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Transformer-based Large Language Models (LLMs) have recently increased in popularity, in part due to their impressive performance on a number of language tasks. While LLMs can produce human-like writing, the extent to which these models can learn to predict spoken language in natural interaction remains unclear. This is a nontrivial question, as spoken and written language differ in syntax, pragmatics, and norms that interlocutors follow. Previous work suggests that while LLMs may develop an understanding of linguistic rules based on statistical regularities, they fail to acquire the knowledge required for language use. This implies that LLMs may not learn the normative structure underlying interactive spoken language, but may instead only model superficial regularities in speech. In this paper, we aim to evaluate LLMs as models of spoken dialogue. Specifically, we investigate whether LLMs can learn that the identity of a speaker in spoken dialogue influences what is likely to be said. To answer this question, we first fine-tuned two variants of a specific LLM (GPT-2) on transcripts of natural spoken dialogue in English. Then, we used these models to compute surprisal values for two-turn sequences with the same first-turn but different second-turn speakers and compared the output to human behavioral data. While the predictability of words in all fine-tuned models was influenced by speaker identity information, the models did not replicate humans' use of this information. Our findings suggest that although LLMs may learn to generate text conforming to normative linguistic structure, they do not (yet) faithfully replicate human behavior in natural conversation., (© 2024 Cognitive Science Society LLC.)

As human-machine teams are being considered for a variety of mixed-initiative tasks, detecting and being responsive to human cognitive states, in particular systematic cognitive states, is among the most critical capabilities for artificial systems to ensure smooth interactions with humans and high overall team performance. Various human physiological parameters, such as heart rate, respiration rate, blood pressure, and skin conductance, as well as brain activity inferred from functional near-infrared spectroscopy or electroencephalogram, have been linked to different systemic cognitive states, such as workload, distraction, or mind-wandering among others. Whether these multimodal signals are indeed sufficient to isolate such cognitive states across individuals performing tasks or whether additional contextual information (e.g., about the task state or the task environment) is required for making appropriate inferences remains an important open problem. In this paper, we introduce an experimental and machine learning framework for investigating these questions and focus specifically on using physiological and neurophysiological measurements to learn classifiers associated with systemic cognitive states like cognitive load, distraction, sense of urgency, mind wandering, and interference. Specifically, we describe a multitasking interactive experimental setting used to obtain a comprehensive multimodal data set which provided the foundation for a first evaluation of various standard state-of-the-art machine learning techniques with respect to their effectiveness in inferring systemic cognitive states. While the classification success of these standard methods based on just the physiological and neurophysiological signals across subjects was modest, which is to be expected given the complexity of the classification problem and the possibility that higher accuracy rates might not in general be achievable, the results nevertheless can serve as a baseline for evaluating future efforts to improve classification, especially methods that take contextual aspects such as task and environmental states into account., (© 2023 Cognitive Science Society LLC.)

A key mechanism in the comprehension of conversation is the ability for listeners to recognize who is speaking and when a speaker switch occurs. Some authors suggest that speaker change detection is accomplished through bottom-up mechanisms in which listeners draw on changes in the acoustic features of the auditory signal. Other accounts propose that speaker change detection involves drawing on top-down linguistic representations to identify who is speaking. The present study investigates these hypotheses experimentally by manipulating the pragmatic coherence of conversational utterances. In experiment 1, participants listened to pairs of utterances and had to indicate whether they heard the same or different speakers. Even though all utterances were spoken by the same speaker, our results show that when two segments of conversation are spoken by the same speaker but make sense for different speakers to say, listeners report hearing different speakers. In experiment 2 we removed pragmatic information from the same stimuli by scrambling word order while leaving acoustic information intact. In contrast to experiment 1, results from the second experiment indicate no difference between our experimental conditions. We interpret these results as a top-down effect of pragmatic expectations: knowledge of conversational structure at least partially determines a listener's perception of speaker changes in conversation., (© 2023. The Author(s).)

Understanding the spread of false or dangerous beliefs-often called misinformation or disinformation-through a population has never seemed so urgent. Network science researchers have often taken a page from epidemiologists, and modeled the spread of false beliefs as similar to how a disease spreads through a social network. However, absent from those disease-inspired models is an internal model of an individual's set of current beliefs, where cognitive science has increasingly documented how the interaction between mental models and incoming messages seems to be crucially important for their adoption or rejection. Some computational social science modelers analyze agent-based models where individuals do have simulated cognition, but they often lack the strengths of network science, namely in empirically-driven network structures. We introduce a cognitive cascade model that combines a network science belief cascade approach with an internal cognitive model of the individual agents as in opinion diffusion models as a public opinion diffusion (POD) model, adding media institutions as agents which begin opinion cascades. We show that the model, even with a very simplistic belief function to capture cognitive effects cited in disinformation study (dissonance and exposure), adds expressive power over existing cascade models. We conduct an analysis of the cognitive cascade model with our simple cognitive function across various graph topologies and institutional messaging patterns. We argue from our results that population-level aggregate outcomes of the model qualitatively match what has been reported in COVID-related public opinion polls, and that the model dynamics lend insights as to how to address the spread of problematic beliefs. The overall model sets up a framework with which social science misinformation researchers and computational opinion diffusion modelers can join forces to understand, and hopefully learn how to best counter, the spread of disinformation and "alternative facts.", Competing Interests: The authors have declared that no competing interests exist.

