The causal structure and computational value of narratives.

Many human behavioral and brain imaging studies have used narratively structured stimuli (e.g., written, audio, or audiovisual stories) to better emulate real-world experience in the laboratory. However, narratives are a special class of real-world experience, largely defined by their causal connections across time. Much contemporary neuroscience research does not consider this key property. We review behavioral and neuroscientific work that speaks to how causal structure shapes comprehension of and memory for narratives. We further draw connections between this work and reinforcement learning, highlighting how narratives help link causes to outcomes in complex environments. By incorporating the plausibility of causal connections between classes of actions and outcomes, reinforcement learning models may become more ecologically valid, while simultaneously elucidating the value of narratives.

The relationship between event boundary strength and pattern shifts across the cortical hierarchy during naturalistic movie-viewing.

Our continuous experience is spontaneously segmented by the brain into discrete events. However, the beginning of a new event (an event boundary) is not always sharply identifiable: phenomenologically, event boundaries vary in salience. How are the response profiles of cortical areas at event boundaries modulated by boundary strength during complex, naturalistic movie-viewing? Do cortical responses scale in a graded manner with boundary strength, or do they merely detect boundaries in a binary fashion? We measured "cortical boundary shifts" as transient changes in multi-voxel patterns at event boundaries with different strengths (weak, moderate, and strong), determined by across-subject agreement. Cortical regions with different processing timescales were examined. In auditory areas, which have short timescales, cortical boundary shifts exhibited a clearly graded profile both in group-level and individual-level analyses. In cortical areas with long timescales, including the default mode network, boundary strength modulated pattern shift magnitude at the individual subject level. We also observed a positive relationship between boundary strength and the extent of temporal alignment of boundary shifts across different levels of the cortical hierarchy. A strictly nested bottom-up hierarchical structure was not necessary to observe this relationship. Additionally, hippocampal activity was highest at event boundaries for which cortical boundary shifts were most aligned across hierarchical levels. Overall, we found that event boundary strength modulated cortical pattern shifts strongly in sensory areas and more weakly in higher-level areas, and that stronger boundaries were associated with greater alignment of these shifts across the cortical hierarchy.

Accelerating attribute-focused process and product development through the development and deployment of autonomous process analytical technology platform system.

Enabling real-time monitoring and control of the biomanufacturing processes through product quality insights continues to be an area of focus in the biopharmaceutical industry. The goal is to manufacture products with the desired quality attributes. To realize this rigorous attribute-focused Quality by Design approach, it is critical to support the development of processes that consistently deliver high-quality products and facilitate product commercialization. Time delays associated with offline analytical testing can limit the speed of process development. Thus, developing and deploying analytical technology is necessary to accelerate process development. In this study, we have developed the micro sequential injection process analyzer and the automatic assay preparation platform system. These innovations address the unmet need for an automatic, online, real-time sample acquisition and preparation platform system for in-process monitoring, control, and release of biopharmaceuticals. These systems can also be deployed in laboratory areas as an offline analytical system and on the manufacturing floor to enable rapid testing and release of products manufactured in a good manufacturing practice environment.

A shared neural code for perceiving and remembering social interactions in the human superior temporal sulcus.

Recognizing and remembering social information is a crucial cognitive skill. Neural patterns in the superior temporal sulcus (STS) support our ability to perceive others' social interactions. However, despite the prominence of social interactions in memory, the neural basis of remembering social interactions is still unknown. To fill this gap, we investigated the brain mechanisms underlying memory of others' social interactions during free spoken recall of a naturalistic movie. By applying machine learning-based fMRI encoding analyses to densely labeled movie and recall data we found that a subset of the STS activity evoked by viewing social interactions predicted neural responses in not only held-out movie data, but also during memory recall. These results provide the first evidence that activity in the STS is reinstated in response to specific social content and that its reactivation underlies our ability to remember others' interactions. These findings further suggest that the STS contains representations of social interactions that are not only perceptually driven, but also more abstract or conceptual in nature.

Self-reactive germline-like TCR alpha chains shared between blood and pancreas.

