Molecular definition of the endogenous Toll-like receptor signalling pathways.

Innate immune pattern recognition receptors, such as the Toll-like receptors (TLRs), are key mediators of the immune response to infection and central to our understanding of health and disease1. After microbial detection, these receptors activate inflammatory signal transduction pathways that involve IκB kinases, mitogen-activated protein kinases, ubiquitin ligases and other adaptor proteins. The mechanisms that connect the proteins in the TLR pathways are poorly defined. To delineate TLR pathway activities, we engineered macrophages to enable microscopy and proteomic analysis of the endogenous myddosome constituent MyD88. We found that myddosomes form transient contacts with activated TLRs and that TLR-free myddosomes are dynamic in size, number and composition over the course of 24 h. Analysis using super-resolution microscopy revealed that, within most myddosomes, MyD88 forms barrel-like structures that function as scaffolds for effector protein recruitment. Proteomic analysis demonstrated that myddosomes contain proteins that act at all stages and regulate all effector responses of the TLR pathways, and genetic analysis defined the epistatic relationship between these effector modules. Myddosome assembly was evident in cells infected with Listeria monocytogenes, but these bacteria evaded myddosome assembly and TLR signalling during cell-to-cell spread. On the basis of these findings, we propose that the entire TLR signalling pathway is executed from within the myddosome.

Structural insights into cytokine cleavage by inflammatory caspase-4.

Inflammatory caspases are key enzymes in mammalian innate immunity that control the processing and release of interleukin-1 (IL-1)-family cytokines1,2. Despite the biological importance, the structural basis for inflammatory caspase-mediated cytokine processing has remained unclear. To date, catalytic cleavage of IL-1-family members, including pro-IL-1ß and pro-IL-18, has been attributed primarily to caspase-1 activities within canonical inflammasomes3. Here we demonstrate that the lipopolysaccharide receptor caspase-4 from humans and other mammalian species (except rodents) can cleave pro-IL-18 with an efficiency similar to pro-IL-1ß and pro-IL-18 cleavage by the prototypical IL-1-converting enzyme caspase-1. This ability of caspase-4 to cleave pro-IL-18, combined with its previously defined ability to cleave and activate the lytic pore-forming protein gasdermin D (GSDMD)4,5, enables human cells to bypass the need for canonical inflammasomes and caspase-1 for IL-18 release. The structure of the caspase-4-pro-IL-18 complex determined using cryogenic electron microscopy reveals that pro-lL-18 interacts with caspase-4 through two distinct interfaces: a protease exosite and an interface at the caspase-4 active site involving residues in the pro-domain of pro-IL-18, including the tetrapeptide caspase-recognition sequence6. The mechanisms revealed for cytokine substrate capture and cleavage differ from those observed for the caspase substrate GSDMD7,8. These findings provide a structural framework for the discussion of caspase activities in health and disease.

Development of early prediction model of in-hospital cardiac arrest based on laboratory parameters.

BACKGROUND: In-hospital cardiac arrest (IHCA) is an acute disease with a high fatality rate that burdens individuals, society, and the economy. This study aimed to develop a machine learning (ML) model using routine laboratory parameters to predict the risk of IHCA in rescue-treated patients. METHODS: This retrospective cohort study examined all rescue-treated patients hospitalized at the First Medical Center of the PLA General Hospital in Beijing, China, from January 2016 to December 2020. Five machine learning algorithms, including support vector machine, random forest, extra trees classifier (ETC), decision tree, and logistic regression algorithms, were trained to develop models for predicting IHCA. We included blood counts, biochemical markers, and coagulation markers in the model development. We validated model performance using fivefold cross-validation and used the SHapley Additive exPlanation (SHAP) for model interpretation. RESULTS: A total of 11,308 participants were included in the study, of which 7779 patients remained. Among these patients, 1796 (23.09%) cases of IHCA occurred. Among five machine learning models for predicting IHCA, the ETC algorithm exhibited better performance, with an AUC of 0.920, compared with the other four machine learning models in the fivefold cross-validation. The SHAP showed that the top ten factors accounting for cardiac arrest in rescue-treated patients are prothrombin activity, platelets, hemoglobin, N-terminal pro-brain natriuretic peptide, neutrophils, prothrombin time, serum albumin, sodium, activated partial thromboplastin time, and potassium. CONCLUSIONS: We developed a reliable machine learning-derived model that integrates readily available laboratory parameters to predict IHCA in patients treated with rescue therapy.