People with aphasia use gestures not only to communicate relevant content but also to compensate for their verbal limitations. The Sketch Model (De Ruiter, 2000) assumes a flexible relationship between gesture and speech with the possibility of a compensatory use of the two modalities. In the successor of the Sketch Model, the AR-Sketch Model (De Ruiter, 2017), the relationship between iconic gestures and speech is no longer assumed to be flexible and compensatory, but instead iconic gestures are assumed to express information that is redundant to speech. In this study, we evaluated the contradictory predictions of the Sketch Model and the AR-Sketch Model using data collected from people with aphasia as well as a group of people without language impairment. We only found compensatory use of gesture in the people with aphasia, whereas the people without language impairments made very little compensatory use of gestures. Hence, the people with aphasia gestured according to the prediction of the Sketch Model, whereas the people without language impairment did not. We conclude that aphasia fundamentally changes the relationship of gesture and speech., (© 2020 Cognitive Science Society, Inc.)

Purpose People with aphasia (PWA) use different kinds of gesture spontaneously when they communicate. Although there is evidence that the nature of the communicative task influences the linguistic performance of PWA, so far little is known about the influence of the communicative task on the production of gestures by PWA. We aimed to investigate the influence of varying communicative constraints on the production of gesture and spoken expression by PWA in comparison to persons without language impairment. Method Twenty-six PWA with varying aphasia severities and 26 control participants (CP) without language impairment participated in the study. Spoken expression and gesture production were investigated in 2 different tasks: (a) spontaneous conversation about topics of daily living and (b) a cartoon narration task, that is, retellings of short cartoon clips. The frequencies of words and gestures as well as of different gesture types produced by the participants were analyzed and tested for potential effects of group and task. Results Main results for task effects revealed that PWA and CP used more iconic gestures and pantomimes in the cartoon narration task than in spontaneous conversation. Metaphoric gestures, deictic gestures, number gestures, and emblems were more frequently used in spontaneous conversation than in cartoon narrations by both participant groups. Group effects show that, in both tasks, PWA's gesture-to-word ratios were higher than those for the CP. Furthermore, PWA produced more interactive gestures than the CP in both tasks, as well as more number gestures and pantomimes in spontaneous conversation. Conclusions The current results suggest that PWA use gestures to compensate for their verbal limitations under varying communicative constraints. The properties of the communicative task influence the use of different gesture types in people with and without aphasia. Thus, the influence of communicative constraints needs to be considered when assessing PWA's multimodal communicative abilities.

Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level. The patient exhibited early-onset neurometabolic abnormality culminating in severe brain atrophy and dystonia leading to death by the age of 3.5 years. Urine and plasma metabolite profiling was consistent with SUCL deficiency which was confirmed by enzyme analysis and lack of mitochondrial substrate-level phosphorylation (mSLP) in skin fibroblasts. Oxygen consumption- but not extracellular acidification rates were altered only when using glutamine as a substrate, and this was associated with mild mtDNA depletion and no changes in ETC activities. Immunoblot analysis revealed no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced. Confocal imaging of triple immunocytochemistry of skin fibroblasts showed that SUCLG2 co-localized only partially with the mitochondrial network which otherwise exhibited an increase in fragmentation compared to control cells. Our results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization of SUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Interactions with artificial agents often lack immediacy because agents respond slower than their users expect. Automatic speech recognisers introduce this delay by analysing a user's utterance only after it has been completed. Early, uncertain hypotheses of incremental speech recognisers can enable artificial agents to respond more timely. However, these hypotheses may change significantly with each update. Therefore, an already initiated action may turn into an error and invoke error cost. We investigated whether humans would use uncertain hypotheses for planning ahead and/or initiating their response. We designed a Ghost-in-the-Machine study in a bar scenario. A human participant controlled a bartending robot and perceived the scene only through its recognisers. The results showed that participants used uncertain hypotheses for selecting the best matching action. This is comparable to computing the utility of dialogue moves. Participants evaluated the available evidence and the error cost of their actions prior to initiating them. If the error cost was low, the participants initiated their response with only suggestive evidence. Otherwise, they waited for additional, more confident hypotheses if they still had time to do so. If there was time pressure but only little evidence, participants grounded their understanding with echo questions. These findings contribute to a psychologically plausible policy for human-robot interaction that enables artificial agents to respond more timely and socially appropriately under uncertainty., Competing Interests: The authors have declared that no competing interests exist.

Miscommunication is a neglected issue in the cognitive sciences, where it has often been discounted as noise in the system. This special issue argues for the opposite view: Miscommunication is a highly structured and ubiquitous feature of human interaction that systematically underpins people's ability to create and maintain shared languages. Contributions from conversation analysis, computational linguistics, experimental psychology, and formal semantics provide evidence for these claims. They highlight the multi-modal, multi-person character of miscommunication. They demonstrate the incremental, contingent, and locally adaptive nature of the processes people use to detect and deal with miscommunication. They show how these processes can drive language change. In doing so, these contributions introduce an alternative perspective on what successful communication is, new methods for studying it, and application areas where these ideas have a particular impact. We conclude that miscommunication is not noise but essential to the productive flexibility of human communication, especially our ability to respond constructively to new people and new situations., (Copyright © 2018 The Authors. Topics in Cognitive Science published by Wiley Periodicals, Inc. on behalf of Cognitive Science Society.)

Conversational repair is the process people use to detect and resolve problems of speaking, hearing, and understanding. Through repair, participants in social interaction display how they establish and maintain communication and mutual understanding. We argue that repair provides a crucial theoretical interface for research between diverse approaches to studying human interaction. We provide an overview of conversation analytic findings about repair in order to encourage further cross-disciplinary research involving both detailed inductive inquiry and more theory-driven experimental approaches. We outline CA's main typologies of repair and its methodological rationale, and we provide transcripts and examples that readers can explore for themselves using open data from online corpora. Since participants in interaction use repair to deal with problems as they emerge at the surface level of talk, we conclude that repair can be a point of convergence for studying mis/communication from multiple methodological perspectives., (Copyright © 2018 The Authors. Topics in Cognitive Science published by Wiley Periodicals, Inc. on behalf of Cognitive Science Society.)