Human islet antigen reactive CD4 + memory T cells (IAR T cells) from peripheral blood have been studied extensively for their role in the pathogenesis of autoimmune type 1 diabetes (T1D). However, IAR T cells are rare, and it remains poorly understood how they affect T1D progression in the pancreas. Using single cell RNA-sequencing coupled with a multiplexed activation induced marker (AIM) enrichment assay, we identified paired TCR alpha/beta (TRA/TRB) T cell receptors (TCRs) in IAR T cells from the blood of healthy, at-risk, new onset, and established T1D donors. Using TCR sequences as barcodes, we measured infiltration of IAR T cells from blood into pancreas of organ donors with and without T1D. We detected extensive TCR sharing between IAR T cells from peripheral blood and pancreatic infiltrating T cells (PIT), with perfectly matched or single mismatched TRA junctions and J gene regions, comprising ~ 34% of unique IAR TCRs. PIT-matching IAR T cells had public TRA chains that showed increased use of germline-encoded residues in epitope engagement and a propensity for cross-reactivity. The link with T cells in the pancreas implicates autoreactive IAR T cells with shared TRA junctions and increased levels in blood with the prediabetic and new onset phases of T1D progression.

Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes.

Variation in the preservation of ß cell function in clinical trials in type 1 diabetes (T1D) has emphasized the need to define biomarkers to predict treatment response. The T1DAL trial targeted T cells with alefacept (LFA-3-Ig) and demonstrated C-peptide preservation in approximately 30% of new-onset T1D individuals. We analyzed islet antigen-reactive (IAR) CD4+ T cells in PBMC samples collected prior to treatment from alefacept- and placebo-treated individuals using flow cytometry and single-cell RNA sequencing. IAR CD4+ T cells at baseline had heterogeneous phenotypes. Transcript profiles formed phenotypic clusters of cells along a trajectory based on increasing maturation and activation, and T cell receptor (TCR) chains showed clonal expansion. Notably, the frequency of IAR CD4+ T cells with a memory phenotype and a unique transcript profile (cluster 3) were inversely correlated with C-peptide preservation in alefacept-treated, but not placebo-treated, individuals. Cluster 3 cells had a proinflammatory phenotype characterized by expression of the transcription factor BHLHE40 and the cytokines GM-CSF and TNF-α, and shared TCR chains with effector memory-like clusters. Our results suggest IAR CD4+ T cells as a potential baseline biomarker of response to therapies targeting the CD2 pathway and warrant investigation for other T cell-related therapies.

Word-timestamped transcripts of two spoken narrative recall functional neuroimaging datasets.

After watching audiovisual movies, human participants produced spoken narrative recollections during functional magnetic resonance imaging (fMRI); presented here are word-level timestamps of their speech, temporally aligned to the publicly shared fMRI data. For the "FilmFestival" dataset, twenty participants watched ten short audiovisual movies, approximately 2-8 minutes each. For the "Sherlock" dataset, seventeen participants watched the first half of the first episode of BBC's Sherlock (48 minutes). After viewing, participants then verbally described what they remembered about the movies in their own words. Participants' speech was recorded using an MR-compatible microphone. The audio recordings were transcribed, then timestamped by a forced aligner; missing timestamps were filled in manually by human transcriptionists referencing the audio recording. Each file contains the participant's recall word by word, onset of each word in seconds with 1/10th-second precision, and the corresponding fMRI volume number (TR). This dataset can be used to investigate topics such as naturalistic memory and language production.

A functional neuroimaging dataset acquired during naturalistic movie watching and narrated recall of a series of short cinematic films.

Whole-brain functional magnetic resonance imaging (fMRI) data from twenty healthy human participants were collected during naturalistic movie watching and free spoken recall tasks. Participants watched ten short (approximately 2 - 8 min) audiovisual movies and then verbally described what they remembered about the movies in their own words. Participants' verbal responses were audio recorded using an MR-compatible microphone. The audio recordings were transcribed and timestamped by independent coders. The neural and behavioral data were organized in the Brain Imaging Data Structure (BIDS) format and made publicly available via OpenNeuro.org. The dataset can be used to explore the neural bases of naturalistic memory and other cognitive functions including but not limited to visual/auditory perception, language comprehension, and speech generation.

Neural representations of naturalistic events are updated as our understanding of the past changes.

