Biology subjects

Tachibana, Y.

Publications and source records attributed to Tachibana, Y..

10 recordsLinked to original sources

bioRxiv2026

Joint Pupillometry and Heart Rate Monitoring Identify Zone-Like High Performance in Esports

Modern digital activities, such as esports, combine intense cognitive demands with limited whole-body movement, weakening calibration between subjective awareness and functional states. Cognitive deterioration during prolonged esports precedes subjective fatigue, suggesting subjective flow likewise fails to reveal efficient cognitive-sensorimotor performance states. Although efficient cognitive-sensorimotor performance may involve central-autonomic coordination reflected in intrapersonal pupil-heart synchrony, the functional role of this coordination remains largely unknown. We hypothesized that, during esports play, central-autonomic coordination contributes to an efficient cognitive-sensorimotor performance state that subjective flow fails to capture. Fourteen young men completed sessions involving watching a fighting game, playing against a computer-controlled opponent, and competing against another person. We assessed pupil diameter, heart rate, subjective flow, subjective workload, and objective in-game performance. Esports competition increased subjective flow without improving objective in-game performance and reduced combat efficiency, demonstrating a subjectively optimal experience need not signal high in-game performance efficiency. Data-driven clustering identified a low-reactivity state combining superior objective in-game performance with lower subjective workload. This state showed selectively sustained pupil-heart synchrony. Reduced workload partly accounted for the association between pupil-heart synchrony and objective in-game performance. Our findings suggest that individuals fail to recognize periods of high in-game performance efficiency, as cognitive deterioration escapes awareness during prolonged esports. This efficiency is associated with pupil-heart synchrony, supporting the hypothesis that central-autonomic coordination contributes to an efficient cognitive-sensorimotor performance state. Pupil-heart synchrony may therefore serve as a mechanism-based biomarker for detecting efficient states beyond awareness, optimizing objective task performance and the timing of recovery in demanding digital environments.

neuroscience↗

bioRxiv2026

Sparkling Water Co-Consumption Enhances Oxytocin-Linked HR Synchrony and Social Connection in Live Sports Spectatorship

Live sport spectatorship can promote social connection, yet scalable, low-burden strategies to strengthen bonding in real-world spectator settings remain limited. We here tested the hypothesis that co-consuming sparkling water during spectating attenuates hunger and fatigue and strengthens enjoyment and perceived unity, potentially via HR synchrony linked to oxytocin dynamics. In an individually randomized field experiment at a collegiate womens basketball home game (sparkling water: n = 21; plain water: n = 19), spectators consumed 200 mL of sparkling water or plain water in synchrony before tip-off and before the end of halftime, with additional ad libitum intake of the assigned beverage permitted thereafter. We assessed acute freshness and hunger, repeated fatigue and enjoyment, interpersonal HR synchrony from the first half to 15-min post-game, perceived unity toward players and fellow spectators, and salivary oxytocin levels. Relative to plain water, sparkling water increased freshness and reduced hunger after intake, attenuated post-game fatigue, and enhanced enjoyment and perceived unity. HR synchrony was preserved in association with attenuated post-game fatigue after the game, and sustained synchrony was associated with higher perceived unity. Oxytocin decreased more in the sparkling-water group, and this decrease was associated with preserved HR synchrony as well as with changes in unity toward fellow fans. These findings support our hypothesis and suggest that co-consuming sparkling water serves as an alcohol-free, low-burden ritual to enhance social connection during and after live sport events. Highlights- Sparkling water increased freshness and reduced hunger after intake in spectators. - Sparkling water attenuated the post-game increase in subjective fatigue. - Sparkling water increased enjoyment and perceived unity. - Post-game HR synchrony was preserved in association with lower fatigue and higher unity. - Oxytocin decreased more with sparkling water and tracked HR synchrony and fan unity. - Co-consuming sparkling water is a low-burden, alcohol-free ritual for social connection.

neuroscience↗

bioRxiv2025

Thalamo-insular pathway regulates tic generation via motor-limbic crosstalk

Tic disorders accompanied by premonitory urges are hallmark symptoms of Tourette syndrome (TS), yet the underlying neuronal mechanisms remain elusive. Here, we establish a mouse model of motor tics by unilateral striatal injection of a GABAA receptor antagonist. This model induces c-Fos activation in both motor and limbic structures, including the insular cortex (IC). Fiber photometry reveals tic-associated activity in IC as well as the primary motor cortex (M1). Viral tracing demonstrates that basal ganglia outputs from the substantia nigra pars reticulata are transmitted to IC via the intralaminar thalamic nuclei (ITN). Chemogenetic inhibition of IC or the thalamo-insular pathway suppresses tic-related cortical activity and alleviates tic-like behaviors. These findings identify IC as a key node in tic generation and highlight ITN as critical relay stations linking motor and limbic circuits. Aberrant thalamo-insular signaling thus contributes to the pathophysiology of tic disorders and represents a potential therapeutic target in TS. HighlightsO_LIc-Fos activation occurs in both motor and limbic structures in a mouse tic model C_LIO_LIBasal ganglia outputs are transmitted to insula via intralaminar thalamic nuclei C_LIO_LIChemogenetic inhibition of thalamo-insular pathway suppresses motor tics C_LIO_LIThalamo-insular inhibition diminishes tic-associated activity in primary motor cortex C_LI In briefAbnormal basal ganglia activity originating from the striatum drives dysfunction of the insular cortex via the intralaminar thalamic nuclei, leading to motor tics. Chemogenetic inhibition of this pathway suppresses tic-like behaviors, highlighting motor-limbic circuit pathology in tic disorders.