A scientific claim is a generalization based on a reported statistically significant effect. The reproducibility of that claim is its scientific meaning. Anything not explicitly mentioned in a scientific claim as a limitation of the claim's scope means that it implicitly generalizes over these unmentioned aspects. Hence, so-called "conceptual" replications that differ in these unmentioned aspects from the original study are legitimate, and necessary to test the generalization implied by the original study's claim.

Purpose: People with aphasia (PWA) face significant challenges in verbally expressing their communicative intentions. Different types of gestures are produced spontaneously by PWA, and a potentially compensatory function of these gestures has been discussed. The current study aimed to investigate how much information PWA communicate through 3 types of gesture and the communicative effectiveness of such gestures., Method: Listeners without language impairment rated the information content of short video clips taken from PWA in conversation. Listeners were asked to rate communication within a speech-only condition and a gesture + speech condition., Results: The results revealed that the participants' interpretations of the communicative intentions expressed in the clips of PWA were significantly more accurate in the gesture + speech condition for all tested gesture types., Conclusion: It was concluded that all 3 gesture types under investigation contributed to the expression of semantic meaning communicated by PWA. Gestures are an important communicative means for PWA and should be regarded as such by their interlocutors. Gestures have been shown to enhance listeners' interpretation of PWA's overall communication.

In every-day conversations, the gap between turns of conversational partners is most frequently between 0 and 200 ms. We were interested how speakers achieve such fast transitions. We designed an experiment in which participants listened to pre-recorded questions about images presented on a screen and were asked to answer these questions. We tested whether speakers already prepare their answers while they listen to questions and whether they can prepare for the time of articulation by anticipating when questions end. In the experiment, it was possible to guess the answer at the beginning of the questions in half of the experimental trials. We also manipulated whether it was possible to predict the length of the last word of the questions. The results suggest when listeners know the answer early they start speech production already during the questions. Speakers can also time when to speak by predicting the duration of turns. These temporal predictions can be based on the length of anticipated words and on the overall probability of turn durations.

Structural priming is a sufficient but not a necessary condition for proving the existence of representations. Absence of evidence is not evidence of absence. Cognitive science relies on the legitimacy of positing representations and processes without "proving" every component. Also, psycholinguistics relies on other methods, including acceptability judgments, to find the materials for priming experiments in the first place.

Background: N-acetylglutamate synthase (NAGS) plays a key role in the removal of ammonia via the urea cycle by catalyzing the synthesis of N-acetylglutamate (NAG), the obligatory cofactor in the carbamyl phosphate synthetase 1 reaction. Enzymatic analysis of NAGS in liver homogenates has remained insensitive and inaccurate, which prompted the development of a novel method., Methods: UPLC-MS/MS was used in conjunction with stable isotope (N-acetylglutamic-2,3,3,4,4-d 5 acid) dilution for the quantitative detection of NAG produced by the NAGS enzyme. The assay conditions were optimized using purified human NAGS and the optimized enzyme conditions were used to measure the activity in mouse liver homogenates., Results: A low signal-to-noise ratio in liver tissue samples was observed due to non-enzymatic formation of N-acetylglutamate and low specific activity, which interfered with quantitative analysis. Quenching of acetyl-CoA immediately after the incubation circumvented this analytical difficulty and allowed accurate and sensitive determination of mammalian NAGS activity. The specificity of the assay was validated by demonstrating a complete deficiency of NAGS in liver homogenates from Nags -/- mice., Conclusion: The novel NAGS enzyme assay reported herein can be used for the diagnosis of inherited NAGS deficiency and may also be of value in the study of secondary hyperammonemia present in various inborn errors of metabolism as well as drug treatment., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is unpredictable. We investigated predictive markers that may determine clinical severity., Methods: We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading., Results: The strongest correlation (r = 0.93; P < 0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P < 0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P < 0.05)., Conclusion: Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.

We used a new method called "Ghost-in-the-Machine" (GiM) to investigate social interactions with a robotic bartender taking orders for drinks and serving them. Using the GiM paradigm allowed us to identify how human participants recognize the intentions of customers on the basis of the output of the robotic recognizers. Specifically, we measured which recognizer modalities (e.g., speech, the distance to the bar) were relevant at different stages of the interaction. This provided insights into human social behavior necessary for the development of socially competent robots. When initiating the drink-order interaction, the most important recognizers were those based on computer vision. When drink orders were being placed, however, the most important information source was the speech recognition. Interestingly, the participants used only a subset of the available information, focussing only on a few relevant recognizers while ignoring others. This reduced the risk of acting on erroneous sensor data and enabled them to complete service interactions more swiftly than a robot using all available sensor data. We also investigated socially appropriate response strategies. In their responses, the participants preferred to use the same modality as the customer's requests, e.g., they tended to respond verbally to verbal requests. Also, they added redundancy to their responses, for instance by using echo questions. We argue that incorporating the social strategies discovered with the GiM paradigm in multimodal grammars of human-robot interactions improves the robustness and the ease-of-use of these interactions, and therefore provides a smoother user experience.