The brain actively reshapes our understanding of past events in light of new incoming information. In the current study, we ask how the brain supports this updating process during the encoding and recall of naturalistic stimuli. One group of participants watched a movie ('The Sixth Sense') with a cinematic 'twist' at the end that dramatically changed the interpretation of previous events. Next, participants were asked to verbally recall the movie events, taking into account the new 'twist' information. Most participants updated their recall to incorporate the twist. Two additional groups recalled the movie without having to update their memories during recall: one group never saw the twist; another group was exposed to the twist prior to the beginning of the movie, and thus the twist information was incorporated both during encoding and recall. We found that providing participants with information about the twist beforehand altered neural response patterns during movie-viewing in the default mode network (DMN). Moreover, presenting participants with the twist at the end of the movie changed the neural representation of the previously-encoded information during recall in a subset of DMN regions. Further evidence for this transformation was obtained by comparing the neural activation patterns during encoding and recall and correlating them with behavioral signatures of memory updating. Our results demonstrate that neural representations of past events encoded in the DMN are dynamically integrated with new information that reshapes our understanding in natural contexts.

Exploring the use of activity-based group therapy in increasing self-efficacy and subjective well-being in acute mental health.

Background/Objectives: Self-efficacy is a key component in mental health recovery and improvement in well-being. Mental illness is often resultant of environmental stressors, highlighting the importance of coping skills. Occupational therapists commonly utilise activity-based group therapy to encourage use of activities as coping strategies. However, there has been little research concerning these groups and their role in enhancing self-efficacy in behavioural-based coping skills. This study aimed to explore factors that affect behavioural-based coping self-efficacy during activity-based group therapy in an acute mental health ward. It investigates the relationships between (1) behavioural-based coping self-efficacy with overall mental health self-efficacy and (2) mental health self-efficacy and subjective well-being. Methods: Immediately after the first group, participants completed a post-group questionnaire. Participation level was also rated. At discharge, the participants were asked to complete the UK Office of National Statistics subjective well-being tool and the Mental Health Self-Efficacy Scale. Descriptive statistics, independent sample t-tests and one-way analysis of variance were done to examine possible covariates and confounders of all outcome variables. General linear models were then conducted. Results: Post-group questionnaire reflected moderate-high self-efficacy (M = 6.92, SD = 2.48) and positive well-being with higher happiness scores (M = 7.42, SD = 2.20) and lower anxiety scores (M = 3.79, SD = 2.85). Coping self-efficacy significantly predicted overall mental health self-efficacy (p = .014), which in turn significantly predicted positive domains of well-being. Conclusions: Performing behavioural-based coping strategies in groups can enhance coping self-efficacy and positive well-being, with possible positive influence on mental health self-efficacy and well-being at discharge.

Predicting memory from the network structure of naturalistic events.

When we remember events, we often do not only recall individual events, but also the connections between them. However, extant research has focused on how humans segment and remember discrete events from continuous input, with far less attention given to how the structure of connections between events impacts memory. Here we conduct a functional magnetic resonance imaging study in which participants watch and recall a series of realistic audiovisual narratives. By transforming narratives into networks of events, we demonstrate that more central events-those with stronger semantic or causal connections to other events-are better remembered. During encoding, central events evoke larger hippocampal event boundary responses associated with memory formation. During recall, high centrality is associated with stronger activation in cortical areas involved in episodic recollection, and more similar neural representations across individuals. Together, these results suggest that when humans encode and retrieve complex real-world experiences, the reliability and accessibility of memory representations is shaped by their location within a network of events.

COVID-19 Variant Detection with a High-Fidelity CRISPR-Cas12 Enzyme.

Laboratory tests for the accurate and rapid identification of SARS-CoV-2 variants can potentially guide the treatment of COVID-19 patients and inform infection control and public health surveillance efforts. Here, we present the development and validation of a rapid COVID-19 variant DETECTR assay incorporating loop-mediated isothermal amplification (LAMP) followed by CRISPR-Cas12 based identification of single nucleotide polymorphism (SNP) mutations in the SARS-CoV-2 spike (S) gene. This assay targets the L452R, E484K/Q/A, and N501Y mutations, at least one of which is found in nearly all major variants. In a comparison of three different Cas12 enzymes, only the newly identified enzyme CasDx1 was able to accurately identify all targeted SNP mutations. An analysis pipeline for CRISPR-based SNP identification from 261 clinical samples yielded a SNP concordance of 97.3% and agreement of 98.9% (258 of 261) for SARS-CoV-2 lineage classification, using SARS-CoV-2 whole-genome sequencing and/or real-time RT-PCR as test comparators. We also showed that detection of the single E484A mutation was necessary and sufficient to accurately identify Omicron from other major circulating variants in patient samples. These findings demonstrate the utility of CRISPR-based DETECTR as a faster and simpler diagnostic method compared with sequencing for SARS-CoV-2 variant identification in clinical and public health laboratories.

