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Ikegami, T.

Publications and source records attributed to Ikegami, T..

11 recordsLinked to original sources

Movement Directions Aligned in Joint Space Are Not Aligned in Muscle Space

Learned movements are thought to be represented in both extrinsic and intrinsic coordinate systems. Intrinsic representations have traditionally been characterized using joint-based coordinates, although the relationship between joint movements and muscle activation depends strongly on limb configuration. Consequently, movement directions aligned in joint space may not be aligned in muscle space, but the implications of this mismatch for motor learning have remained largely unexplored. We addressed this question by combining electromyographic (EMG) analysis with a visuomotor adaptation experiment. In Experiment 1, participants performed planar reaching movements in two workspaces separated by a 45{degrees} shoulder rotation while EMG activity was recorded from nine upper-limb muscles. Muscle-pattern similarity analysis revealed that movement directions aligned in joint space were not always aligned in muscle space and that the degree of misalignment varied systematically across movement directions. Based on these results, we predicted that visuomotor adaptation to clockwise (CW) and counterclockwise (CCW) rotations would produce different patterns of motor generalization, contrary to the prediction of conventional joint-space accounts. Experiment 2 confirmed this prediction, revealing a systematic shift between the CW and CCW generalization patterns that was consistent with the muscle-space prediction. These findings suggest that intrinsic representations of learned movements are not fully captured by joint-based coordinates alone and that muscle-based coordinates contribute to motor learning and its generalization. Together, these findings highlight the importance of considering underlying biomechanics when interpreting motor representations using generalization paradigms.

neuroscience↗

An Integrated Computational Antigen Discovery Pipeline with Hierarchical Filtering for Emerging Viral Variants

Emerging and evolving viral diseases, such as SARS-CoV-2, continue to pose significant global health challenges, underscoring the urgent need for rapid and scalable antigen discovery pipelines. This work presents a computational pipeline that integrates diverse computational tools and machine learning models to accelerate the identification and optimization of antigen candidates. The pipeline employs efficient filtering and consensus-based strategies to highlight epitopes with high therapeutic potential. We demonstrate its utility by significantly narrowing the antigen search space for Rift Valley fever virus (RVFV) and Mayaro virus (MAYV), and by effectively identifying conserved neutralizing epitopes in SARS-CoV-2. Our proposed computational antigen pipeline offers a powerful framework for expediting the development of future vaccines and therapeutics in response to emerging pathogens.

bioinformatics↗

Fine-Tuning α-Synuclein Phase Separation through Sequence-Optimized Peptide Modulators

Liquid-liquid phase separation (LLPS) of intrinsically disordered proteins underlies the formation of biomolecular condensates that regulate diverse cellular processes, while its dysregulation contributes to protein aggregation and disease. Despite its importance, molecularly defined and target-specific strategies to control LLPS remain limited. Here, we present a systematic framework for designing de novo peptides that induce and modulate LLPS of -synuclein. By integrating deep mutational scanning with peptide screening, we identified sequence features that govern condensate formation and enabled the creation of optimized peptides with high efficiency and specificity. Biophysical analyses revealed that LLPS efficiency is dictated by the interplay of solubility, multivalency, and cooperative interactions, resulting in a distinctive bell-shaped phase diagram. Thermodynamic measurements and imaging-based analyses further demonstrated that condensate stability and material properties can be rationally tuned through peptide optimization. Together, these findings establish generalizable design principles for engineering LLPS modulators in biologically and pathologically relevant protein systems.

biophysics↗

Analysis of the high-order conformational changes in glyceraldehyde-3-phosphate dehydrogenase induced by nicotinamide adenine dinucleotide, adenosine triphosphate, and oxidants