3-Hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is a rare inborn error of the valine catabolic pathway associated with Leigh-like disease. We report a female patient who presented at the age of 5months with hypotonia, developmental delay and cerebral atrophy on MRI. Pyruvate dehydrogenase deficiency was initially suspected and decreased activity was shown in fibroblasts. Urine tandem mass spectrometry screening showed large increases in the cysteine conjugate of methacrylate previously described in HIBCHD. 3-hydroxyisobutyryl-CoA hydrolase activity in fibroblasts was below the limit of detection of the enzymatic assay and two novel HIBCH mutations were identified (c.[129dupA];[1033G>A]). Urine metabolite investigations also showed increases in 3-hydroxyisobutyryl carnitine, 2,3-dihydroxy-2-methylbutyrate and several metabolites indicating accumulation and subsequent metabolism of methacrylyl-CoA and acryloyl-CoA. The metabolites derived from acryloyl-CoA were also increased in patients with inborn errors of propionyl-CoA metabolism, indicating the involvement of a secondary propionyl-CoA pathway utilising 3-hydroxyisobutyryl-CoA hydrolase. With the exception of 3-hydroxyisobutyryl carnitine, the metabolite abnormalities were essentially the same as those observed in patients with ECHS1 mutations, a recently described disorder that also affects valine metabolism. Our findings demonstrate the benefits of urine tandem mass spectrometry screening for diagnosing HIBCH and ECHS1 defects and that propionate metabolism may play a role in their pathogenesis. These disorders should be considered during the differential diagnosis of Leigh like-diseases and hypotonia., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the metabolism of branched-chain amino acids. Recently, the first patients with SCEH deficiency have been reported revealing only a defect in valine catabolism. We investigated the role of SCEH in fatty acid and branched-chain amino acid metabolism in four newly identified patients. In addition, because of the Leigh-like presentation, we studied enzymes involved in bioenergetics., Methods: Metabolite, enzymatic, protein and genetic analyses were performed in four patients, including two siblings. Palmitate loading studies in fibroblasts were performed to study mitochondrial β-oxidation. In addition, enoyl-CoA hydratase activity was measured with crotonyl-CoA, methacrylyl-CoA, tiglyl-CoA and 3-methylcrotonyl-CoA both in fibroblasts and liver to further study the role of SCEH in different metabolic pathways. Analyses of pyruvate dehydrogenase and respiratory chain complexes were performed in multiple tissues of two patients., Results: All patients were either homozygous or compound heterozygous for mutations in the ECHS1 gene, had markedly reduced SCEH enzymatic activity and protein level in fibroblasts. All patients presented with lactic acidosis. The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities. The third patient showed a slow neurodegenerative condition with global brain atrophy and the fourth patient showed Leigh-like lesions with a single episode of metabolic acidosis. Clinical picture and metabolite analysis were not consistent with a mitochondrial fatty acid oxidation disorder, which was supported by the normal palmitate loading test in fibroblasts. Patient fibroblasts displayed deficient hydratase activity with different substrates tested. Pyruvate dehydrogenase activity was markedly reduced in particular in muscle from the most severely affected patients, which was caused by reduced expression of E2 protein, whereas E2 mRNA was increased., Conclusions: Despite its activity towards substrates from different metabolic pathways, SCEH appears to be only crucial in valine metabolism, but not in isoleucine metabolism, and only of limited importance for mitochondrial fatty acid oxidation. In severely affected patients SCEH deficiency can cause a secondary pyruvate dehydrogenase deficiency contributing to the clinical presentation.

During conversations participants alternate smoothly between speaker and hearer roles with only brief pauses and overlaps. There are two competing types of accounts about how conversationalists accomplish this: (a) the signaling approach and (b) the anticipatory ('projection') approach. We wanted to investigate, first, the relative merits of these two accounts, and second, the relative contribution of semantic and syntactic information to the timing of next turn initiation. We performed three button-press experiments using turn fragments taken from natural conversations to address the following questions: (a) Is turn-taking predominantly based on anticipation or on reaction, and (b) what is the relative contribution of semantic and syntactic information to accurate turn-taking. In our first experiment we gradually manipulated the information available for anticipation of the turn end (providing information about the turn end in advance to completely removing linguistic information). The results of our first experiment show that the distribution of the participants' estimation of turn-endings for natural turns is very similar to the distribution for pure anticipation. We conclude that listeners are indeed able to anticipate a turn-end and that this strategy is predominantly used in turn-taking. In Experiment 2 we collected purely reacted responses. We used the distributions from Experiments 1 and 2 together to estimate a new dependent variable called Reaction Anticipation Proportion. We used this variable in our third experiment where we manipulated the presence vs. absence of semantic and syntactic information by low-pass filtering open-class and closed class words in the turn. The results suggest that for turn-end anticipation, both semantic and syntactic information are needed, but that the semantic information is a more important anticipation cue than syntactic information.

Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in a patient with recurrent, severe ketoacidosis and identified a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 (SLC16A1, also called MCT1). Genetic analysis in 96 patients suspected of having ketolytic defects yielded seven additional inactivating mutations in MCT1, both homozygous and heterozygous. Mutational status was found to be correlated with ketoacidosis severity, MCT1 protein levels, and transport capacity. Thus, MCT1 deficiency is a novel cause of profound ketoacidosis; the present work suggests that MCT1-mediated ketone-body transport is needed to maintain acid-base balance.

RTs in conversation, with average gaps of 200 msec and often less, beat standard RTs, despite the complexity of response and the lag in speech production (600 msec or more). This can only be achieved by anticipation of timing and content of turns in conversation, about which little is known. Using EEG and an experimental task with conversational stimuli, we show that estimation of turn durations are based on anticipating the way the turn would be completed. We found a neuronal correlate of turn-end anticipation localized in ACC and inferior parietal lobule, namely a beta-frequency desynchronization as early as 1250 msec, before the end of the turn. We suggest that anticipation of the other's utterance leads to accurately timed transitions in everyday conversations.