Children across cultures respond emotionally to the acoustic environment.

Among human and non-human animals, the ability to respond rapidly to biologically significant events in the environment is essential for survival and development. Research has confirmed that human adult listeners respond emotionally to environmental sounds by relying on the same acoustic cues that signal emotionality in speech prosody and music. However, it is unknown whether young children also respond emotionally to environmental sounds. Here, we report that changes in pitch, rate (i.e. playback speed), and intensity (i.e. amplitude) of environmental sounds trigger emotional responses in 3- to 6-year-old American and Chinese children, including four sound types: sounds of human actions, animal calls, machinery, and natural phenomena such as wind and waves. Children's responses did not differ across the four types of sounds used but developed with age - a finding observed in both American and Chinese children. Thus, the ability to respond emotionally to non-linguistic, non-music environmental sounds is evident at three years of age - an age when the ability to decode emotional prosody in language and music emerges. We argue that general mechanisms that support emotional prosody decoding are engaged by all sounds, as reflected in emotional responses to non-linguistic acoustic input such as music and environmental sounds.

The Influence of Action Video Gaming Experience on the Perception of Emotional Faces and Emotional Word Meaning.

Action video gaming (AVG) experience has been found related to sensorimotor and attentional development. However, the influence of AVG experience on the development of emotional perception skills is still unclear. Using behavioral and ERP measures, this study examined the relationship between AVG experience and the ability to decode emotional faces and emotional word meanings. AVG experts and amateurs completed an emotional word-face Stroop task prior to (the pregaming phase) and after (the postgaming phase) a 1 h AVG session. Within-group comparisons showed that after the 1 h AVG session, a more negative N400 was observed in both groups of participants, and a more negative N170 was observed in the experts. Between-group comparisons showed that the experts had a greater change of N170 and N400 amplitudes across phases than the amateurs. The results suggest that both the 1 h and long-term AVG experiences may be related to an increased difficulty of emotional perception. Furthermore, certain behavioral and ERP measures showed neither within- nor between-group differences, suggesting that the relationship between AVG experience and emotional perception skills still needs further research.

Young Mandarin learners use function words to distinguish between nouns and verbs.

Mandarin requires neither determiners nor morphological inflections, which casts doubt on Mandarin-speaking children's ability to use function words as a syntactic bootstrapping tool to identify the form class of a new word. This study examined 3- and 5-year-old Mandarin learners' ability to use function words to interpret new words as either nouns or verbs in the absence of the requirement for determiners and inflections in the ambient language. In Experiment 1, 3-, and 5-year-old Mandarin-speaking children were exposed to eight novel words embedded in sentence frames differing only in the form class markers used. The 5-year-olds interpreted the novel words as either nouns or verbs depending on the form class markers they heard, while the 3-year-olds learned only the nouns. Experiment 2 confirmed that the 5-year-olds understood the function of the verb-marker. Thus, Mandarin-speaking children can use function words to distinguish nouns versus verbs, and this ability appears between three and five years of age.

Electronic-Sports Experience Related to Functional Enhancement in Central Executive and Default Mode Areas.

Electronic-sports (e-sports) is a form of organized, online, multiplayer video game competition, which requires both action skills and the ability and process of forming and adapting a strategy (referred to as strategization hereafter) to achieve goals. Over the past few decades, research has shown that video gaming experience has an important impact on the plasticity of the sensorimotor, attentional, and executive brain areas. However, little research has examined the relationship between e-sports experience and the plasticity of brain networks that are related to strategization. Using resting-state fMRI data and the local functional connectivity density (lFCD) analysis, this study investigated the relationship between e-sports experience (League of Legends [LOL] in this study) and brain plasticity by comparing between top-ranking LOL players and lower-ranking (yet experienced) LOL players. Results showed that the top-ranking LOL players had superior local functional integration in the executive areas compared to lower-ranking players. Furthermore, the top-ranking players had higher lFCD in the default mode areas, which have been found related to various subprocesses (e.g., memory and planning) essential for strategization. Finally, the top-ranking players' lFCD was related to their LOL expertise rank level, as indicated by a comprehensive score assigned by the gaming software based on players' gaming experience and expertise. Thus, the result showed that the local functional connectivity in central executive and default mode brain areas was enhanced in the top-ranking e-sports players, suggesting that e-sports experience is related to the plasticity of the central executive and default mode areas.

