Spatiotemporal brain hierarchies of auditory memory recognition and predictive coding

bioRxiv

Psychedelics are serotonergic drugs that profoundly alter consciousness, yet their neural mechanisms are not fully understood. A popular theory, RElaxed Beliefs Under pSychedelics (REBUS), posits that psychedelics flatten the hierarchy of information flow in the brain. Here, we investigate hierarchy based on the imbalance between sending and receiving brain signals, as determined by directed functional connectivity. We measure directed functional hierarchy in a magnetoencephalography (MEG) dataset of 16 healthy human participants who were administered a psychedelic dose (75 micrograms, intravenous) of lysergic acid diethylamide (LSD) under four different conditions. LSD diminishes the asymmetry of directed connectivity when averaged across time. Additionally, we demonstrate that machine learning classifiers distinguish between LSD and placebo more accurately when trained on one of our hierarchy metrics than when trained on traditional measures of functional connectivity. Taken together, these results indicate that LSD weakens the hierarchy of directed connectivity in the brain by increasing the balance between senders and receivers of neural signals.

Neuron

“Supporting human flourishing” is a goal of governments and societies, yet the construct may appear hard to define. We discuss the emerging science of pleasure and flourishing, insights into the brain mechanisms of meaning making and thriving, and the potential for interdisciplinary studies to advance this promising scientific field.

Psychology of Music

Cognitive aging is characterized by the gradual decline of a number of abilities, such as attention, executive functioning, and memory. Research on memory aging has reported age-related deficits in short-term (STM), long-term (LTM), and working memory (WM) and linked these to structural and functional changes in the brain that occur with aging. However, only a few studies have drawn direct comparisons between these memory subsystems in the auditory domain. In this study, we assessed auditory STM, LTM, and WM abilities of young (under 25 years of age) and older (over 60 years of age) adults using musical and numerical tasks. In addition, we measured musical training history and tested its modulating effects on auditory memory performance. Overall, we found that older adults underperformed in specific memory tasks, such as STM related to discrimination of rhythmic sequences, LTM associated with …

bioRxiv

A fundamental topological principle is that the container always shapes the content. In neuroscience, this translates into how the brain anatomy shapes brain dynamics. From neuroanatomy, the topology of the mammalian brain can be approximated by local connectivity, accurately described by an exponential distance rule (EDR). The compact, folded geometry of the cortex is shaped by this local connectivity and the geometric harmonic modes can reconstruct much of the functional dynamics. However, this ignores the fundamental role of the rare long-range cortical connections, crucial for improving information processing in the mammalian brain, but not captured by local cortical folding and geometry. Here we show the superiority of harmonics mode combining rare long-range with EDR (EDR+LR) in capturing functional dynamics (specifically long-range functional connectivity and task-evoked brain activity) compared to geometry and EDR representations. Importantly, the orchestration of dynamics is carried out by a more efficient manifold made up of a low number of fundamental EDR+LR modes. Our results show the importance of long-range connectivity for capturing the complexity of functional brain activity through a low-dimensional manifold shaped by fundamental EDR+LR modes.

National Science Review

The human brain is a complex system, whose activity exhibits flexible and continuous reorganisation across space and time. The decomposition of whole-brain recordings into harmonic modes has revealed a repertoire of gradient-like activity patterns associated with distinct brain functions. However, the way these activity patterns are expressed over time with their changes in various brain states remains unclear. Here, we investigate healthy participants taking the serotonergic psychedelic N, N-Dimethyltryptamine (DMT) with the Harmonic Decomposition of Spacetime (HADES) framework that can characterise how different harmonic modes defined in space are expressed over time. HADES demonstrates significant decreases in contributions across most low-frequency harmonic modes in the DMT-induced brain state. When normalizing the contributions by condition (DMT and non-DMT), we detect a decrease …

Methods:We recruited first-time pregnant women at the end of the second trimester with a complaint of poor sleep. Participants in the music group received standard sleep hygiene advice and were instructed to listen to music daily at bedtime for four weeks. They could choose among six sleep playlists of different genres. Participants randomised to the sleep hygiene group received standard sleep hygiene alone. Primary outcomes were sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI) and insomnia severity measured with the Insomnia Severity Index.Results:Among the 98 participants receiving the online intervention 31 participants in the music group (62%) and 40 participants in the sleep hygiene group (80%) completed the post-measurements. Both groups experienced improved sleep quality during the intervention period (PSQI change-2.10, 95% CI-3.27 to-0.93, p< 0.001) with no significant difference between the groups. Similarly, insomnia symptoms were reduced (ISI change-3.42, 95% CI-5.02 to-1.83, p< 0.001) with no significant difference in the effect. There was a significant difference in the compliance between the groups, with 42% of participants in the music group not implementing the sleep hygiene advice.Discussion:Sleep quality and insomnia severity can be improved in pregnant women with relatively simple interventions like music listening and sleep hygiene advice. These results are in line with previous research, but larger trials are recommended to support introduction into clinical practice.