A generalized cortical activity pattern at internally generated mental context boundaries during unguided narrative recall.

Current theory and empirical studies suggest that humans segment continuous experiences into events based on the mismatch between predicted and actual sensory inputs; detection of these 'event boundaries' evokes transient neural responses. However, boundaries can also occur at transitions between internal mental states, without relevant external input changes. To what extent do such 'internal boundaries' share neural response properties with externally driven boundaries? We conducted an fMRI experiment where subjects watched a series of short movies and then verbally recalled the movies, unprompted, in the order of their choosing. During recall, transitions between movies thus constituted major boundaries between internal mental contexts, generated purely by subjects' unguided thoughts. Following the offset of each recalled movie, we observed stereotyped spatial activation patterns in the default mode network, especially the posterior medial cortex, consistent across different movie contents and even across the different tasks of movie watching and recall. Surprisingly, the between-movie boundary patterns did not resemble patterns at boundaries between events within a movie. Thus, major transitions between mental contexts elicit neural phenomena shared across internal and external modes and distinct from within-context event boundary detection, potentially reflecting a cognitive state related to the flushing and reconfiguration of situation models.

Naturalistic stimuli reveal a sensitive period in cross modal responses of visual cortex: Evidence from adult-onset blindness.

How do life experiences impact cortical function? In people who are born blind, the "visual" cortices are recruited during nonvisual tasks, such as Braille reading and sound localization. Do visual cortices have a latent capacity to respond to nonvisual information throughout the lifespan? Alternatively, is there a sensitive period of heightened plasticity that makes visual cortex repurposing especially possible during childhood? To gain insight into these questions, we leveraged meaningful naturalistic auditory stimuli to simultaneously engage a broad range of cognitive domains and quantify cross-modal responses across congenitally blind (n = 22), adult-onset blind (vision loss >18 years-of-age, n = 14) and sighted (n = 22) individuals. During fMRI scanning, participants listened to two types of meaningful naturalistic auditory stimuli: excerpts from movies and a spoken narrative. As controls, participants heard the same narrative with the sentences shuffled and the narrative played backwards (i.e., meaningless sounds). We correlated the voxel-wise timecourses of different participants within condition and group. For all groups, all stimulus conditions induced synchrony in auditory cortex while only the narrative stimuli synchronized responses in higher-cognitive fronto-parietal and temporal regions. As previously reported, inter-subject synchrony in visual cortices was higher in congenitally blind than sighted blindfolded participants and this between-group difference was particularly pronounced for meaningful stimuli (movies and narrative). Critically, visual cortex synchrony was no higher in adult-onset blind than sighted blindfolded participants and did not increase with blindness duration. Sensitive period plasticity enables cross-modal repurposing in visual cortices.

Neural signatures associated with temporal compression in the verbal retelling of past events.

When we retell our past experiences, we aim to reproduce some version of the original events; this reproduced version is often temporally compressed relative to the original. However, it is currently unclear how this compression manifests in brain activity. One possibility is that a compressed retrieved memory manifests as a neural pattern which is more dissimilar to the original, relative to a more detailed or vivid memory. However, we argue that measuring raw dissimilarity alone is insufficient, as it confuses a variety of interesting and uninteresting changes. To address this problem, we examine brain pattern changes that are consistent across people. We show that temporal compression in individuals' retelling of past events predicts systematic encoding-to-recall transformations in several higher associative regions. These findings elucidate how neural representations are not simply reactivated, but can also be transformed due to temporal compression during a universal form of human memory expression: verbal retelling.

Perceptual Learning of Altered Vowel Space Improves Identification of Vowels Produced by Individuals With Dysarthria Secondary to Amyotrophic Lateral Sclerosis.