Human emotions track changes in the acoustic environment.

Emotional responses to biologically significant events are essential for human survival. Do human emotions lawfully track changes in the acoustic environment? Here we report that changes in acoustic attributes that are well known to interact with human emotions in speech and music also trigger systematic emotional responses when they occur in environmental sounds, including sounds of human actions, animal calls, machinery, or natural phenomena, such as wind and rain. Three changes in acoustic attributes known to signal emotional states in speech and music were imposed upon 24 environmental sounds. Evaluations of stimuli indicated that human emotions track such changes in environmental sounds just as they do for speech and music. Such changes not only influenced evaluations of the sounds themselves, they also affected the way accompanying facial expressions were interpreted emotionally. The findings illustrate that human emotions are highly attuned to changes in the acoustic environment, and reignite a discussion of Charles Darwin's hypothesis that speech and music originated from a common emotional signal system based on the imitation and modification of environmental sounds.

Children's Use of Morphological Cues in Real-Time Event Representation.

The present study investigated whether and how fast young children can use information encoded in morphological markers during real-time event representation. Using the visual world paradigm, we tested 35 adults, 34 5-year-olds and 33 3-year-olds. The results showed that the adults, the 5-year-olds and the 3-year-olds all exhibited eye gaze patterns that reflected a rapid use of morphological cues during real-time event representation. There was no difference in the time course of the eye gaze patterns of the 5-year-olds and those of the adults, indicating that 5-year-old children already have adult-like processing abilities and they can use morphological cues as effectively as adults during real-time event representation. However, a 400 ms delay was observed in the eye gaze patterns by the 3-year-olds as compared to the 5-year-olds and the adults. We proposed that the observed difference might reflect a difference in the general cognitive processing abilities between the three age groups. Due to the immature cognitive processing abilities of 3-year-olds, it took longer for them to progress their eye movements to the target pictures as compared to older children and adults.

Action Video Game Experience Related to Altered Large-Scale White Matter Networks.

With action video games (AVGs) becoming increasingly popular worldwide, the cognitive benefits of AVG experience have attracted continuous research attention over the past two decades. Research has repeatedly shown that AVG experience can causally enhance cognitive ability and is related to neural plasticity in gray matter and functional networks in the brain. However, the relation between AVG experience and the plasticity of white matter (WM) network still remains unclear. WM network modulates the distribution of action potentials, coordinating the communication between brain regions and acting as the framework of neural networks. And various types of cognitive deficits are usually accompanied by impairments of WM networks. Thus, understanding this relation is essential in assessing the influence of AVG experience on neural plasticity and using AVG experience as an interventional tool for impairments of WM networks. Using graph theory, this study analyzed WM networks in AVG experts and amateurs. Results showed that AVG experience is related to altered WM networks in prefrontal networks, limbic system, and sensorimotor networks, which are related to cognitive control and sensorimotor functions. These results shed new light on the influence of AVG experience on the plasticity of WM networks and suggested the clinical applicability of AVG experience.

Functional Integration between Salience and Central Executive Networks: A Role for Action Video Game Experience.

Action video games (AVGs) have attracted increasing research attention as they offer a unique perspective into the relation between active learning and neural plasticity. However, little research has examined the relation between AVG experience and the plasticity of neural network mechanisms. It has been proposed that AVG experience is related to the integration between Salience Network (SN) and Central Executive Network (CEN), which are responsible for attention and working memory, respectively, two cognitive functions essential for AVG playing. This study initiated a systematic investigation of this proposition by analyzing AVG experts' and amateurs' resting-state brain functions through graph theoretical analyses and functional connectivity. Results reveal enhanced intra- and internetwork functional integrations in AVG experts compared to amateurs. The findings support the possible relation between AVG experience and the neural network plasticity.