Background: Even though research in turn-taking in spoken dialogues is now abundant, a typical EEG-signature associated with the anticipation of turn-ends has not yet been identified until now., New Method: The purpose of this study was to examine if readiness potentials (RP) can be used to study the anticipation of turn-ends by using it in a motoric finger movement and articulatory movement task. The goal was to determine the preconscious onset of turn-end anticipation in early, preconscious turn-end anticipation processes by the simultaneous registration of EEG measures (RP) and behavioural measures (anticipation timing accuracy, ATA). For our behavioural measures, we used both button-press and verbal response ("yes"). In the experiment, 30 subjects were asked to listen to auditorily presented utterances and press a button or utter a brief verbal response when they expected the end of the turn. During the task, a 32-channel-EEG signal was recorded., Results: The results showed that the RPs during verbal- and button-press-responses developed similarly and had an almost identical time course: the RP signals started to develop 1170 vs. 1190 ms before the behavioural responses., Comparison With Existing Methods: Until now, turn-end anticipation is usually studied using behavioural methods, for instance by measuring the anticipation timing accuracy, which is a measurement that reflects conscious behavioural processes and is insensitive to preconscious anticipation processes., Conclusion: The similar time course of the recorded RP signals for both verbal- and button-press responses provide evidence for the validity of using RPs as an online marker for response preparation in turn-taking and spoken dialogue research., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Oxidation of unsaturated fatty acids requires the action of auxiliary enzymes, such as Δ(3),Δ(2)-enoyl-CoA isomerases. Here we describe a detailed biochemical, molecular, histological, and evolutionary characterization of Eci3, the fourth member of the mammalian enoyl-CoA isomerase family. Eci3 specifically evolved in rodents after gene duplication of Eci2. Eci3 is with 79% identity homologous to Eci2 and contains a peroxisomal targeting signal type 1. Subcellular fractionation of mouse kidney and immunofluorescence studies revealed a specific peroxisomal localization for Eci3. Expression studies showed that mouse Eci3 is almost exclusively expressed in kidney. By using immunohistochemistry, we found that Eci3 is not only expressed in cells of the proximal tubule, but also in a subset of cells in the tubulointerstitium and the glomerulus. In vitro, Eci3 catalyzed the isomerization of trans-3-nonenoyl-CoA to trans-2-nonenoyl-CoA equally efficient as Eci2, suggesting a role in oxidation of unsaturated fatty acids. However, in contrast to Eci2, in silico gene coexpression and enrichment analysis for Eci3 in kidney did not yield carboxylic acid metabolism, but diverse biological functions, such as ion transport (P=7.1E-3) and tissue morphogenesis (P=1.0E-3). Thus, Eci3 picked up a novel and unexpected role in kidney function during rodent evolution.

The importance of mitochondrial fatty acid β-oxidation (FAO) as a glucose-sparing process is illustrated by patients with inherited defects in FAO, who may present with life-threatening fasting-induced hypoketotic hypoglycemia. It is unknown why peripheral glucose demand outpaces hepatic gluconeogenesis in these patients. In this study, we have systematically addressed the fasting response in long-chain acyl-CoA dehydrogenase-deficient (LCAD KO) mice. We demonstrate that the fasting-induced hypoglycemia in LCAD KO mice was initiated by an increased glucose requirement in peripheral tissues, leading to rapid hepatic glycogen depletion. Gluconeogenesis did not compensate for the increased glucose demand, which was not due to insufficient hepatic glucogenic capacity but rather caused by a shortage in the supply of glucogenic precursors. This shortage in supply was explained by a suppressed glucose-alanine cycle, decreased branched-chain amino acid metabolism and ultimately impaired protein mobilization. We conclude that during fasting, FAO not only serves to spare glucose but is also indispensable for amino acid metabolism, which is essential for the maintenance of adequate glucose production.

We investigate effects of priming and preference on frame of reference (FOR) selection in dialog. In a first study, we determine FOR preferences for specific object configurations to establish a baseline. In a second study, we focus on the selection of the relative or the intrinsic FOR in dialog using the same stimuli and addressing the questions whether (a) interlocutors prime each other to use the same FOR consistently or (b) the preference for the intrinsic FOR predominates priming effects. Our results show effects of priming (more use of the relative FOR) and a decreased preference for the intrinsic FOR. However, as FOR selection did not have an effect on target trial accuracy, neither effect alone represents the key to successful communication in this domain. Rather, we found that successful communication depended on the adaptation of strategies between interlocutors: the more the interlocutors adapted to each other's strategies, the more successful they were.

Recognizing the intention of others is important in all social interactions, especially in the service domain. Enabling a bartending robot to serve customers is particularly challenging as the system has to recognize the social signals produced by customers and respond appropriately. Detecting whether a customer would like to order is essential for the service encounter to succeed. This detection is particularly challenging in a noisy environment with multiple customers. Thus, a bartending robot has to be able to distinguish between customers intending to order, chatting with friends or just passing by. In order to study which signals customers use to initiate a service interaction in a bar, we recorded real-life customer-staff interactions in several German bars. These recordings were used to generate initial hypotheses about the signals customers produce when bidding for the attention of bar staff. Two experiments using snapshots and short video sequences then tested the validity of these hypothesized candidate signals. The results revealed that bar staff responded to a set of two non-verbal signals: first, customers position themselves directly at the bar counter and, secondly, they look at a member of staff. Both signals were necessary and, when occurring together, sufficient. The participants also showed a strong agreement about when these cues occurred in the videos. Finally, a signal detection analysis revealed that ignoring a potential order is deemed worse than erroneously inviting customers to order. We conclude that (a) these two easily recognizable actions are sufficient for recognizing the intention of customers to initiate a service interaction, but other actions such as gestures and speech were not necessary, and (b) the use of reaction time experiments using natural materials is feasible and provides ecologically valid results.

