Using network science to provide insights into the structure of event knowledge.

The structure of event knowledge plays a critical role in prediction, reconstruction of memory for personal events, construction of possible future events, action, language usage, and social interactions. Despite numerous theoretical proposals such as scripts, schemas, and stories, the highly variable and rich nature of events and event knowledge have been formidable barriers to characterizing the structure of event knowledge in memory. We used network science to provide insights into the temporal structure of common events. Based on participants' production and ordering of the activities that make up events, we established empirical profiles for 80 common events to characterize the temporal structure of activities. We used the event networks to investigate multiple issues regarding the variability in the richness and complexity of people's knowledge of common events, including: the temporal structure of events; event prototypes that might emerge from learning across many experiential instances and be expressed by people; the degree to which scenes (communities) are present in various events; the degree to which people believe certain activities are central to an event; how centrality might be distributed across an event's activities; and similarities among events in terms of their content and their temporal structure. Thus, we provide novel insights into human event knowledge, and describe 18 predictions for future human studies.

Integrating High-Resolution Mass Spectral Data, Bioassays and Computational Models to Annotate Bioactives in Botanical Extracts: Case Study Analysis of C. asiatica Extract Associates Dicaffeoylquinic Acids with Protection against Amyloid-ß Toxicity.

Rapid screening of botanical extracts for the discovery of bioactive natural products was performed using a fractionation approach in conjunction with flow-injection high-resolution mass spectrometry for obtaining chemical fingerprints of each fraction, enabling the correlation of the relative abundance of molecular features (representing individual phytochemicals) with the read-outs of bioassays. We applied this strategy for discovering and identifying constituents of Centella asiatica (C. asiatica) that protect against Aß cytotoxicity in vitro. C. asiatica has been associated with improving mental health and cognitive function, with potential use in Alzheimer's disease. Human neuroblastoma MC65 cells were exposed to subfractions of an aqueous extract of C. asiatica to evaluate the protective benefit derived from these subfractions against amyloid ß-cytotoxicity. The % viability score of the cells exposed to each subfraction was used in conjunction with the intensity of the molecular features in two computational models, namely Elastic Net and selectivity ratio, to determine the relationship of the peak intensity of molecular features with % viability. Finally, the correlation of mass spectral features with MC65 protection and their abundance in different sub-fractions were visualized using GNPS molecular networking. Both computational methods unequivocally identified dicaffeoylquinic acids as providing strong protection against Aß-toxicity in MC65 cells, in agreement with the protective effects observed for these compounds in previous preclinical model studies.

Sulforaphane and Sulforaphane-Nitrile Metabolism in Humans Following Broccoli Sprout Consumption: Inter-individual Variation, Association with Gut Microbiome Composition, and Differential Bioactivity.

SCOPE: The glucosinolate glucoraphanin from broccoli is converted to sulforaphane (SFN) or sulforaphane-nitrile (SFN-NIT) by plant enzymes or the gut microbiome. Human feeding studies typically observe high inter-individual variation in absorption and excretion of SFN, however, the source of this variation is not fully known. To address this, a human feeding trial to comprehensively evaluate inter-individual variation in the absorption and excretion of all known SFN metabolites in urine, plasma, and stool, and tested the hypothesis that gut microbiome composition influences inter-individual variation in total SFN excretion has been conducted. METHODS AND RESULTS: Participants (n = 55) consumed a single serving of broccoli or alfalfa sprouts and plasma, stool, and total urine are collected over 72 h for quantification of SFN metabolites and gut microbiome profiling using 16S gene sequencing. SFN-NIT excretion is markedly slower than SFN excretion (72 h vs 24 h). Members of genus Bifidobacterium, Dorea, and Ruminococcus torques are positively associated with SFN metabolite excretion while members of genus Alistipes and Blautia has a negative association. CONCLUSION: This is the first report of SFN-NIT metabolite levels in human plasma, urine, and stool following consumption of broccoli sprouts. The results help explain factors driving inter-individual variation in SFN metabolism and are relevant for precision nutrition.

Investigating the Extent to which Distributional Semantic Models Capture a Broad Range of Semantic Relations.