Child word learning in song and speech.

Listening to sung words rather than spoken words can facilitate word learning and memory in adults and school-aged children. To explore the development of this effect in young children, this study examined word learning (assessed as forming word-object associations) in 1- to 2-year olds and 3- to 4-year olds, and word long-term memory (LTM) in 4- to 5-year olds several days after the initial learning. In an intermodal preferential looking paradigm, children were taught a pair of words utilising adult-directed speech (ADS) and a pair of sung words. Word learning performance was better with sung words than with ADS words in 1- to 2-year olds (Experiments 1a and 1b), 3- to 4-year olds (Experiment 1a), and 4- to 5-year olds (Experiment 2b), revealing a benefit of song in word learning in all age ranges recruited. We also examined whether children successfully learned the words by comparing their performance against chance. The 1- to 2-year olds only learned sung words, but the 3- to 4-year olds learned both sung and ADS words, suggesting that the reliance on music features in word learning observed at ages 1-2 decreased with age. Furthermore, song facilitated the word mapping-recognition processes. Results on children's LTM performance showed that the 4- to 5-year olds' LTM performance did not differ between sung and ADS words. However, the 4- to 5-year olds reliably recalled sung words but not spoken words. The reliable LTM of sung words arose from hearing sung words during the initial learning rather than at test. Finally, the benefit of song on word learning and the reliable LTM of sung words observed at ages 3-5 cannot be explained as an attentional effect.

Co-activation patterns during viewing of different video game genres.

Past research has revealed cognitive improvements resulting from engagement with both traditional action video games and newer action-like video games, such as action real-time strategy games (ARSG). However, the cortical dynamics elicited by different video gaming genres remain unclear. This study explored the temporal dynamics of cortical networks in response to different gaming genres. Functional magnetic resonance imaging (fMRI) data were obtained during eye-closed resting and passive viewing of gameplay videos of three genres: life simulation games (LSG), first-person shooter games (FPS), and ARSG. Data analysis used a seed-free Co-Activation Pattern (CAP) based on Regions of Interest (ROIs). When comparing the viewing of action-like video games (FPS and ARSG) to LSG viewing, significant dynamic distinctions were observed in both primary and higher-order networks. Within action-like video games, compared to FPS viewing, ARSG viewing elicited a more pronounced increase in the Fraction of Time and Counts of attentional control-related CAPs, along with an increased Transition Probability from sensorimotor-related CAPs to attentional control-related CAPs. Compared to ARSG viewing, FPS viewing elicited a significant increase in the Fraction of Time of sensorimotor-related CAPs, when gaming experience was considered as a covariate. Thus, different video gaming genres, including distinct action-like video gaming genres, elicited unique dynamic patterns in whole-brain CAPs, potentially influencing the development of various cognitive processes.

Behavioral state-dependent associations between EEG temporal correlations and depressive symptoms.

Previous studies have shown abnormal long-range temporal correlations in neuronal oscillations among individuals with Major Depressive Disorders, occurring during both resting states and transitions between resting and task states. However, the understanding of this effect in preclinical individuals with depression remains limited. This study investigated the association between temporal correlations of neuronal oscillations and depressive symptoms during resting and task states in preclinical individuals, specifically focusing on male action video gaming experts. Detrended fluctuation analysis (DFA), Lifetimes, and Waitingtimes were employed to explore temporal correlations across long-range and short-range scales. The results indicated widespread changes from the resting state to the task state across all frequency bands and temporal scales. Rest-task DFA changes in the alpha band exhibited a negative correlation with depressive scores at most electrodes. Significant positive correlations between DFA values and depressive scores were observed in the alpha band during the resting state but not in the task state. Similar patterns of results emerged concerning maladaptive negative emotion regulation strategies. Additionally, short-range temporal correlations in the alpha band echoed the DFA results. These findings underscore the state-dependent relationships between temporal correlations of neuronal oscillations and depressive symptoms, as well as maladaptive emotion regulation strategies, in preclinical individuals.

Control of Inflammatory Response by Tissue Microenvironment.