Stress

Maternal prenatal distress (PD), frequently defined as in utero prenatal stress exposure (PSE) to the developing fetus, influences the developing brain and numerous associations between PSE and brain structure have been described both in neonates and in older children. Previous studies addressing PSE-linked alterations in neonates’ brain activity have focused on connectivity analyses from predefined seed regions, but the effects of PSE at the level of distributed functional networks remains unclear. In this study, we investigated the impact of prenatal distress on the spatial and temporal properties of functional networks detected in functional MRI data from 20 naturally sleeping, term-born (age 25.85 ± 7.72 days, 11 males), healthy neonates. First, we performed group level independent component analysis (GICA) to evaluate an association between PD and the identified functional networks. Second, we …

Psychology of Music

Cognitive aging is characterized by the gradual decline of a number of abilities, such as attention, executive functioning, and memory. Research on memory aging has reported age-related deficits in short-term (STM), long-term (LTM), and working memory (WM) and linked these to structural and functional changes in the brain that occur with aging. However, only a few studies have drawn direct comparisons between these memory subsystems in the auditory domain. In this study, we assessed auditory STM, LTM, and WM abilities of young (under 25 years of age) and older (over 60 years of age) adults using musical and numerical tasks. In addition, we measured musical training history and tested its modulating effects on auditory memory performance. Overall, we found that older adults underperformed in specific memory tasks, such as STM related to discrimination of rhythmic sequences, LTM associated with …

bioRxiv

The brain is able to sustain many different states as shown by the daily natural transitions between wakefulness and sleep. Yet, the underlying complex dynamics of these brain states are essentially in non-equilibrium. Here, we develop a thermodynamical formalism based on the off-equilibrium extension of the fluctuation-dissipation theorem (FDT) together with a whole-brain model. This allows us to investigate the non-equilibrium dynamics of different brain states and more specifically to apply this formalism to wakefulness and deep sleep brain states. We show that the off-equilibrium thermodynamical signatures of brain states are significantly different in terms of the overall level of differential and integral violation of FDT. Furthermore, the framework allows for a detailed understanding of how different brain regions and networks are contributing to the off-equilibrium signatures in different brain states. Overall, this framework shows great promise for characterising and differentiating any brain state in health and disease.

bioRxiv

The transition towards the brain state induced by psychedelic drugs is frequently neglected in favor of a static description of their acute effects. We used a time-dependent whole-brain model to reproduce large-scale brain dynamics measured with fMRI from 15 volunteers under 20 mg of bolus intravenous N,N-Dimethyltryptamine (DMT), a short-lasting psychedelic. To capture the transient effects of DMT, we parametrized the proximity to a global bifurcation using a pharmacokinetic equation and adopted the empirical functional connectivity dynamics (FCD) as optimization target. Post-administration, DMT rapidly destabilized brain dynamics, peaking after ≈5 minutes, followed by a recovery to baseline. Simulated perturbations revealed a transient of heightened reactivity, where stimulation maximally impacted the FCD. Local reactivity concentrated in fronto-parietal regions and visual cortices, and correlated with serotonin 5HT2a receptor density, the primary target of psychedelics. These advances suggest a mechanism to explain key features of the psychedelic state, such as increased brain complexity, diversity, and flexibility. Our model also predicts that the temporal evolution of these features aligns with pharmacokinetics. These results contribute to understanding how psychedelics introduce a transient where minimal perturbations can achieve a maximal effect, shedding light on how short psychedelic episodes may extend an overarching influence over time.

Network Neuroscience

It has been previously shown that traumatic brain injury (TBI) is associated with reductions in metastability in large-scale networks in resting-state fMRI (rsfMRI). However, little is known about how TBI affects the local level of synchronization and how this evolves during the recovery trajectory. Here, we applied a novel turbulent dynamics framework to investigate whole-brain dynamics using an rsfMRI dataset from a cohort of moderate to severe TBI patients and healthy controls (HCs). We first examined how several measures related to turbulent dynamics differ between HCs and TBI patients at 3, 6, and 12 months post-injury. We found a significant reduction in these empirical measures after TBI, with the largest change at 6 months post-injury. Next, we built a Hopf whole-brain model with coupled oscillators and conducted in silico perturbations to investigate the mechanistic principles underlying the reduced …

The brain is hierarchically organised across many levels, from the underlying anatomical connectivity to the resulting functional dynamics, which supports the necessary orchestration to ensure sufficient cognitive and behavioural flexibility. Here, we show how two emerging frameworks have been used to determine the brain’s functional hierarchy and its reconfiguration in different cognitive tasks. One study used direct estimation of the information flow across a whole experiment to reveal the common top hierarchical regions orchestrating brain dynamics across rest and seven cognitive tasks. Another study used complementary, indirect spatiotemporal measures defining hierarchy as the asymmetry in the directionality of information flow to identify a set of regions within the prefrontal cortex (PFC) that serve as the common, unifying drivers of brain dynamics during tasks. Overall, these studies are beginning to reveal …