neuroscience↗

bioRxiv2025

An in vivo fitness gene of Toxoplasma, MIC11, is essential for PLP1-mediated egress from host cells

After invasion and replication, intracellular pathogens must egress from infected host cells. Toxoplasma gondii facilitates this process by permeabilizing host cells by releasing perforin-like protein 1 (PLP1) through induced microneme secretion. However, the precise mechanism of host cell permeabilization remains enigmatic. Here, we identified the secretory microneme protein MIC11 as a key factor for membrane disruption. A CRISPR-based in vivo screen revealed several genes including MIC11 as an essential gene for virulence. Deletion of MIC11 resulted in severe defects in both membrane rupture and egress. Scanning mutagenesis identified functional motifs in MIC11, and mechanistic analyses demonstrated that MIC11 directly associates with PLP1, regulating its activity in membrane disruption. The MIC11 paralogue MIC22 compensated for MIC11 deletion, suggesting a conserved mechanism of egress in the feline-restricted stages of T. gondii. The discovery of MIC11 advances the understanding of how parasites disrupt host cells to facilitate rapid egress and successful dissemination.

microbiology↗

bioRxiv2025

Discovery of The Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19

The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health and an unmet need for therapeutic options. Herein, we report the discovery of S-892216, a second-generation SARS-CoV-2 3C-like protease (3CLpro) inhibitor, to treat COVID-19. S-892216 is a reversible covalent 3CLpro inhibitor with highly potent antiviral activity and an EC50 value of 2.48 nM against SARS-CoV-2 infected cells. Structure-based design of a covalent modifier for compound 1 revealed that introducing a nitrile warhead increased 3CLpro inhibition activity by 180-fold. Subsequent optimization efforts yielded S-892216, which combined a favorable pharmacokinetic profile and high off-target selectivity. S-892216 exhibited antiviral activity against diverse SARS-CoV-2 variants, with no cross-resistance to major mutations reducing antiviral activities of nirmatrelvir and ensitrelvir. In SARS-CoV-2-infected mice, S-892216 inhibited viral replication in the lungs similar to ensitrelvir, although at a 30-fold lower dose.

biochemistry↗

bioRxiv2024

In vivo CRISPR screens identify novel virulence genes among proteins of unassigned subcellular localization in Toxoplasma

The research field to identify and characterize virulence genes in Toxoplasma gondii has been dramatically advanced by a series of in vivo CRISPR screens. Although subcellular localizations of thousands of proteins were predicted by the spatial proteomic method called hyperLOPIT, those of more than 1000 proteins remained unassigned and their essentiality in virulence was also unknown. In this study, we generated two small-scale gRNA libraries targeting approximately 600 hyperLOPIT-unassigned proteins and performed in vivo CRISPR screens. As a result, we identified several in vivo fitness-conferring genes that were previously unreported. We further characterized two candidates, TgGTPase and TgRimM, which are localized in the cytoplasm and the apicoplast, respectively. Both genes are essential for parasite virulence and widely conserved in the phylum Apicomplexa. Collectively, our current study provides a resource for estimating the in vivo essentiality of Toxoplasma proteins with previously unknown localizations. IMPORTANCEToxoplasma gondii is a protozoan parasite that causes severe infection in immunocompromised patients or newborns. Toxoplasma possesses more than 8000 genes; however, the genes that determine parasite virulence were not fully identified. The apicomplexan parasites, including Toxoplasma, developed unique organelles that do not exist in other model organisms; thus, determining the subcellular location of parasite proteins is important for understanding their functions. Here, we used in vivo CRISPR genetic screens that enabled us to investigate hundreds of genes in Toxoplasma during mouse infection. We screened approximately 600 parasite proteins with previously unknown subcellular localizations. We identified many novel genes that confer parasite fitness in mice. Among the top hits, we characterized two essential virulence genes, TgGTPase and TgRimM, which are widely conserved in the phylum Apicomplexa. Our findings will contribute to understanding how apicomplexans adapt to the host environment and cause disease.

microbiology↗

bioRxiv2022

Distribution of intraperitoneally administered D2O in AQP4-knockout mouse brain after MCA occlusion

