multivariate pattern analysis, we were able to isolate the processing stages related to error sources and post-error adjustments. Whereas errors were linked to deviations in the N2pc and the SPCN, only for the N2pc we identified a post-error adjustment, which exhibits key features of source-specific adaptivity. While errors were associated with an increased N2pc, post-error adjustments consisted in an N2pc decrease. We interpret this as an adaptive adjustment of target selection to prevent errors due to disproportionate processing of the task-irrelevant target location. Our study thus provides evidence for adaptive post-error adjustments in visual search.

A Radical-Based Synthesis of Lingzhiol.

The polycyclic natural product lingzhiol [(±)-1] was synthesized from dimethoxytetralone 8 via cyclization of an intermediate benzylic radical, generated from spiroepoxide 14, onto an alkynyl substituent generating tetracyclic compound 13 with an exocyclic double bond. After oxidative cleavage of the double bond of 13 and reduction of the keto function of 23, the correct diastereomer, 12-syn, was converted to lingzhiol (1) via known steps. In a similar manner, lingzhiol analogue 39 was synthesized from 5-methoxy-1-tetralone (27).

Intramolecular Diels-Alder Reactions of Tethered Enoate Substituted Furans Induced by Dialkylaluminum Chloride.

Gold(I)-catalyzed cycloisomerization of enynols 11 and 17, obtained by Sonogashira coupling, led to the tethered enoate-substituted furans 14 and 19. While attempts at thermal and several Lewis acid induced intramolecular Diels-Alder reactions remained fruitless, dialkylaluminum chloride led to the formation of hexahydroindene and octahydronaphthalene derivatives 20-23. Their formation can be explained by Lewis acid induced opening of the epoxy bridge with transfer of one alkyl group to the intermediate cycloadduct.

Error-related brain activity and error awareness in an error classification paradigm.

Error-related brain activity has been linked to error detection enabling adaptive behavioral adjustments. However, it is still unclear which role error awareness plays in this process. Here, we show that the error-related negativity (Ne/ERN), an event-related potential reflecting early error monitoring, is dissociable from the degree of error awareness. Participants responded to a target while ignoring two different incongruent distractors. After responding, they indicated whether they had committed an error, and if so, whether they had responded to one or to the other distractor. This error classification paradigm allowed distinguishing partially aware errors, (i.e., errors that were noticed but misclassified) and fully aware errors (i.e., errors that were correctly classified). The Ne/ERN was larger for partially aware errors than for fully aware errors. Whereas this speaks against the idea that the Ne/ERN foreshadows the degree of error awareness, it confirms the prediction of a computational model, which relates the Ne/ERN to post-response conflict. This model predicts that stronger distractor processing - a prerequisite of error classification in our paradigm - leads to lower post-response conflict and thus a smaller Ne/ERN. This implies that the relationship between Ne/ERN and error awareness depends on how error awareness is related to response conflict in a specific task. Our results further indicate that the Ne/ERN but not the degree of error awareness determines adaptive performance adjustments. Taken together, we conclude that the Ne/ERN is dissociable from error awareness and foreshadows adaptive performance adjustments. Our results suggest that the relationship between the Ne/ERN and error awareness is correlative and mediated by response conflict.

Error monitoring is related to processing internal affective states.

Detecting behavioral errors is critical for optimizing performance. Here, we tested whether error monitoring is enhanced in emotional task contexts, and whether this enhancement depends on processing internal affective states. Event-related potentials were recorded in individuals with low and high levels of alexithymia-that is, individuals with difficulties identifying and describing their feelings. We administered a face word Stroop paradigm (Egner, Etkin, Gale, & Hirsch, 2008) in which the task was to classify emotional faces either with respect to their expression (happy or fearful; emotional task set) or with respect to their gender (female or male; neutral task set). The error-related negativity, a marker of rapid error monitoring, was enhanced in individuals with low alexithymia when they adopted the emotional task set. By contrast, individuals with high alexithymia did not show such an enhancement. Moreover, in the high-alexithymia group, the difference in the error-related negativities between the emotional and neutral task sets correlated negatively with difficulties identifying their own feelings, as measured by the Toronto Alexithymia Scale. These results show that error-monitoring activity is stronger in emotional task contexts and that this enhancement depends on processing internal affective states.

Formal Total Synthesis of Amphidinolide Q.

With the preparation of macrolactone 33a we describe a formal total synthesis of amphidinolide Q. The corresponding seco acid 32 originated from an aldol reaction between methyl ketone 6 and methyl (E)-3-methyl-4-oxobut-2-enoate (5). The synthesis of ketone 6 (C5-C16 fragment) started with desymmetrized meso-diol 9. Chain extension reactions involving cyanide, lithium trimethylsilylacetylide, and a Wittig reaction led to aldehyde 22. The two additional stereocenters at C11 and C13 were set by a Noyori transfer hydrogenation on alkynone 14 and a Feringa-Minnaard methyl cuprate addition on enoate 21. The but-1-ene-2-yl subunit on the side chain terminus was created from an unsaturated aldehyde by a substitution reaction on a derived allylic tosylate.

Design and synthesis of analogues of natural products.