Biomedical Signal Processing and Control

A popular approach for modeling brain activity in MEG and EEG is based on a small set of current dipoles, where each dipole represents the combined activation of a local area of the brain. Here, we address the problem of multiple dipole localization with a novel solution called Alternating Projection (AP). The AP solution is based on minimizing the least-squares (LS) criterion by transforming the multi-dimensional optimization required for direct LS solution, to a sequential and iterative solution in which one source at a time is localized, while keeping the other sources fixed. Results from simulated, phantom, and human MEG data demonstrated the high accuracy of the AP method, with superior localization results than popular scanning methods from the multiple-signal classification (MUSIC) and beamformer families. In addition, the AP method was more robust to forward model errors resulting from head rotations …

bioRxiv

Deterioration in the peripheral and central auditory systems is common in older adults and often leads to hearing and speech comprehension difficulties. Even when hearing remains intact, electrophysiological data of older adults frequently exhibit altered neural responses across the auditory pathway, reflected in variability in the phase alignment of neural activity to speech sound onsets. However, it remains unclear whether speech processing challenges in older adults stem from more fundamental deficits in auditory and timing processing. Here, we investigated the efficiency of aging individuals in encoding temporal regularities in acoustic sequences and their ability to predict future events. We recorded EEG in older and young individuals listening to simple isochronous tone sequences. A comprehensive analysis pipeline evaluated the amplitude, latency, and variability of event-related responses (ERPs) to each tone onset along the auditory sequences. Spectral parametrization and Inter-Trial Phase Coherence (ITPC) analyses assessed how participants encoded the temporal regularity in the acoustic environment. Our findings indicate that aging individuals exhibit altered temporal processing and reduced capacity to generate and utilize temporal predictions to time-lock and adaptively suppress neural responses to predictable and repeated tones in auditory sequences. Given that deteriorations in these basic timing capacities may affect other higher-order cognitive processes (e.g., attention, perception, and action), our results underscore the need for future research examining the link between timing abilities and general cognition across the …

Music and psychedelics have been intertwined throughout the existence of Homo sapiens, from the early shamanic rituals of the Americas and Africa to the modern use of psychedelic‐assisted therapy for a variety of mental health conditions. Across such settings, music has been highly prized for its ability to guide the psychedelic experience. Here, we examine the interplay between music and psychedelics, starting by describing their association with the brain's functional hierarchy that is relied upon for music perception and its psychedelic‐induced manipulation, as well as an exploration of the limited research on their mechanistic neural overlap. We explore music's role in Western psychedelic therapy and the use of music in indigenous psychedelic rituals, with a specific focus on ayahuasca and the Santo Daime Church. Furthermore, we explore work relating to the evolution and onset of music and psychedelic …

Despite significant improvements in our understanding of brain diseases, many barriers remain. Cognitive neuroscience faces four major challenges: complex structure–function associations; disease phenotype heterogeneity; the lack of transdiagnostic models; and oversimplified cognitive approaches restricted to the laboratory. Here, we propose a synergetics framework that can help to perform the necessary dimensionality reduction of complex interactions between the brain, body, and environment. The key solutions include low-dimensional spatiotemporal hierarchies for brain-structure associations, whole-brain modeling to handle phenotype diversity, model integration of shared transdiagnostic pathophysiological pathways, and naturalistic frameworks balancing experimental control and ecological validity. Creating whole-brain models with reduced manifolds combined with ecological measures can improve …

The Neuroscientist

Scientific theories on the functioning and dysfunction of the human brain require an understanding of its development—before and after birth and through maturation to adulthood—and its evolution. Here we bring together several accounts of human brain evolution by focusing on the central role of oxygen and brain metabolism. We argue that evolutionary expansion of human transmodal association cortices exceeded the capacity of oxygen delivery by the vascular system, which led these brain tissues to rely on nonoxidative glycolysis for additional energy supply. We draw a link between the resulting lower oxygen tension and its effect on cytoarchitecture, which we posit as a key driver of genetic developmental programs for the human brain—favoring lower intracortical myelination and the presence of biosynthetic materials for synapse turnover. Across biological and temporal scales, this protracted capacity for …

To not only survive, but also thrive, the brain must efficiently orchestrate distributed computation across space and time. This requires hierarchical organisation facilitating fast information transfer and processing at the lowest possible metabolic cost. Quantifying brain hierarchy is difficult but can be estimated from the asymmetry of information flow. Thermodynamics has successfully characterised hierarchy in many other complex systems. Here, we propose the ‘Thermodynamics of Mind' framework as a natural way to quantify hierarchical brain orchestration and its underlying mechanisms. This has already provided novel insights into the orchestration of hierarchy in brain states including movie watching, where the hierarchy of the brain is flatter than during rest. Overall, this framework holds great promise for revealing the orchestration of cognition.