Distributional semantic models (DSMs) are a primary method for distilling semantic information from corpora. However, a key question remains: What types of semantic relations among words do DSMs detect? Prior work typically has addressed this question using limited human data that are restricted to semantic similarity and/or general semantic relatedness. We tested eight DSMs that are popular in current cognitive and psycholinguistic research (positive pointwise mutual information; global vectors; and three variations each of Skip-gram and continuous bag of words (CBOW) using word, context, and mean embeddings) on a theoretically motivated, rich set of semantic relations involving words from multiple syntactic classes and spanning the abstract-concrete continuum (19 sets of ratings). We found that, overall, the DSMs are best at capturing overall semantic similarity and also can capture verb-noun thematic role relations and noun-noun event-based relations that play important roles in sentence comprehension. Interestingly, Skip-gram and CBOW performed the best in terms of capturing similarity, whereas GloVe dominated the thematic role and event-based relations. We discuss the theoretical and practical implications of our results, make recommendations for users of these models, and demonstrate significant differences in model performance on event-based relations.

Knowledge of the temporal structure of events in relation to autistic traits and social ability.

Event knowledge, a person's understanding of patterns of activities in the world, is crucial for everyday social interactions. Social communication differences are prominent in autism, which may be related to atypical event knowledge, such as atypical knowledge of the sequences of activities that comprise the temporal structure of events. Previous research has found that autistic individuals have atypical event knowledge, but research in this area is minimal, particularly regarding autistic individuals' knowledge of the temporal structure of events. Furthermore, no studies have investigated the link between event knowledge and autistic traits in a non-clinical sample. We investigated relationships between event knowledge and autistic traits in individuals from the general population with varying degrees of autistic traits. We predicted that atypical ordering of event activities is related to autistic traits, particularly social communication abilities, but not other clinical traits. In Study 1, atypical ordering of event activities correlated with social ability, but not with most measures of repetitive behaviours and restricted interests. In Study 2, the typicality of activity ordering varied by participants' social ability and the social nature of the events. Relationships were not found between event activity ordering and other clinical traits. These findings suggest a relationship between autistic traits, specifically social abilities, and knowledge of the temporal structure of events in a general population sample.

Role of Sea Surface Physical Processes in Mixed-Layer Temperature Changes During Summer Marine Heat Waves in the Chile-Peru Current System.

We identified anomalously warm sea surface temperature (SST) events during 1980-2019 near the major upwelling center at Punta Lavapié in the central Chile-Peru Current System, using the European Centre for Medium-Range Weather Forecasts reanalysis and focusing on time scales of 10 days to 6 months. Extreme warm SST anomalies on these time scales mostly occurred in the austral summer, December through February, and had spatial scales of 1000s of km. By compositing over the 37 most extreme warm events, we estimated terms in a heat budget for the ocean surface mixed layer at the times of strongest warming preceding the events. The net surface heat flux anomaly is too small to explain the anomalous warming, even when allowing for uncertainty in mixed-layer depth. The composite mean anomaly of wind stress, from satellite ocean vector wind swath data, during the 37 anomalous warming periods has a spatial pattern similar to the resulting warm SST anomalies, analogous to previous studies in the California Current System. The weakened surface wind stress suggests reduced entrainment of cold water from below the mixed layer. Within 100-200 km of the coast, the typical upwelling-favorable wind stress curl decreases, suggesting reduced upwelling of cold water. In a 1000-km area of anomalous warming offshore, the typical downwelling-favorable wind stress curl also decreases, implying reduced downward Ekman pumping, which would allow mixed-layer shoaling and amplify the effect of the positive climatological summertime net surface heat flux.

Multiple cryoprotectant toxicity model for vitrification solution optimization.

Vitrification is a promising cryopreservation technique for complex specimens such as tissues and organs. However, it is challenging to identify mixtures of cryoprotectants (CPAs) that prevent ice formation without exerting excessive toxicity. In this work, we developed a multi-CPA toxicity model that predicts the toxicity kinetics of mixtures containing five of the most common CPAs used in the field (glycerol, dimethyl sulfoxide (DMSO), propylene glycol, ethylene glycol, and formamide). The model accounts for specific toxicity, non-specific toxicity, and interactions between CPAs. The proposed model shows reasonable agreement with training data for single and binary CPA solutions, as well as ternary CPA solution validation data. Sloppy model analysis was used to examine the model parameters that were most important for predictions, providing clues about mechanisms of toxicity. This analysis revealed that the model terms for non-specific toxicity were particularly important, especially the non-specific toxicity of propylene glycol, as well as model terms for specific toxicity of formamide and interactions between formamide and glycerol. To demonstrate the potential for model-based design of vitrification methods, we paired the multi-CPA toxicity model with a published vitrification/devitrification model to identify vitrifiable CPA mixtures that are predicted to have minimal toxicity. The resulting optimized vitrification solution composition was a mixture of 7.4 molal glycerol, 1.4 molal DMSO, and 2.4 molal formamide. This demonstrates the potential for mathematical optimization of vitrification solution composition and sets the stage for future studies to optimize the complete vitrification process, including CPA mixture composition and CPA addition and removal methods.