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzes the sixth step of glycolysis. As a moonlighting protein, GAPDH interacts with other molecules, seemingly unrelated to glycolysis, to exert additional functions, such as inducing apoptosis. However, specific mechanisms underlying these interactions remain unclear. Therefore, in this study, we aimed to elucidate these mechanisms by analyzing human and porcine GAPDHs based on their three-dimensional (3D) structures using various biophysical techniques, including nuclear magnetic resonance spectroscopy, gel filtration chromatography, and thermal shift assay. Although GAPDH became unstable when nicotinamide adenine dinucleotide (NAD+) was removed (apo state), the 3D structure of the tetramer was maintained regardless of the temperature. However, in the presence of adenosine triphosphate (ATP), GAPDH split into dimers at low temperatures, exposing the interface between the dimers and increasing the flexibility of the side chains at the site. Moreover, subunit splitting also occurred upon exposure to oxidizing agents, such as hydrogen peroxide. These findings suggest that GAPDH maintains a stable tetramer in the presence of NAD+ but becomes unstable and easily oxidized upon NAD+ depletion. When multiple residues, including those other than the cysteine residue at the active site, are oxidized by reactive oxygen species or nitric oxide, or when it interacts with ATP, GAPDH splits into dimers. This subunit splitting may trigger interactions with other molecules.

biochemistry↗

NMR analysis of the homodimeric structure of a D-Ala-D-Ala metallopeptidase, VanX, from vancomycin-resistant bacteria

Bacteria that have acquired resistance to most antibiotics, particularly those causing nosocomial infections, create serious problems. Among these, the emergence of vancomycin-resistant enterococci was a tremendous shock considering that vancomycin is the last resort for controlling methicillin-resistant Staphylococcus aureus. Therefore, there is an urgent need to develop an inhibitor of VanX, a protein involved in vancomycin resistance. Although the crystal structure of VanX has been resolved, its asymmetric unit contains six molecules aligned in a row. We have developed a structural model of VanX as a stable dimer in solution, primarily utilizing nuclear magnetic resonance (NMR) residual dipolar coupling. Despite the 46 kDa molecular mass of the dimer, which is typically considered too large for NMR studies, we successfully assigned the main chain using an amino acid-selective unlabeling method. Because we found that the Zn2+-coordinating active sites in the dimer structure were situated in the opposite direction to the dimer interface, we generated an active monomer by mutating the dimer interface. The monomer consists of only 202 amino acids and is expected to be used in future studies to screen and improve inhibitors using NMR.

biochemistry↗

Revealing Gene Expression Heterogeneity in a Clonal Population of Tetrahymena thermophila through Single-Cell RNA Sequencing

We performed single-cell RNA sequencing (scRNA-seq) on a population of 5,000 Tetrahymena thermophila, using the 10x Genomics 3 gene expression analysis, to investigate gene expression variability within this clonal population. Initially, we estimated the 3-untranslated regions (3 UTRs), which were absent in existing annotation files but are crucial for the 10x Genomics 3 gene expression analysis, using the peaks2utr method. This allowed us to create a modified annotation file, which was then utilized in our scRNA-seq analysis. Our analysis revealed significant gene expression variability within the population, even after removing the effect of cell phase-related features. This variability predominantly appeared in six distinct clusters. Through gene ontology and KEGG pathway enrichment analyses, we identified that these were primarily associated with ribosomal proteins, proteins specific to mitochondria, proteins involved in peroxisome-specific carbon metabolism, cytoskeletal proteins, motor proteins, and immobilized antigens.

microbiology↗

From autopoiesis to self-optimization: Toward an enactive model of biological regulation

The theory of autopoiesis has been influential in many areas of theoretical biology, especially in the fields of artificial life and origins of life. However, it has not managed to productively connect with mainstream biology, partly for theoretical reasons, but arguably mainly because deriving specific working hypotheses has been challenging. The theory has recently undergone significant conceptual development in the enactive approach to life and mind. Hidden complexity in the original conception of autopoiesis has been explicated in the service of other operationalizable concepts related to self-individuation: precariousness, adaptivity, and agency. Here we advance these developments by highlighting the interplay of these concepts with considerations from thermodynamics: reversibility, irreversibility, and path-dependence. We interpret this interplay in terms of the self-optimization model, and present modeling results that illustrate how these minimal conditions enable a system to re-organize itself such that it tends toward coordinated constraint satisfaction at the system level. Although the model is still very abstract, these results point in a direction where the enactive approach could productively connect with cell biology.