Brain Communications

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression—to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a healthy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions …

ACS Chemical Neuroscience

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes, such as personality changes. These findings are particularly intriguing, given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g., from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience by studying participants under the effects of lysergic acid diethylamide (LSD) or placebo, either with gross state changes (eyes closed vs open) or different stimuli (no stimulus vs music vs video). Results …

bioRxiv

Hemispheric lateralization is linked to potential cognitive advantages. It is considered a driving force behind the generation of human intelligence. However, establishing quantitative links between the degree of lateralization and intelligence in humans remains elusive. In this study, we propose a novel framework that utilizes the hyperaligned multidimensional representation space derived from hemispheric functional gradients to compute between-hemisphere distances within this space. Our analysis improves the functional alignment between the hemispheres, making it possible to delineate aspects of human brain lateralization that relate to individual differences in cognitive ability more precisely. Applying this framework to the Human Connectome Project (HCP) large cohort (N = 777) identified the highest functional divergence within the frontoparietal control network across the two hemispheres. We found that spatial variability in between-hemisphere functional divergence aligned with the lateralized response patterns across multiple tasks, cortical myelination and evolutionary expansion. Furthermore, both global divergence between the cerebral hemispheres and regional divergence within the multiple demand network were positively associated with fluid composite score and partially mediated the influence of brain size on individual differences in fluid intelligence. Together, these findings illuminate the profound significance of brain lateralization as a fundamental organizational principle of the human brain, providing direct evidence that hemispheric lateralization supports human fluid intelligence.

bioRxiv

The rate of force development (RFD), is seen as a determining characteristic in fast actions present in basketball. However, we observed different relationships between RFD and maximum strength, as well as different relationships between RFD and neuromuscular variables according to the evaluated population. The aim of the present study is to evaluate the degree of determination of maximum strength (Tmax) and neuromuscular recruitment variables (RMS), Absolute Energy (AE) and the motor units firing frequencies (MPF) in rate of force development (RFD) for basketball athletes. Nine basketball athletes from the same team (mean ± SD; age: 20.8 ± 2.08 years; body mass: 84.33 ± 8.80kg; height: 1.86 ± 0.095 meters; practice time: 11.67 ± 1.65 years) were evaluated through maximum isometric contraction with highest value of maximum force among 3 attempts. The RFD were evaluated and correlated with the RMS and AE values and the MPF values of the electromyographic signal at instants 0-50; 50-100, 100-150 and 150-200 milliseconds. The results show a reduction in RFD and MPF over the evaluated time windows and also a correlation between MPF and TDF in the 0-50ms time window (R2 0.67 p<0.05). The results show no relationship between RFD and RMS and AE, in addition to these variables not showing significant reductions in the evaluated time windows. The levels of RFD show to be more related to the firing frequency of the motor units than the maximum force and the level of recruitment of the motor units.

bioRxiv

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes. However, the biological relationships between the identified COPD susceptibility genes are largely unknown. Genes associated with a complex disease are often in close network proximity, i.e. their protein products often interact directly with each other and/or similar proteins. In this study, we use affinity purification mass spectrometry (AP-MS) to identify protein interactions with HHIP, a well-established COPD GWAS gene which is part of the sonic hedgehog pathway, in two disease-relevant lung cell lines (IMR90 and 16HBE). To better understand the network neighborhood of HHIP, its proximity to the protein products of other COPD GWAS genes, and its functional role in COPD pathogenesis, we create HUBRIS, a protein-protein interaction network compiled from 8 publicly available databases. We identified both common and cell type-specific protein-protein interactors of HHIP. We find that our newly identified interactions shorten the network distance between HHIP and the protein products of several COPD GWAS genes, including DSP, MFAP2, TET2, and FBLN5. These new shorter paths include proteins that are encoded by genes involved in extracellular matrix and tissue organization. We found and validated interactions to proteins that …

BioRxiv

Education sculpts specialized neural circuits for skills like reading that are critical to success in modern society but were not anticipated by the selective pressures of evolution. Does the emergence of brain regions that selectively process novel visual stimuli like words occur at the expense of cortical representations of other stimulus categories like faces and objects? To answer this question we designed a randomized controlled trial where pre-literate children (five years of age) were randomly assigned to intervention programs that either taught reading skills (Letter Intervention) or oral language comprehension skills (Language Intervention). Magnetoencephalography (MEG) data collected before and after the interventions revealed that being assigned to the Letter versus Language Intervention induced different patterns of changes in category selective responses in high-level visual cortex. We found moderate support for the notion that words compete with other objects for cortical territory as children become attuned to this new class of visual stimuli. How these changes play out over a longer timescale is still unclear but, based on these data, we can surmise that high-level visual cortex undergoes rapid changes as children enter school and begin establishing new skills like literacy.