Analysis of sloppiness in model simulations: Unveiling parameter uncertainty when mathematical models are fitted to data.

This work introduces a comprehensive approach to assess the sensitivity of model outputs to changes in parameter values, constrained by the combination of prior beliefs and data. This approach identifies stiff parameter combinations strongly affecting the quality of the model-data fit while simultaneously revealing which of these key parameter combinations are informed primarily by the data or are also substantively influenced by the priors. We focus on the very common context in complex systems where the amount and quality of data are low compared to the number of model parameters to be collectively estimated, and showcase the benefits of this technique for applications in biochemistry, ecology, and cardiac electrophysiology. We also show how stiff parameter combinations, once identified, uncover controlling mechanisms underlying the system being modeled and inform which of the model parameters need to be prioritized in future experiments for improved parameter inference from collective model-data fitting.

Computation-Assisted Identification of Bioactive Compounds in Botanical Extracts: A Case Study of Anti-Inflammatory Natural Products from Hops.

The slow pace of discovery of bioactive natural products can be attributed to the difficulty in rapidly identifying them in complex mixtures such as plant extracts. To overcome these hurdles, we explored the utility of two machine learning techniques, i.e., Elastic Net and Random Forests, for identifying the individual anti-inflammatory principle(s) of an extract of the inflorescences of the hops (Humulus lupulus) containing hundreds of natural products. We fractionated a hop extract by column chromatography to obtain 40 impure fractions, determined their anti-inflammatory activity using a macrophage-based bioassay that measures inhibition of iNOS-mediated formation of nitric oxide, and characterized the chemical composition of the fractions by flow-injection HRAM mass spectrometry and LC-MS/MS. Among the top 10 predictors of bioactivity were prenylated flavonoids and humulones. The top Random Forests predictor of bioactivity, xanthohumol, was tested in pure form in the same bioassay to validate the predicted result (IC50 7 µM). Other predictors of bioactivity were identified by spectral similarity with known hop natural products using the Global Natural Products Social Networking (GNPS) algorithm. Our machine learning approach demonstrated that individual bioactive natural products can be identified without the need for extensive and repetitive bioassay-guided fractionation of a plant extract.

Structured patterns of activity in pulse-coupled oscillator networks with varied connectivity.

Identifying coordinated activity within complex systems is essential to linking their structure and function. We study collective activity in networks of pulse-coupled oscillators that have variable network connectivity and integrate-and-fire dynamics. Starting from random initial conditions, we see the emergence of three broad classes of behaviors that differ in their collective spiking statistics. In the first class ("temporally-irregular"), all nodes have variable inter-spike intervals, and the resulting firing patterns are irregular. In the second ("temporally-regular"), the network generates a coherent, repeating pattern of activity in which all nodes fire with the same constant inter-spike interval. In the third ("chimeric"), subgroups of coherently-firing nodes coexist with temporally-irregular nodes. Chimera states have previously been observed in networks of oscillators; here, we find that the notions of temporally-regular and chimeric states encompass a much richer set of dynamical patterns than has yet been described. We also find that degree heterogeneity and connection density have a strong effect on the resulting state: in binomial random networks, high degree variance and intermediate connection density tend to produce temporally-irregular dynamics, while low degree variance and high connection density tend to produce temporally-regular dynamics. Chimera states arise with more frequency in networks with intermediate degree variance and either high or low connection densities. Finally, we demonstrate that a normalized compression distance, computed via the Lempel-Ziv complexity of nodal spike trains, can be used to distinguish these three classes of behavior even when the phase relationship between nodes is arbitrary.

Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts*.

Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described.[1] In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events: 1) ortho- deprotonation of aryl(Mes)iodonium salts to generate a substituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reported reaction conditions to generate arynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.

Prediction-Based Learning and Processing of Event Knowledge.