Inflammation is an essential defense response but operates at the cost of normal functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as a novel intracellular pH sensor. Acidic pH disrupts the transcription condensates containing BRD4 and MED1, via histidine-enriched intrinsically disordered regions. Crucially, decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environmental sensing to directly control inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.

Slow tempo music preserves attentional efficiency in young children.

Past research has shown that listening to slow- or fast-tempo music can affect adults' executive attention (EA) performance. This study examined the immediate impact of brief exposure to slow- or fast-tempo music on EA performance in 4- to 6-year-old children. A within-subject design was used, where each child completed three blocks of the EA task after listening to fast-tempo music (fast-tempo block), slow-tempo music (slow-tempo block), and ocean waves (control block), with block-order counterbalanced. In each block, children were also asked to report their pre-task subjective emotional status (experienced arousal and valence) before listening to music and their post-task emotional status after the EA task. Three major results emerged. First, reaction time (RT) was significantly faster in the slow-tempo block than in the fast-tempo, suggesting that listening to slow-tempo music preserves processing efficiency, relative to fast-tempo music. Second, children's accuracy rate in the EA task did not differ across blocks. Third, children's subjective emotional status did not differ across blocks and did not change across the pre- and post-task phases in any block, suggesting the faster RT observed in the slow-tempo block cannot be explained by changes in arousal or mood.

Children's decoding of emotional prosody in four languages.

It is well established that adults can interpret emotional speech prosody independent of word meaning comprehension, even for emotional speech prosody in an unfamiliar language. However, the acquisition of this ability remains unclear. This study examined the decoding of four emotions (happy, sad, surprise, angry) conveyed with speech prosody in four languages (English, Chinese, French, Spanish) by American and Chinese children at 3 to 5 years of age-an age range when the ability to decode emotional prosody in one's native language emerges but remains fragile. Chinese and American children could decode the emotional meaning of speech prosody in both familiar and unfamiliar languages as young as 3 years old. Performance did not differ across the four languages used-a finding observed in both American and Chinese children. Thus, the in-group advantage of emotional prosody decoding reported for adults may not be evident by 5 years of age. Furthermore, emotional prosody decoding skills improved with age. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Information transmission in action video gaming experts: Inferences from the lateralized readiness potential.

Research showed that action real-time strategy gaming (ARSG) experience is related to cognitive and neural plasticity, including visual selective attention and working memory, executive control, and information processing. This study explored the relationship between ARSG experience and information transmission in the auditory channel. Using an auditory, two-choice, go/no-go task and lateralized readiness potential (LRP) as the index to partial information transmission, this study examined information transmission patterns in ARSG experts and amateurs. Results showed that experts had a higher accuracy rate than amateurs. More importantly, experts had a smaller stimulus-locked LRP component (250 - 450 ms) than amateurs on no-go trials, while the response-locked LRP component (0 - 300 ms) on go trials did not differ between groups. Thus, whereas amateurs used an asynchronous information transmission pattern, experts used a reduced asynchronous information transmission pattern or a synchronous pattern where most of processing occurred prior to response execution - an information transmission pattern that supports rapid, error-free performance. Thus, experts and amateurs may use different information transmission patterns in auditory processing. In addition, the information transmission pattern used by experts is typically observed only after long-term auditory training according to past research. This study supports the relationship between ARSG experience and the development of information processing patterns.

Action Video Gaming Experience Related to Altered Resting-State EEG Temporal and Spatial Complexity.

Action video gaming (AVG) places sustained cognitive load on various behavioral systems, thus offering new insights into learning-related neural plasticity. This study aims to determine whether AVG experience is associated with resting-state electroencephalogram (rs-EEG) temporal and spatial complexity, and if so, whether this effect is observable across AVG subgenres. Two AVG games - League of Legends (LOL) and Player Unknown's Battle Grounds (PUBG) that represent two major AVG subgenres - were examined. We compared rs-EEG microstate and omega complexity between LOL experts and non-experts (Experiment 1) and between PUBG experts and non-experts (Experiment 2). We found that the experts and non-experts had different rs-EEG activities in both experiments, thus revealing the adaptive effect of AVG experience on brain development. Furthermore, we also found certain subgenre-specific complexity changes, supporting the recent proposal that AVG should be categorized based on the gaming mechanics of a specific game rather than a generic genre designation.