bioRxiv

The multi-enzyme pyruvate dehydrogenase complex (PDC) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A and is essential for cellular energy metabolism. Although individual components have been characterized, the structure of intact PDC remains unclear, hampering our understanding of its composition and multi-step catalytic reactions. Here, we report the in-situ architecture of intact PDC within mammalian mitochondria by cryo-electron tomography. The organization of peripheral E1 and E3 multimers varies substantially among PDCs. We discovered 1-46 E1 heterotetramers surrounding each PDC core, and up to 12 E3 dimers locating primarily along the pentagonal openings. Furthermore, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, implicating the mechanism of substrate channeling. Our findings reveal the intrinsic dynamics of PDC peripheral compositions, suggesting an additional model in which the number of assembled E1 heterotetramer, E3 dimer, and functional LDs of PDC may be regulated to further control its catalytic activity.

bioRxiv

Collagen cross-links created by the lysyl oxidase and lysyl hydroxylase families of enzymes are a significant contributing factor to the biomechanical strength and rigidity of tissues, which in turn influence cell signaling and ultimately cell phenotype. In the clinic, the proteolytically liberated N-terminal cross-linked peptide of collagen I (NTX) is used as a biomarker of bone and connective tissue turnover, which is altered in several disease processes. Despite the clinical utility of these collagen breakdown products, the majority of the cross-linked peptide species have not been identified in proteomic datasets. Here we evaluate several parameters for the preparation and identification of these peptides from the collagen I-rich Achilles tendon. Our refined approach involving chemical digestion for protein solubilization coupled with mass spectrometry allows for the identification of the NTX cross-links in a range of modification states. Based on the specificity of the enzymatic cross-linking reaction we utilized follow-up variable modification searches to facilitate identification with a wider range of analytical workflows. We then applied a spectral library approach to identify differences in collagen cross-links in bovine pulmonary hypertension. The presented method offers unique opportunities to understand extracellular matrix remodeling events in development, aging, wound healing, and fibrotic disease that modulate collagen architecture through lysyl-hydroxylase and lysyl-oxidase enzymes.

bioRxiv

The secreted mucins MUC5AC and MUC5B play critical defensive roles in airway pathogen entrapment and mucociliary clearance by encoding large glycoproteins with variable number tandem repeats (VNTRs). These polymorphic and degenerate protein coding VNTRs make the loci difficult to investigate with short reads. We characterize the structural diversity of MUC5AC and MUC5B by long-read sequencing and assembly of 206 human and 20 nonhuman primate (NHP) haplotypes. We find that human MUC5B is largely invariant (5761-5762aa); however, seven haplotypes have expanded VNTRs (6291-7019aa). In contrast, 30 allelic variants of MUC5AC encode 16 distinct proteins (5249-6325aa) with cysteine-rich domain and VNTR copy number variation. We grouped MUC5AC alleles into three phylogenetic clades: H1 (46%, ~5654aa), H2 (33%, ~5742aa), and H3 (7%, ~6325aa). The two most common human MUC5AC variants are smaller than NHP gene models, suggesting a reduction in protein length during recent human evolution. Linkage disequilibrium (LD) and Tajima's D analyses reveal that East Asians carry exceptionally large MUC5AC LD blocks with an excess of rare variation (p<0.05). To validate this result, we used Locityper for genotyping MUC5AC haplogroups in 2,600 unrelated samples from the 1000 Genomes Project. We observed signatures of positive selection in H1 and H2 among East Asians and a depletion of the likely ancestral haplogroup (H3). In Africans and Europeans, H3 alleles show an excess of common variation and deviate from Hardy-Weinberg equilibrium, consistent with heterozygote advantage and …

bioRxiv

Dinoflagellates are eukaryotic algae with large genomes that rely heavily on post-transcriptional control for the regulation of gene expression. Dinoflagellate mRNAs are trans-spliced with a conserved 22 base spliced leader sequence (SL) that includes the 5′-cap to which the translation initiation factor 4E (eIF4E) binds to facilitate ribosomal recruitment. The binding of an eIF4E to a specific mRNA SL is a potential regulatory point in controlling dinoflagellate gene expression. Here we show that m7G is the 5′-cap base of the 65 bp SL RNA with additional methylations throughout the SL to give a mixture of novel multi-methylated sequences in Amphidinium carterae (CCMP1314). There is also sequence variability in all four bases seen at the first position followed by a variety of polymorphisms. Three novel clades of eIF4E have been shown in dinoflagellates that are distinct from the three metazoan classes of eIF4E. Members of each clade differ significantly from each other, but all bear the distinctive features of a cap-binding protein. Here we show large differences in expression and activity in six of the eight eIF4E family members from A. carterae. Transcripts of each are expressed throughout the diel cycle, but only eIF4E-1 family members and eIF4E-2a show discernable expression at the level of protein. Recombinant eIF4E-1 family members and eIF4E-3a, but not eIF4E-2a, are able to bind to m7GTP substrates in vitro. Overall, eIF4E-1a emerges with characteristics consistent with the role of a prototypical initiation factor; eIF4E-1a is the most conserved and highly expressed eIF4E family member, has the highest affinity for m7GpppG and m7 …