We encourage Pickering & Garrod (P&G) to implement this promising theory in a computational model. The proposed theory crucially relies on having an efficient and reliable mechanism for early intention recognition. Furthermore, the generation of impoverished predictions is incompatible with a number of key phenomena that motivated P&G's theory. Explaining these phenomena requires fully specified perceptual predictions in both comprehension and production.

The selection and processing of a spatial frame of reference (FOR) in interpreting verbal scene descriptions is of great interest to psycholinguistics. In this study, we focus on the choice between the relative and the intrinsic FOR, addressing two questions: (a) does the presence or absence of a background in the scene influence the selection of a FOR, and (b) what is the effect of a previously selected FOR on the subsequent processing of a different FOR. Our results show that if a scene includes a realistic background, this will make the selection of the relative FOR more likely. We attribute this effect to the facilitation of mental simulation, which enhances the relation between the viewer and the objects. With respect to the response accuracy, we found both a higher (with the same FOR) and a lower accuracy (with a different FOR), while for the response latencies, we only found a delay effect with a different FOR.

Background: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia., Methods: We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features., Results: We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1., Conclusions: Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.

Isovaleric acidemia (IVA) is one of the most common organic acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.

During conversation listeners have to perform several tasks simultaneously. They have to comprehend their interlocutor's turn, while also having to prepare their own next turn. Moreover, a careful analysis of the timing of natural conversation reveals that next speakers also time their turns very precisely. This is possible only if listeners can predict accurately when the speaker's turn is going to end. But how are people able to predict when a turn-ends? We propose that people know when a turn-ends, because they know how it ends. We conducted a gating study to examine if better turn-end predictions coincide with more accurate anticipation of the last words of a turn. We used turns from an earlier button-press experiment where people had to press a button exactly when a turn-ended. We show that the proportion of correct guesses in our experiment is higher when a turn's end was estimated better in time in the button-press experiment. When people were too late in their anticipation in the button-press experiment, they also anticipated more words in our gating study. We conclude that people made predictions in advance about the upcoming content of a turn and used this prediction to estimate the duration of the turn. We suggest an economical model of turn-end anticipation that is based on anticipation of words and syntactic frames in comprehension.

The reliable automatic visual recognition of indoor scenes with complex object constellations using only sensor data is a nontrivial problem. In order to improve the construction of an accurate semantic 3D model of an indoor scene, we exploit human-produced verbal descriptions of the relative location of pairs of objects. This requires the ability to deal with different spatial reference frames (RF) that humans use interchangeably. In German, both the intrinsic and relative RF are used frequently, which often leads to ambiguities in referential communication. We assume that there are certain regularities that help in specific contexts. In a first experiment, we investigated how speakers of German describe spatial relationships between different pieces of furniture. This gave us important information about the distribution of the RFs used for furniture-predicate combinations, and by implication also about the preferred spatial predicate. The results of this experiment are compiled into a computational model that extracts partial orderings of spatial arrangements between furniture items from verbal descriptions. In the implemented system, the visual scene is initially scanned by a 3D camera system. From the 3D point cloud, we extract point clusters that suggest the presence of certain furniture objects. We then integrate the partial orderings extracted from the verbal utterances incrementally and cumulatively with the estimated probabilities about the identity and location of objects in the scene, and also estimate the probable orientation of the objects. This allows the system to significantly improve both the accuracy and richness of its visual scene representation.

Hydroxybutyrylcarnitine (HB-carnitine) is a metabolite that has been associated with insulin resistance and type 2 diabetes mellitus. It is currently unknown whether HB-carnitine can be produced from D-3-hydroxybutyrate (D-3HB), a ketone body; but its formation from L-3-HB-CoA, a fatty acid β-oxidation intermediate, is well established. We aimed to assess which stereoisomers of 3-HB-carnitine are present in vivo. Ketosis and increased fatty acid oxidation were induced in 12 lean healthy men by a 38-hour fasting period. The D-3HB kinetics (stable isotope technique) and stereoisomers of muscle 3-HB-carnitine (high-performance liquid chromatography/ultra-performance liquid chromatography-tandem mass spectrometry) were measured. Muscle D-3HB-carnitine content was much higher compared with L-3HB-carnitine. In addition, muscle D-3HB-carnitine correlated significantly with D-3-HB production. Following the finding that a ketone body can be converted into a carnitine ester in vivo, we show in vitro that D-3-HB can be converted into HB-carnitine (ketocarnitine) via an acyl-CoA synthetase reaction in several tissues including human muscle. During fasting, HB-carnitine in muscle is derived mainly from the ketone body D-3HB. The role of D-3HB-carnitine synthesis in metabolism remains to be elucidated., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Valproic acid (VPA) is a widely used anticonvulsant drug which affects mitochondrial metabolism including the catabolism of fatty acids and branched-chain amino acids., Aims: To elucidate the effect of valproate on the leucine pathway through a targeted metabolomics approach and the evaluation of the effects of valproate on the activity of biotinidase and 3-methylcrotonyl-CoA carboxylase (3MCC)., Methods: Urine organic acid analysis was performed in patients under VPA therapy and healthy controls using gas-chromatography/mass spectrometry (GC-MS). Biotinidase activity was determined in plasma samples of both groups using an optimized spectrophotometric assay. After immunoprecipitation of short-chain enoyl-CoA hydratase (crotonase, ECHS1), 3MCC activity was measured in human liver homogenate using high-performance liquid chromatography (HPLC), in the absence and presence of valproyl-CoA., Results: The levels of 3-hydroxyisovaleric acid (3OH-IVA), one secondary metabolite of the leucine pathway, were significantly elevated in human urine after VPA treatment. Biotinidase activity in plasma samples ranged from very low to normal levels in treated patients as compared with controls. Enzyme activity measurements revealed inhibition of 3-methylcrotonyl-CoA carboxylase by valproyl-CoA (IC(50) = 1.36 mM). Furthermore, we show that after complete immunoprecipitation of crotonase in a human liver homogenate, 3-hydroxyisovaleryl-CoA is not formed., Discussion: Our results suggest the interference of VPA with the activity of 3MCC through a potential cumulative effect: direct inhibition of the enzyme activity by the drug metabolite valproyl-CoA and the inhibition of biotinidase by valproate and/or its metabolites. These interactions may be associated with the skin rash and hair loss which are side effects often reported in VPA-treated patients.