PURPOSE: This study examines the efficacy of perceptual training for improving typical listeners' identification of vowels produced by individuals with dysarthria. We examined whether training on a subset of vowels can generalize to (a) untrained vowels and (b) other speakers with similar overall intelligibility. METHOD: Sixty naive listeners completed a pretest/posttest perceptual learning task. In the pretraining test and posttraining test, participants identified nine American English monophthongs produced by two speakers with dysarthria secondary to amyotrophic lateral sclerosis (ALS). In the 20-min training task, a two-alternative forced choice (2AFC) task with feedback trained listeners on a subset of the vowels and speakers presented in the pretraining test. RESULTS: Vowel identification accuracy improved overall as a function of training. However, patterns of generalization between speakers and vowel types were not symmetric. Specifically, listeners generalized training from front vowels to back vowels but not vice versa. Likewise, listeners generalized from one speaker to another but not in the opposite direction. Examination of confusion matrices for the pretraining and posttraining revealed complex patterns of vowel-specific improvement. CONCLUSIONS: This study demonstrates that listeners benefit from a very simple training paradigm targeting vowels. Additionally, error patterns revealed that vowels are both resistant to and responsive to perceptual learning. Implications for future research and clinical training paradigms are discussed.

Prevention of antimicrobial prescribing among infants following maternal vaccination against respiratory syncytial virus.

SignificanceStrategies to reduce consumption of antimicrobial drugs are needed to contain the growing burden of antimicrobial resistance. Respiratory syncytial virus (RSV) is a prominent cause of upper and lower respiratory tract infections, as a single agent and in conjunction with bacterial pathogens, and may thus contribute to the burden of both inappropriately treated viral infections and appropriately treated polymicrobial infections involving bacteria. In a double-blind, randomized, placebo-controlled trial, administering an RSV vaccine to pregnant mothers reduced antimicrobial prescribing among their infants by 12.9% over the first 3 mo of life. Our findings implicate RSV as an important contributor to antimicrobial exposure among infants and demonstrate that this exposure is preventable by use of effective maternal vaccines against RSV.

Naturalistic Audio-Movies reveal common spatial organization across "visual" cortices of different blind individuals.

Occipital cortices of different sighted people contain analogous maps of visual information (e.g. foveal vs. peripheral). In congenital blindness, "visual" cortices respond to nonvisual stimuli. Do visual cortices of different blind people represent common informational maps? We leverage naturalistic stimuli and inter-subject pattern similarity analysis to address this question. Blindfolded sighted (n = 22) and congenitally blind (n = 22) participants listened to 6 sound clips (5-7 min each): 3 auditory excerpts from movies; a naturalistic spoken narrative; and matched degraded auditory stimuli (Backwards Speech, scrambled sentences), during functional magnetic resonance imaging scanning. We compared the spatial activity patterns evoked by each unique 10-s segment of the different auditory excerpts across blind and sighted people. Segments of meaningful naturalistic stimuli produced distinctive activity patterns in frontotemporal networks that were shared across blind and across sighted individuals. In the blind group only, segment-specific, cross-subject patterns emerged in visual cortex, but only for meaningful naturalistic stimuli and not Backwards Speech. Spatial patterns of activity within visual cortices are sensitive to time-varying information in meaningful naturalistic auditory stimuli in a broadly similar manner across blind individuals.

High-Order Areas and Auditory Cortex Both Represent the High-Level Event Structure of Music.

Recent fMRI studies of event segmentation have found that default mode regions represent high-level event structure during movie watching. In these regions, neural patterns are relatively stable during events and shift at event boundaries. Music, like narratives, contains hierarchical event structure (e.g., sections are composed of phrases). Here, we tested the hypothesis that brain activity patterns in default mode regions reflect the high-level event structure of music. We used fMRI to record brain activity from 25 participants (male and female) as they listened to a continuous playlist of 16 musical excerpts and additionally collected annotations for these excerpts by asking a separate group of participants to mark when meaningful changes occurred in each one. We then identified temporal boundaries between stable patterns of brain activity using a hidden Markov model and compared the location of the model boundaries to the location of the human annotations. We identified multiple brain regions with significant matches to the observer-identified boundaries, including auditory cortex, medial prefrontal cortex, parietal cortex, and angular gyrus. From these results, we conclude that both higher-order and sensory areas contain information relating to the high-level event structure of music. Moreover, the higher-order areas in this study overlap with areas found in previous studies of event perception in movies and audio narratives, including regions in the default mode network.