bioRxiv

Glycogen synthase kinase-3 (GSK-3) plays important roles in the pathogenesis of cardiovascular, metabolic, neurological disorders and cancer. Isoform-specific loss of either GSK-3α or GSK-β often provides cytoprotective effects under such clinical conditions. However, available synthetic small molecule inhibitors are relatively non-specific, and their chronic use may lead to adverse effects. Therefore, screening for natural compound inhibitors to identify the isoform-specific inhibitors may provide improved clinical utility. Here, we screened 70 natural compounds to identify novel natural GSK-3 inhibitors employing comprehensive in silico and biochemical approaches. Molecular docking and pharmacokinetics analysis identified two natural compounds Psoralidin and Rosmarinic acid as potential GSK-3 inhibitors. Specifically, Psoralidin and Rosmarinic acid exhibited the highest binding affinities for GSK-3α and GSK-3β, respectively. Consistent with in silico findings, the kinase assay-driven IC50 revealed superior inhibitory effects of Psoralidin against GSK-3α (IC50=2.26 μM) vs. GSK-3β (IC50=4.23 μM) while Rosmarinic acid was found to be more potent against GSK-3β (IC50=2.24 μM) than GSK-3α (IC50=5.14 μM). Taken together, these studies show that the identified natural compounds may serve as GSK-3 inhibitors with Psoralidin serving as a better inhibitor for GSK-3α and Rosmarinic for GSK-3β isoform, respectively. Further characterization employing in vitro and preclinical models will be required to test the utility of these compounds as GSK-3 inhibitors for cardiometabolic and neurological disorders and cancers.

bioRxiv

Bats are remarkably long-lived for their size with many species living more than 20-40 years, suggesting that they possess efficient anti-aging and anti-cancer defenses. Here we investigated requirements for malignant transformation in primary bat fibroblasts in four bat species - little brown bat (Myotis lucifugus), big brown bat (Eptesicus fuscus), cave nectar bat (Eonycteris spelaea) and Jamaican fruit bat (Artibeus jamaicensis), spanning the bat evolutionary tree and including the longest-lived genera. We show that bat fibroblasts do not undergo replicative senescence and express active telomerase. Bat cells displayed attenuated stress induced premature senescence with a dampened secretory phenotype. Unexpectedly, we discovered that bat cells could be readily transformed by only two oncogenic perturbations or hits: inactivation of either p53 or pRb and activation of oncogenic RASV12. This was surprising …

bioRxiv

Over the past century, multichannel fluorescence imaging has been pivotal in myriad scientific breakthroughs by enabling the spatial visualization of proteins within a biological sample. With the shift to digital methods and visualization software, experts can now flexibly pseudocolor and combine image channels, each corresponding to a different protein, to explore their spatial relationships. We thus propose psudo, an interactive system that allows users to create optimal color palettes for multichannel spatial data. In psudo, a novel optimization method generates palettes that maximize the perceptual differences between channels while mitigating confusing color blending in overlapping channels. We integrate this method into a system that allows users to explore multi-channel image data and compare and evaluate color palettes for their data. An interactive lensing approach provides on-demand feedback on channel overlap and a color confusion metric while giving context to the underlying channel values. Color palettes can be applied globally or, using the lens, to local regions of interest. We evaluate our palette optimization approach using three graphical perception tasks in a crowdsourced user study with 150 participants, showing that users are more accurate at discerning and comparing the underlying data using our approach. Additionally, we showcase psudo in a case study exploring the complex immune responses in cancer tissue data with a biologist.

bioRxiv

Sensory systems utilise stimulus-driven attention to survey the environment for significant features. The question arises: are the cortical networks that influence stimulus-driven attention supramodal or specific to each sensory modality? Here we employed a hierarchical target detection task (n=30), examining cortical responses linked to the detection of salient targets in the somatosensory and auditory modality. In a temporal decoding analysis, we reveal a transient early supramodal process activated by target detection. We also demonstrate that both common and unique modulations of salience-related cortical responses to somatosensory and auditory targets involve modality-specific and frontal regions using Parametric Empirical Bayes. Specifically, we found that the inferior frontal gyri share information across both sensory modalities, while recurrent information transfer between ipsilateral inferior frontal gyri and …