The tradeoff hypothesis in the speech-gesture relationship claims that (a) when gesturing gets harder, speakers will rely relatively more on speech, and (b) when speaking gets harder, speakers will rely relatively more on gestures. We tested the second part of this hypothesis in an experimental collaborative referring paradigm where pairs of participants (directors and matchers) identified targets to each other from an array visible to both of them. We manipulated two factors known to affect the difficulty of speaking to assess their effects on the gesture rate per 100 words. The first factor, codability, is the ease with which targets can be described. The second factor, repetition, is whether the targets are old or new (having been already described once or twice). We also manipulated a third factor, mutual visibility, because it is known to affect the rate and type of gesture produced. None of the manipulations systematically affected the gesture rate. Our data are thus mostly inconsistent with the tradeoff hypothesis. However, the gesture rate was sensitive to concurrent features of referring expressions, suggesting that gesture parallels aspects of speech. We argue that the redundancy between speech and gesture is communicatively motivated., (Copyright © 2012 Cognitive Science Society, Inc.)

Unlabelled: Valproic acid (VPA) is a simple branched medium-chain fatty acid with expanding therapeutic applications beyond its prime anticonvulsant properties., Aims: (1) To resolve the underlying basis for the interference of valproate with the isoleucine degradative pathway and (2) to shed new light on the enzymology of the β-oxidation pathway of valproate., Methods: Urine organic acids were analyzed by gas chromatography/mass spectrometry. In vitro studies were performed with heterologously expressed human 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) and fibroblasts from controls and a patient with MHBD deficiency using 2-methyl-3-hydroxybutyryl-CoA and 3-hydroxyvalproyl-CoA as substrates. The respective enzymatic activities were measured using optimized HPLC procedures. Short-chain enoyl-CoA hydratase (ECHS1) immunoprecipitation in a human liver homogenate was performed and hydratase activity was measured in the supernatants by HPLC, using crotonyl-CoA and Δ(2(E))-valproyl-CoA as substrates., Results: Patients on valproate therapy had a moderately increased urinary excretion of the isoleucine metabolite 2-methyl-3-hydroxybutyric acid. MHBD was found to convert 3-hydroxyvalproyl-CoA into 3-ketovalproyl-CoA. MHBD activity in control fibroblasts was comparable using both 2-methyl-3-hydroxybutyryl-CoA and 3-hydroxyvalproyl-CoA as substrates. In fibroblasts of a patient with MHBD deficiency, there was no detectable MHBD activity when 3-hydroxyvalproyl-CoA was used as substrate. Samples with immunoprecipitated crotonase had no detectable hydratase activity using both crotonyl-CoA and Δ(2(E))-valproyl-CoA as substrates., Discussion: This work demonstrates for the first time, that MHBD is the unique enzyme responsible for the dehydrogenation of 3-hydroxyvalproyl-CoA. Furthermore, we show that crotonase is the major, if not the single hydratase involved in VPA β-oxidation, next to its role in isoleucine catabolism., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Many biological systems including the oxidative catabolic pathway for branched-chain amino acids (BCAAs) are affected in vivo by valproate therapy. In this study, we investigated the potential effect of valproic acid (VPA) and some of its metabolites on the metabolism of BCAAs. In vitro studies were performed using isovaleryl-CoA dehydrogenase (IVD), isobutyryl-CoA dehydrogenase (IBD), and short branched-chain acyl-CoA dehydrogenase (SBCAD), enzymes involved in the degradation pathway of leucine, valine, and isoleucine. The enzymatic activities of the three purified human enzymes were measured using optimized high-performance liquid chromatography procedures, and the respective kinetic parameters were determined in the absence and presence of VPA and the corresponding CoA and dephosphoCoA conjugates. Valproyl-CoA and valproyl-dephosphoCoA inhibited IVD activity significantly by a purely competitive mechanism with K(i) values of 74 ± 4 and 170 ± 12 μM, respectively. IBD activity was not affected by any of the tested VPA esters. However, valproyl-CoA did inhibit SBCAD activity by a purely competitive mechanism with a K(i) of 249 ± 29 μM. In addition, valproyl-dephosphoCoA inhibited SBCAD activity via a distinct mechanism (K(i) = 511 ± 96 μM) that appeared to be of the mixed type. Furthermore, we show that both SBCAD and IVD are active, using valproyl-CoA as a substrate. The catalytic efficiency of SBCAD turned out to be much higher than that of IVD, demonstrating that SBCAD is the most probable candidate for the first dehydrogenation step of VPA β-oxidation. Our data explain some of the effects of valproate on the branched-chain amino acid metabolism and shed new light on the biotransformation pathway of valproate.