systems biology↗

Structural basis for the unique multifaceted interaction of DPPA3 with the UHRF1 PHD finger

Ubiquitin-like with PHD and RING finger domain-containing protein 1 (UHRF1)-dependent DNA methylation is essential for maintaining cell fate during cell proliferation. Developmental pluripotency-associated 3 (DPPA3) is an intrinsically disordered protein that specifically interacts with UHRF1 and promotes passive DNA demethylation by inhibiting UHRF1 chromatin localization. However, the molecular basis of how DPPA3 interacts with and inhibits UHRF1 remains unclear. We aimed to determine the structure of the mouse UHRF1 plant homeodomain (PHD) complexed with DPPA3 using nuclear magnetic resonance. Induced - helices in DPPA3 upon binding of UHRF1 PHD contribute to stable complex formation with multifaceted interactions, unlike canonical ligand proteins of the PHD domain. Mutations in the binding interface and unfolding of the DPPA3 helical structure inhibited binding to UHRF1 and its chromatin localization. Our results provide structural insights into the mechanism and specificity underlying the inhibition of UHRF1 by DPPA3.

biochemistry↗

Transcranial magnetic stimulation of the occipital cortex interferes with foot movements in blind individuals

Research has shown that the occipital cortex can be reorganized and repurposed for nonvisual perception and cognitive functions following visual loss in blind individuals. However, no studies have directly examined the involvement of the visual cortex in motor function. Here, we show that a rhythmic foot movement performed by acquired blind individuals can be disrupted by transcranial magnetic stimulation (TMS) to their primary and secondary visual cortex (V1/V2). This disruptive effect was absent for congenitally blind or sighted individuals. As a control, TMS to the neck muscles of acquired blind individuals confirms that this disruptive effect was not caused solely by the sensory (tactile/auditory) sensations accompanying the stimulation. Our results provide the direct evidence that functional repurposing of the human visual cortex is not restricted to perception and cognitive functions but also extends to motor function. Moreover, our findings suggest the nessecity of the visual experience before visual loss for the functional reorganization of the visual cortex for motor function. Significance statementThe brain can adapt remarkably after sensory loss. One striking example is that after visual loss, the visual cortex--deprived of visual input--is often reused for nonvisual perception and higher cognition. Here, we show that it can also support motor control. Using transcranial magnetic stimulation, we transiently disrupted processing in the visual cortex while participants performed rhythmic foot movements. This disruption impaired performance in people who became blind after birth, but not in sighted individuals or those blind from birth. These findings demonstrate that the visual cortex can take on a motor function after vision is lost, but only with prior visual experience.

neuroscience↗

Hierarchical motor adaptations negotiate failures during force field learning

Humans have the amazing ability to learn the dynamics of the body and environment to develop motor skills. Traditional motor studies using arm reaching paradigms have viewed this ability as the process of internal model adaptation. However, the behaviors have not been fully explored in the case when reaches fail to attain the intended target. Here we examined human reaching under two force fields types; one that induces failures (i.e., target errors), and the other that does not. Our results show the presence of a distinct failure-driven adaptation process that enables quick task success after failures, and before completion of internal model adaptation, but that can result in persistent changes to the undisturbed trajectory. These behaviors can be explained by considering a hierarchical interaction between internal model adaptation and the failure-driven adaptation of reach direction. Our findings suggest that movement failure is negotiated using hierarchical motor adaptations by humans.

neuroscience↗

Prediction error induced motor contagions in human behaviors

Motor contagions refer to implicit effects on ones actions induced by observation of others actions. Motor contagions are believed to be induced simply by action observation and cause an observers action to become similar to the observed action. In contrast, here we report a new motor contagion that is induced only when the observation is accompanied by prediction errors-differences between actions one observes and those he/she predicts or expects. Moreover, this contagion may not manifest as a similarity between ones own and observed actions. In our experiment, observation of the same action induced distinct motor contagions, depending on whether prediction errors are present or not. In the absence of prediction errors, similarly to previous reports, participants actions changed to become similar to the observed action, while in the presence of prediction errors, their actions changed to diverge away from it. Our results suggest distinct effects of action observation and action prediction on human actions.

neuroscience↗