bioRxiv

Early diagnosis remains of pivotal importance in reducing patient morbidity and mortality in cancer. To this end, liquid biopsy is emerging as a tool to perform broad cancer screenings. Small extracellular vesicles (sEVs) found in bodily fluids can serve as important cancer biomarkers in these screenings. Our group has recently developed a nanopipette dielectrophoretic approach to extract sEVs from blood. Herein, we demonstrate the feasibility to integrate this approach with surface-enhanced Raman scattering (SERS) analysis. SERS can be used to characterized extracted exosomes through their vibrational fingerprint that changes depending on the origin of sEVs. While these changes are not easily identified in spectra, they can be modeled with machine learning (ML) approaches. Common ML approaches in the field of spectral analysis use dimensionality reduction method that often function as a black box. To avoid this pitfall, we used Shapley additive explanations (SHAP) is a type of explainable AI (XAI) that bridges ML models and human comprehension by calculating the specific contribution of individual features to a model predictions, directly correlating model/decisions with the original data. Using these approaches we demonstrated a proof-of-concept model predictive of cancer from isolated exosomes, integrating nanopipette dielectrophoresis and SERS. This work demonstrates the use of explainable AI to perform diagnostic analysis on complex SERS data of clinical samples, while reporting interpretable biochemical information.

bioRxiv

The ability to differentiate between different facial expressions is an important part of human social and emotional development that begins in infancy. Studies have shown that within the first year of life, infants develop a distinctive attentional bias towards fearful facial expressions. Investigations into the neural basis for this bias have highlighted the significance of the amygdala. The amygdala's role in directing attention towards fearful facial expressions underscores its importance in early emotional development, significantly influencing how infants interpret and react to facial expressions. To date, no studies have been conducted to investigate the associations between the amygdala microstructure and infants' perception of emotional faces. This study aimed to elucidate this relationship while also investigating whether this association is sex specific. We measured the amygdala microstructural properties using diffusion tensor imaging mean diffusivity (MD) measurements in 40 healthy infants aged 2 to 5 weeks. Eye tracking was used to assess attention disengagement from fearful vs. non-fearful (happy and neutral) facial expressions as well as scrambled non-face control picture at 8 months. Generally, infants were age-typically less likely to disengage from fearful faces than from non-fearful faces towards salient distractors. A significant negative association was observed between the right amygdala MD measures and disengagement probability from fearful faces in the overall sample. Moreover, there was a positive association between the bilateral amygdala MD measures and the disengagement probability from scrambled non-face control …

bioRxiv

The accurate processing of neonatal and infant brain MRI data is crucially important for developmental neuroscience, but presents challenges that child and adult data do not. Tissue segmentation and image coregistration accuracy can be improved by optimizing template images and / or related segmentation procedures. Here, we describe the construction of the FinnBrain Neonate (FBN-125) template; a multi-contrast template with T1- and T2-weighted as well as diffusion tensor imaging derived fractional anisotropy and mean diffusivity images. The template is symmetric and aligned to the Talairach-like MNI 152 template and has high spatial resolution (0.5 mm3). In addition, we provide atlas labels, constructed from manual segmentations, for cortical grey matter, white matter, cerebrospinal fluid, brainstem, and cerebellum as well as the bilateral hippocampi, amygdalae, caudate nuclei, putamina, globi pallidi, and thalami. We provide this multi-contrast template along with the labelled atlases for the use of the neuroscience community in the hope that it will prove useful in advancing developmental neuroscience, for example, by helping to achieve reliable means for spatial normalization and measures of neonate brain structure via automated computational methods. Additionally, we provide standard co-registration files that will enable investigators to reliably transform their statistical maps to the adult MNI space, which has the potential to improve the consistency and comparability of neonatal studies or the use of adult MNI space atlases in neonatal neuroimaging.

bioRxiv

The global biodiversity loss resulting from anthropogenic land-use activities is a pressing concern, requiring precise assessments of impacts at large spatial extents. Existing models primarily focus on quantifying impacts on species richness and abundance, often overlooking the ecological relevance of species traits and their contributions to ecosystem functioning. To address this gap, we conducted a comprehensive analysis throughout Europe, investigating the effect of human land use on plant functional diversity across different land-use classes and bioregions.Integrating extensive databases of vegetation plots with spatial data on land use and land cover, we paired plots from areas actively used and modified by humans with plots from natural habitats under similar environmental conditions. Employing species occurrences and traits from the same databases, we computed three functional diversity metrics (functional richness, evenness, and divergence) per each plot. We assessed the impact of land use by comparing the functional diversity values in the paired.Our findings revealed that land used and modified by humans generally exhibits lower functional richness and divergence, but higher functional evenness compared to natural habitats, across most land-use classes and bioregions. Particularly noteworthy was the impact on functional richness in croplands and urban areas, identified as having the lowest functional richness values in multiple bioregions. Furthermore, the impact of human land use on plant communities displayed less variation among land-use classes than among bioregions.Our study emphasizes how land use impacts …