Background: Variations in the gene ACADS, encoding the mitochondrial protein short-chain acyl CoA-dehydrogenase (SCAD), have been observed in individuals with clinical symptoms. The phenotype of SCAD deficiency (SCADD) is very heterogeneous, ranging from asymptomatic to severe, without a clear genotype-phenotype correlation, which suggests a multifactorial disorder. The pathophysiological relevance of the genetic variations in the SCAD gene is therefore disputed, and has not yet been elucidated, which is an important step in the investigation of SCADD etiology., Aim: To determine whether the disease-associated misfolding variant of SCAD protein, p.Arg107Cys, disturbs mitochondrial function., Methods: We have developed a cell model system, stably expressing either the SCAD wild-type protein or the misfolding SCAD variant protein, p.Arg107Cys (c.319 C > T). The model system was used for investigation of SCAD with respect to expression, degree of misfolding, and enzymatic SCAD activity. Furthermore, cell proliferation and expression of selected stress response genes were investigated as well as proteomic analysis of mitochondria-enriched extracts in order to study the consequences of p.Arg107Cys protein expression using a global approach., Conclusions: We found that expression of the p.Arg107Cys variant SCAD protein gives rise to inactive misfolded protein species, eliciting a mild toxic response manifested though a decreased proliferation rate and oxidative stress, as shown by an increased demand for the mitochondrial antioxidant SOD2. In addition, we found markers of apoptotic activity in the p.Arg107Cys expressing cells, which points to a possible pathophysiological role of this variant protein.

Objective: To investigate whether statin therapy affects coenzyme Q10 (CoQ10) status in children with heterozygous familial hypercholesterolemia (FH)., Study Design: Samples were obtained at baseline (treatment naïve) and after dose titration with rosuvastatin, aiming for a low-density lipoprotein cholesterol level of 110 mg/dL. Twenty-nine patients were treated with 5, 10, or 20 mg of rosuvastatin for a mean period of 29 weeks., Results: We found a significant (32%) decrease in peripheral blood mononuclear cell (PBMC) CoQ10 level (P = .02), but no change in PBMC adenosine triphosphate synthesis (P = .60). Uncorrected plasma CoQ10 values were decreased significantly, by 45% (P < .01). In contrast, ratios of plasma CoQ10/total cholesterol and CoQ10/low-density lipoprotein cholesterol remained equal during treatment., Conclusions: In children with FH, rosuvastatin causes a significant decrease in cellular PBMC CoQ10 status but does not affect mitochondrial adenosine triphosphate synthesis in children with FH. Further studies should address whether (rare) side effects of statin therapy could be explained by a deterioration in CoQ10 status., (Copyright © 2011 Mosby, Inc. All rights reserved.)

We know a great deal about the neurophysiological mechanisms supporting instrumental actions, i.e., actions designed to alter the physical state of the environment. In contrast, little is known about our ability to select communicative actions, i.e., actions directly designed to modify the mental state of another agent. We have recently provided novel empirical evidence for a mechanism in which a communicator selects his actions on the basis of a prediction of the communicative intentions that an addressee is most likely to attribute to those actions. The main novelty of those findings was that this prediction of intention recognition is cerebrally implemented within the intention recognition system of the communicator, is modulated by the ambiguity in meaning of the communicative acts, and not by their sensorimotor complexity. The characteristics of this predictive mechanism support the notion that human communicative abilities are distinct from both sensorimotor and linguistic processes.

Oxidation of fatty acids in mitochondria is a key physiological process in higher eukaryotes including humans. The importance of the mitochondrial beta-oxidation system in humans is exemplified by the existence of a group of genetic diseases in man caused by an impairment in the mitochondrial oxidation of fatty acids. Identification of patients with a defect in mitochondrial beta-oxidation has long remained notoriously difficult, but the introduction of tandem-mass spectrometry in laboratories for genetic metabolic diseases has revolutionalized the field by allowing the rapid and sensitive analysis of acylcarnitines. Equally important is that much progress has been made with respect to the development of specific enzyme assays to identify the enzyme defect in patients subsequently followed by genetic analysis. In this review, we will describe the current state of knowledge in the field of fatty acid oxidation enzymology and its application to the follow-up analysis of positive neonatal screening results.

Mitochondrial dysfunction and oxidative stress are central to the molecular basis of several human diseases associated with neuromuscular disabilities. We hypothesize that mitochondrial dysfunction also contributes to the neuromuscular symptoms observed in patients with ethylmalonic aciduria and homozygosity for ACADS c.625G>A-a common variant of the short-chain acyl-coenzyme A (CoA) dehydrogenase (SCAD) enzyme in the mitochondrial fatty acid oxidation pathway. This study sought to identify the specific factors that initiate cell dysfunction in these patients. We investigated fibroblast cultures from 10 patients with neuromuscular disabilities, elevated levels of ethylmalonic acid (EMA) (>50 mmol/mol creatinine), and ACADS c.625G>A homozygosity. Functional analyses, i.e., ACADS gene and protein expression as well as SCAD enzyme activity measurements, were performed together with a global nano liquid chromatography tandem mass spectroscopy (nano-LC-MS/MS)-based screening of the mitochondrial proteome in patient fibroblasts. Moreover, cell viability of patient fibroblasts exposed to menadione-induced oxidative stress was evaluated. Loss of SCAD function was detected in the patient group, most likely due to decreased ACADS gene expression and/or elimination of misfolded SCAD protein. Analysis of the mitochondrial proteome in patient fibroblasts identified a number of differentially expressed protein candidates, including reduced expression of the antioxidant superoxide dismutase 2 (SOD2). Additionally, patient fibroblasts demonstrated significantly higher sensitivity to oxidative stress than control fibroblasts. We propose that reduced mitochondrial antioxidant capacity is a potential risk factor for ACADS c.625G>A-associated ethylmalonic aciduria and that mitochondrial dysfunction contributes to the neurotoxicity observed in patients.