Knowledge of common events is central to many aspects of cognition. Intuitively, it seems as though events are linear chains of the activities of which they are comprised. In line with this intuition, a number of theories of the temporal structure of event knowledge have posited mental representations (data structures) consisting of linear chains of activities. Competing theories focus on the hierarchical nature of event knowledge, with representations comprising ordered scenes, and chains of activities within those scenes. We present evidence that the temporal structure of events typically is not well-defined, but it is much richer and more variable both within and across events than has usually been assumed. We also present evidence that prediction-based neural network models can learn these rich and variable event structures and produce behaviors that reflect human performance. We conclude that knowledge of the temporal structure of events in the human mind emerges as a consequence of prediction-based learning.

Monomerization of far-red fluorescent proteins.

Anthozoa-class red fluorescent proteins (RFPs) are frequently used as biological markers, with far-red (λem ∼ 600-700 nm) emitting variants sought for whole-animal imaging because biological tissues are more permeable to light in this range. A barrier to the use of naturally occurring RFP variants as molecular markers is that all are tetrameric, which is not ideal for cell biological applications. Efforts to engineer monomeric RFPs have typically produced dimmer and blue-shifted variants because the chromophore is sensitive to small structural perturbations. In fact, despite much effort, only four native RFPs have been successfully monomerized, leaving the majority of RFP biodiversity untapped in biomarker development. Here we report the generation of monomeric variants of HcRed and mCardinal, both far-red dimers, and describe a comprehensive methodology for the monomerization of red-shifted oligomeric RFPs. Among the resultant variants is mKelly1 (emission maximum, λem = 656 nm), which, along with the recently reported mGarnet2 [Matela G, et al. (2017) Chem Commun (Camb) 53:979-982], forms a class of bright, monomeric, far-red FPs.

Universal Features in Phonological Neighbor Networks.

Human speech perception involves transforming a countinuous acoustic signal into discrete linguistically meaningful units (phonemes) while simultaneously causing a listener to activate words that are similar to the spoken utterance and to each other. The Neighborhood Activation Model posits that phonological neighbors (two forms [words] that differ by one phoneme) compete significantly for recognition as a spoken word is heard. This definition of phonological similarity can be extended to an entire corpus of forms to produce a phonological neighbor network (PNN). We study PNNs for five languages: English, Spanish, French, Dutch, and German. Consistent with previous work, we find that the PNNs share a consistent set of topological features. Using an approach that generates random lexicons with increasing levels of phonological realism, we show that even random forms with minimal relationship to any real language, combined with only the empirical distribution of language-specific phonological form lengths, are sufficient to produce the topological properties observed in the real language PNNs. The resulting pseudo-PNNs are insensitive to the level of lingustic realism in the random lexicons but quite sensitive to the shape of the form length distribution. We therefore conclude that "universal" features seen across multiple languages are really string universals, not language universals, and arise primarily due to limitations in the kinds of networks generated by the one-step neighbor definition. Taken together, our results indicate that caution is warranted when linking the dynamics of human spoken word recognition to the topological properties of PNNs, and that the investigation of alternative similarity metrics for phonological forms should be a priority.

Perspective: Sloppiness and emergent theories in physics, biology, and beyond.

Large scale models of physical phenomena demand the development of new statistical and computational tools in order to be effective. Many such models are "sloppy," i.e., exhibit behavior controlled by a relatively small number of parameter combinations. We review an information theoretic framework for analyzing sloppy models. This formalism is based on the Fisher information matrix, which is interpreted as a Riemannian metric on a parameterized space of models. Distance in this space is a measure of how distinguishable two models are based on their predictions. Sloppy model manifolds are bounded with a hierarchy of widths and extrinsic curvatures. The manifold boundary approximation can extract the simple, hidden theory from complicated sloppy models. We attribute the success of simple effective models in physics as likewise emerging from complicated processes exhibiting a low effective dimensionality. We discuss the ramifications and consequences of sloppy models for biochemistry and science more generally. We suggest that the reason our complex world is understandable is due to the same fundamental reason: simple theories of macroscopic behavior are hidden inside complicated microscopic processes.

Structurally-constrained relationships between cognitive states in the human brain.