In this article strategies for the design and synthesis of natural product analogues are summarized and illustrated with some selected examples. Proven strategies include diverted total synthesis (DTS), function-oriented synthesis (FOS), biology-oriented synthesis (BIOS), complexity to diversity (CtD), hybrid molecules, and biosynthesis inspired synthesis. The latter includes mutasynthesis, the synthesis of natural products encoded by silent genes, and propionate scanning. Most of the examples from our group fall in the quite general concept of DTS. Thus, in case an efficient strategy to a natural product is at hand, modifications are possible at almost any stage of a synthesis. However, even for compounds of moderate complexity, organic synthesis remains a bottle neck. Unless some method for predicting the biological activity of a designed molecule becomes available, the design and synthesis of natural product analogues will remain what it is now, namely it will largely rely on trial and error.

Updating expected action outcome in the medial frontal cortex involves an evaluation of error type.

Forming expectations about the outcome of an action is an important prerequisite for action control and reinforcement learning in the human brain. The medial frontal cortex (MFC) has been shown to play an important role in the representation of outcome expectations, particularly when an update of expected outcome becomes necessary because an error is detected. However, error detection alone is not always sufficient to compute expected outcome because errors can occur in various ways and different types of errors may be associated with different outcomes. In the present study, we therefore investigate whether updating expected outcome in the human MFC is based on an evaluation of error type. Our approach was to consider an electrophysiological correlate of MFC activity on errors, the error-related negativity (Ne/ERN), in a task in which two types of errors could occur. Because the two error types were associated with different amounts of monetary loss, updating expected outcomes on error trials required an evaluation of error type. Our data revealed a pattern of Ne/ERN amplitudes that closely mirrored the amount of monetary loss associated with each error type, suggesting that outcome expectations are updated based on an evaluation of error type. We propose that this is achieved by a proactive evaluation process that anticipates error types by continuously monitoring error sources or by dynamically representing possible response-outcome relations.

Unseen fearful faces influence face encoding: evidence from ERPs in hemianopic patients.

Visual threat-related signals are not only processed via a cortical geniculo-striatal pathway to the amygdala but also via a subcortical colliculo-pulvinar-amygdala pathway, which presumably mediates implicit processing of fearful stimuli. Indeed, hemianopic patients with unilateral damage to the geniculo-striatal pathway have been shown to respond faster to seen happy faces in their intact visual field when unseen fearful faces were concurrently presented in their blind field [Bertini, C., Cecere, R., & Làdavas, E. I am blind, but I "see" fear. Cortex, 49, 985-993, 2013]. This behavioral facilitation in the presence of unseen fear might reflect enhanced processing of consciously perceived faces because of early activation of the subcortical pathway for implicit fear perception, which possibly leads to a modulation of cortical activity. To test this hypothesis, we examined ERPs elicited by fearful and happy faces presented to the intact visual field of right and left hemianopic patients, whereas fearful, happy, or neutral faces were concurrently presented in their blind field. Results showed that the amplitude of the N170 elicited by seen happy faces was selectively increased when an unseen fearful face was concurrently presented in the blind field of right hemianopic patients. These results suggest that when the geniculo-striate visual pathway is lesioned, the rapid and implicit processing of threat signals can enhance facial encoding. Notably, the N170 modulation was only observed in left-lesioned patients, favoring the hypothesis that implicit subcortical processing of fearful signals can influence face encoding only when the right hemisphere is intact.

Inhibition by cellular vacuolar ATPase impairs human papillomavirus uncoating and infection.

Several viruses, including human papillomaviruses, depend on endosomal acidification for successful infection. Hence, the multisubunit enzyme vacuolar ATPase (V-ATPase), which is mainly responsible for endosome acidification in the cell, represents an attractive target for antiviral strategies. In the present study, we show that V-ATPase is required for human papillomavirus (HPV) infection and that uncoating/disassembly but not endocytosis is affected by V-ATPase inhibition. The infection inhibitory potencies of saliphenylhalamide, a proven V-ATPase inhibitor, and its derivatives, as well as those of other V-ATPase inhibitors, were analyzed on different HPV types in relevant cell lines. Variation in the selectivity indices among V-ATPase inhibitors was high, while variation for the same inhibitor against different HPV subtypes was low, indicating that broad-spectrum anti-HPV activity can be provided.

The mechanism of gold(I)-catalyzed hydroalkoxylation of alkynes: an extensive experimental study.

An extensive experimental study of the mechanism of gold(I)-catalyzed hydroalkoxylation of internal alkynes has been conducted by using NMR spectroscopy. This study was focused on the organogold intermediates, observations of actual catalytic intermediates in situ, and the reaction kinetics that are involved in this reaction. Based on the experimental results, a complete mechanistic picture was established, including on- and off-cycle processes that explain the role of diaurated species. We have shown that gold-catalyzed hydroalkoxylation of internal alkynes is a reaction that requires only one gold atom for the catalytic cycle, disproving a recent hypothesis regarding the involvement of cooperative gold catalysis.

Mechanistic study of gold(I)-catalyzed hydroamination of alkynes: outer or inner sphere mechanism?

An experimental mechanistic study of the gold(I)-catalyzed hydroamination shows the formation of conformationally flexible auro-iminium salts Au-Im, which originate from the protonation of a vinyl gold species. Rotation around the C-CAu bond is the reason for the loss of stereospecificity of protodeauration, which explains the stereochemical result of the Stradiotto reaction. The ambiguity about inner or outer sphere mechanism is thus resolved in favor of the outer sphere mechanism.