As the movement of water in the brain is known to be involved in neural activity and various brain pathologies, the ability to assess water dynamics in the brain will be important for the understanding of brain function and the diagnosis and treatment of brain diseases. Aquaporin-4 (AQP4) is a membrane channel protein that is highly expressed in brain astrocytes and is important for the movement of water molecules in the brain. In this study, we investigated the contribution of AQP4 to brain water dynamics by administering deuterium-labeled water (D2O) intraperitoneally to wild-type and AQP4 knockout (AQP4-ko) mice that had undergone surgical occlusion of the middle cerebral artery. Water dynamics in the infarct region and on either side of the anterior cerebral artery (ACA) was monitored with proton-density-weighted imaging (PDWI) performed on a 7T animal MRI. D2O caused a negative signal change quickly after administration. The AQP4-ko mice showed a delay of the time-to-minimum in both contralateral and ipsilateral ACA region compared to wild-type mice. Also, only the AQP4-ko mice showed a delay of the time-to-minimum in the ipsilateral ACA region compared to the contralateral side. In only the wild-type mice, the signal minimum in the ipsilateral ACA region was higher than that in the contralateral ACA region. In the infarct region, the signal attenuation was slower for the AQP4-ko mice in comparison to the wild-type mice. These results suggest that AQP4 loss affects water dynamics in the ACA region not only in the infarct region. Dynamic PDWI after D2O administration may be a useful tool for showing the effects of AQP4 in vivo. HighlightsO_LIThe measurement of brain water dynamics with D2O. C_LIO_LIIn vivo investigation of AQP4 loss and focal brain ischemia. C_LIO_LIAQP4 loss affects water dynamics in the ACA region not only in the infarct region. C_LI

physiology↗

bioRxiv2022

Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral non-covalent, non-peptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug-design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel non-covalent inhibitor could be a potential oral agent for treating COVID-19.

biochemistry↗

bioRxiv2021

Quantitative Measurement of Diffusion-weighted Imaging Signal Using Expression-controlled Aquaporin-4 Cells: Comparative Study of 2-compartment and Diffusion Kurtosis Imaging Models

PurposeThe purpose of this study was to compare parameter estimates for the 2-compartment (2Comp) and diffusion kurtosis imaging (DKm) models obtained from diffusion-weighted imaging (DWI) of aquaporin-4 (AQP4) expression-controlled cells, and to look for biomarkers that indicate differences in the cell membrane water permeability. MethodsDWI was performed on AQP4-expressing and non-expressing cells and the signal was analyzed with the 2Comp and DKm models. For the 2Comp model, the diffusion coefficients (Df, Ds) and volume fractions (Ff, Fs, Ff=1-Fs) of the fast and slow compartments were estimated. For the DKm model, estimates of the diffusion kurtosis (K) and corrected diffusion coefficient (D) were obtained. ResultsFor the 2Comp model, Ds and Fs showed clear differences between AQP4-expressing and non-expressing cells. Fs was also sensitive to cell density. There was no clear relationship with the cell type for the DKm parameters. ConclusionsChanges to cell membrane water permeability due to AQP4 expression affected DWI of cell suspensions. For the 2Comp and DKm models, Ds was the parameter most sensitive to differences in AQP4 expression.

cell biology↗

bioRxiv2020

Htr6 and Sstr3 ciliary targeting relies on both IC3 loops and C-terminal tails

G protein-coupled receptors (GPCRs) are the most common pharmacological target in clinical practice. To perform their signaling functions, many GPCRs must accumulate at primary cilia, microtubule-based plasma membrane protrusions that work as cellular antennae. Despite their great importance, the molecular mechanisms underlying GPCR ciliary targeting remain poorly understood. Serotonin receptor 6 (Htr6) and somatostatin receptor 3 (Sstr3) are two brain-enriched ciliary GPCRs controlling cognition and involved in multiple pathologies such as Alzheimers disease and cancer. We previously showed that the third intracellular loops (IC3s) of Htr6 and Sstr3 contain ciliary targeting sequences (CTSs) that are sufficient to confer ciliary localization to non-ciliary GPCRs. However, these CTSs are dispensable for the ciliary targeting of Htr6 and Sstr3 themselves, suggesting these GPCRs have additional CTSs. Herein, we show that the C-terminal tails of Htr6 and Sstr3 also contain CTSs, which act redundantly with those in the IC3s. Accordingly, simultaneous disruption of CTS1 (IC3) and CTS2 (C-terminal tail) abolishes ciliary targeting of both receptors. Mapping the individual residues required for Htr6 ciliary targeting reveals RKQ and LPG motifs critical for CTS1 and CTS2 function, respectively. In Sstr3, CTS1 function relies on the tandem AP[AS]CQ motifs and a subsequent arginine-rich stretch, whereas CTS2 operation requires the juxtamembrane residues. Furthermore, we shed light on the mechanisms of action of Htr6 CTSs by showing how they regulate binding to Tulp3 and Rabl2, two adapters needed for ciliary GPCR targeting.

cell biology↗