bioRxiv

During continuous speech perception, patterns of endogenous neural activity become time-locked to acoustic stimulus features, such as the speech amplitude envelope. This speech-brain coupling can be decoded using non-invasive brain imaging techniques, including electroencephalography (EEG). Methods like these may provide clinical use as an objective measure of stimulus encoding by the brain, for example, in the case of cochlear implant (CI) listening. Yet, the CI-transmitted speech signal is severely spectrally degraded, rendering its amenability to neural decoding unknown. Furthermore, interplay between acoustic and linguistic factors may lead to top-down modulation of perception, thereby challenging potential audiological applications. We assess neural decoding of the speech envelope under spectral degradation with EEG in acoustically hearing listeners (n = 38; 18-35 years old) using vocoded speech. Additionally, we dissociate sensory from higher-order processing by employing intelligible (English) and non-intelligible (Dutch) stimuli. Subject-specific and group decoders were trained to reconstruct the speech envelope from held-out EEG, with decoder significance determined via random permutation testing. Whereas speech envelope reconstruction did not vary by acoustic clarity, intelligible speech was associated with better decoding accuracy in general. Results were similar across subject-specific and group analyses, with less consistent effects of spectral degradation in group decoding. Permutation tests revealed possible differences in decoder statistical significance by experimental condition. In general, while robust …

bioRxiv

The advent of rapid whole genome sequencing has created new opportunities for computational prediction of antimicrobial resistance (AMR) phenotypes directly from genomic data. Both rule-based and machine learning (ML) approaches have been explored for this task, but systematic benchmarking to evaluate the performance of these methods is still needed. Here, we evaluated four state-of-the-art ML methods (Kover, PhenotypeSeeker, Seq2Geno2Pheno, Aytan-Aktug), a ML baseline and the rule-based ResFinder, by training and testing each of them across 78 species-antibiotic datasets, using a rigorous benchmarking workflow that integrates three evaluation approaches, each paired with three distinct sample splitting methods. Our analysis revealed considerable performance variation across techniques and datasets. While ML methods generally excelled for closely related strains, ResFinder better handled divergent genomes. Overall, Kover most frequently ranked top among ML approaches, followed by PhenotypeSeeker and Seq2Geno2Pheno. AMR phenotypes for antibiotic classes like macrolides, and sulfonamides, were predicted with the highest accuracies. Prediction quality varied substantially across species-antibiotic combinations particularly for beta-lactams; across species, resistance phenotyping of the beta-lactams compound, aztreonam, amox-clav, cefoxitin, ceftazidime, and piperacillin/tazobactam, together with tetracyclines demonstrated more variable performances than the other benchmarked antibiotics. By organism, C. jejuni and E. faecium phenotypes were more robustly predicted than Escherichia coli, Staphylococcus …

bioRxiv

The rapid emergence of artemisinin resistance (ART-R) poses a challenge to global malaria control efforts. ART potency is triggered by ferrous iron- and/or heme-mediated cleavage of the endoperoxide bond to generate reactive heme-ART alkoxy radicals and covalent heme-ART adducts that alkylate parasite targets or inhibit the detoxification of heme into β-hematin crystals; both of which lead to parasite death. Mutations in the P. falciparum Kelch-containing protein Kelch13 (PfKekch13) confer clinical ART-R, in which the resistant parasites exhibit impaired hemoglobin uptake, reduced heme yield, and thus decreased ART activation. However, a more direct involvement of PfKelch13 in heme-mediated ART activation has not been reported. Here, we show that recombinant, purified PfKelch13 wild-type (WT) protein displays measurable binding affinity for both iron and heme, the main effectors for ART activation. Comparative biochemical analyses further indicate weaker heme-binding affinities in the two Southeast Asian ART-R PfKelch13 mutants C580Y and R539T compared to the ART-sensitive WT and A578S mutant proteins, which ultimately translates into reduced yield of heme-ART derivatives. In conclusion, this study provides the first evidence for regulated ART activation via the heme-binding propensity of PfKelch13, which may contribute towards modulating the level of ART-R in malaria parasites with PfKelch13 mutations.

bioRxiv

A major trait of Eukarya is the independent evolution of complex multicellular lineages of animals and plants with specialized cell types organized in tissues, organs and systems. The number of cell types (NCT) has been commonly adopted as a proxy in comparative studies investigating the genomic evolution of biological complexity. Although expansions of homologous genes playing roles in extracellular processes, signal transduction pathways, and the immune system have been reported as associated with NCT variation in metazoans, the evolutionary patterns coordinating the genomic evolution of multicellularity throughout Eukarya remain poorly understood. We used Gene Ontology (GO) as a genome annotation scaffold to represent biological functions shared by genes regardless of their homology relationships to search for molecular functional convergences associated with NCT. For that we integrated phenotypic, genomic, annotation and phylogenetic data to build phylogeny-aware models and searched for expansions of homologous regions and of GO terms associated with NCT values across 49 eukaryotic species, including complex multicellular plants and metazoans. Virtually all homologous regions associated with NCT are metazoan- and vertebrate-specific expansions of paralogs with key roles in developmental pathways. The functional annotation, in contrast, detected previously unknown biological themes coded by non-homologous genes independently expanded in multicellular plants and metazoans, such as system and anatomical development, immunity, regulatory mechanisms of embryogenesis, response to external …