The anatomical connectivity of the human brain supports diverse patterns of correlated neural activity that are thought to underlie cognitive function. In a manner sensitive to underlying structural brain architecture, we examine the extent to which such patterns of correlated activity systematically vary across cognitive states. Anatomical white matter connectivity is compared with functional correlations in neural activity measured via blood oxygen level dependent (BOLD) signals. Functional connectivity is separately measured at rest, during an attention task, and during a memory task. We assess these structural and functional measures within previously-identified resting-state functional networks, denoted task-positive and task-negative networks, that have been independently shown to be strongly anticorrelated at rest but also involve regions of the brain that routinely increase and decrease in activity during task-driven processes. We find that the density of anatomical connections within and between task-positive and task-negative networks is differentially related to strong, task-dependent correlations in neural activity. The space mapped out by the observed structure-function relationships is used to define a quantitative measure of separation between resting, attention, and memory states. We find that the degree of separation between states is related to both general measures of behavioral performance and relative differences in task-specific measures of attention versus memory performance. These findings suggest that the observed separation between cognitive states reflects underlying organizational principles of human brain structure and function.

Reproducible paired sources from concurrent EEG-fMRI data using BICAR.

We introduce BICAR, an algorithm for obtaining robust, reproducible pairs of temporal and spatial components at the individual subject level from concurrent electroencephalographic and functional magnetic resonance imaging data. BICAR assigns a task-independent measure of component quality, reproducibility, to each paired source. Under BICAR a reproducibility cutoff is derived that can be used to objectively discard spuriously paired EEG-fMRI components. BICAR is run on minimally processed data: fMRI images undergo the standard preprocessing steps (alignment, motion correction, etc.) and EEG data, after scanner artifact removal, are simply bandpass filtered. This minimal processing allows the secondary scoring of the same set of BICAR components for a variety of different endpoint analyses; in this manuscript we propose a general method for scoring components for task event synchronization (evoked response analysis), but scoring using many other criteria, for example frequency content, are possible. BICAR is applied to five subjects performing a visual search task, and among the most reproducible components we find biologically relevant paired sources involved in visual processing, motor planning, execution, and attention.

Structural foundations of resting-state and task-based functional connectivity in the human brain.

Magnetic resonance imaging enables the noninvasive mapping of both anatomical white matter connectivity and dynamic patterns of neural activity in the human brain. We examine the relationship between the structural properties of white matter streamlines (structural connectivity) and the functional properties of correlations in neural activity (functional connectivity) within 84 healthy human subjects both at rest and during the performance of attention- and memory-demanding tasks. We show that structural properties, including the length, number, and spatial location of white matter streamlines, are indicative of and can be inferred from the strength of resting-state and task-based functional correlations between brain regions. These results, which are both representative of the entire set of subjects and consistently observed within individual subjects, uncover robust links between structural and functional connectivity in the human brain.

BICAR: a new algorithm for multiresolution spatiotemporal data fusion.

We introduce a method for spatiotemporal data fusion and demonstrate its performance on three constructed data sets: one entirely simulated, one with temporal speech signals and simulated spatial images, and another with recorded music time series and astronomical images defining the spatial patterns. Each case study is constructed to present specific challenges to test the method and demonstrate its capabilities. Our algorithm, BICAR (Bidirectional Independent Component Averaged Representation), is based on independent component analysis (ICA) and extracts pairs of temporal and spatial sources from two data matrices with arbitrarily different spatiotemporal resolution. We pair the temporal and spatial sources using a physical transfer function that connects the dynamics of the two. BICAR produces a hierarchy of sources ranked according to reproducibility; we show that sources which are more reproducible are more similar to true (known) sources. BICAR is robust to added noise, even in a "worst case" scenario where all physical sources are equally noisy. BICAR is also relatively robust to misspecification of the transfer function. BICAR holds promise as a useful data-driven assimilation method in neuroscience, earth science, astronomy, and other signal processing domains.

Insulation for daydreams: a role for tonic norepinephrine in the facilitation of internally guided thought.

Although consciousness can be brought to bear on both perceptual and internally generated information, little is known about how these different cognitive modes are coordinated. Here we show that between-participant variance in thoughts unrelated to the task being performed (known as task unrelated thought, TUT) is associated with longer response times (RT) when target presentation occurs during periods when baseline Pupil Diameter (PD) is increased. As behavioral interference due to high baseline PD can reflect increased tonic activity in the norepinephrine system (NE), these results might implicate high tonic NE activity in the facilitation of TUTs. Based on these findings, it is hypothesised that high tonic mode NE leads to a generalised de-amplification of task relevant information that prioritses internally generated thought and insulates it from the potentially disruptive events taking place in the external environment.