Biology subjects

Yamamoto, S.

Publications and source records attributed to Yamamoto, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Altered kinematics and muscle activities during half squats in people with ankle sprain history

Regardless of the high recurrence rate, copers manage the damage after a sprain. Copers do not experience ankle instability and continue their daily activities. However, it is unclear whether copers can use movement strategies similar to people without an ankle sprain. Identifying movement strategies can improve efficacy and prevent unwanted effects during training. Therefore, we aimed to compare the kinematics and muscular activities of the lower limbs during half squats and gait between copers and healthy controls. Ten copers (7 men, 3 women; age = 21.6 {+/-} 1.1 years) and 10 controls (6 men, 4 women; age = 22.5 {+/-} 2.8 years) were included in the cross-sectional study. We compared angles of the thigh, shank, and foot calculated from inertial measurement units and muscle activities of the biceps femoris long head, rectus femoris, gastrocnemius, and tibialis anterior between copers and controls during half squats and gait. For half squats, copers demonstrated thigh restriction with an effect size of 0.67-1.35, whereas we observed no significant differences in the shank and foot angles in the descending phase. Copers demonstrated less activity with an effect size of 0.61-1.58 in all four muscles. Copers showed lower activities of the rectus femoris and tibialis anterior during the same period of thigh restriction. For gait, there were no significant differences in lower limb angles and muscle activities between copers and controls. Copers may restrict thigh rotation unintentionally, leading to less muscle activity during half squats. Removing unconscious restrictions using sensor-based quantitative feedback can enable copers to obtain more efficient training. Our results suggest that assessing the limb movements of copers is important for efficient training, even if they do not experience instability to continue with their daily activities.

physiology↗

bioRxiv2025

Mating status-dependent dopaminergic modulation of auditory sensory neurons in Drosophila

Mating status often modulates responses to courtship sounds in animals. The neural mechanisms underlying this modulation, however, have not been well clarified. Here, we show that dopaminergic signals are involved in modulating the responses of auditory sensory neurons in Drosophila melanogaster females depending on their mating status. These neurons abundantly express three types of dopamine receptors, with some having direct synaptic connections with dopaminergic neurons. Of these receptors, suppressing the expression of Dop1R2 reduces sound responses of auditory sensory neurons in unmated but not mated females. Moreover, expression of Dop1R2 in auditory sensory neurons enhances the song response behavior of unmated females, manifested by copulation receptivity when exposed to songs. Our research suggests that dopaminergic modulation via Dop1R2 is involved in mating state-dependent regulation of auditory sensory processing.

neuroscience↗

bioRxiv2025

Perturbing postural stability during treadmill walking with dysfunctional electrical stimulation

Functional electrical stimulation is commonly used to enhance human movement through low-level electrical activation of muscles. More recently, dysfunctional electrical stimulation (DFES) has been proposed as a method to perturb gait by artificially inducing discomfort and mimicking inadequate muscle activity. Here we investigated strategies to induce internal perturbations during treadmill walking using DFES by systematically varying the timing and target muscle. Eleven healthy participants walked at three different speeds while DFES was applied to the tibialis anterior (TA), soleus (SOL), rectus femoris (RF), and biceps femoris (BF) muscles at 25%, 50%, 75%, and 100% of the gait cycle, each for a duration of 0.2 seconds. The gait cycle was time-locked to heel contact (0%). Results showed a significant reduction in the anterior-posterior margin of stability compared to baseline, particularly when DFES was applied to the SOL at 75%, the RF at 50%, and the BF at 75% of the gait cycle. Under these conditions, increased knee flexion and shorter stride intervals were observed relative to baseline. In conclusion, we identified effective DFES conditions to induce postural instability during walking. By mimicking inadequate muscle activity, DFES provides a promising method to study dynamic balance control and mechanisms underlying falls in neurological populations.

bioengineering↗

bioRxiv2025

Asian elephants (Elephas maximus) recognise human visual attention from body and face orientation

Visual attention has mostly been studied in primarily visual species, such as dogs and nonhuman primates. Although elephants rely more on acoustic and olfactory cues, they also use visual displays and gestures to communicate. Smet and Byrne (2014) showed that African savanna elephants (Loxodonta africana) recognise human visual attention based on face and body orientation, but this has not been investigated in Asian elephants (Elephas maximus). Here, we examined whether Asian elephants are sensitive to human attentional states. We tested ten captive female elephants in Thailand and analysed the frequency of experimenter-directed signals in a food-requesting task based on the experimenters body and face orientation. Elephants gestured significantly more when the experimenters body was oriented towards them than when it was turned away, and they gestured most frequently when her face was also oriented towards them. This suggests that body orientation may be the more salient visual cue, with face orientation contributing to the effect only when accompanied by body orientation. These findings show that Asian elephants, like African savanna elephants, understand the importance of visual attention for effective communication, contributing to our understanding of cognitive abilities across the elephant taxon and visual attention in animals.

animal behavior and cognition↗

bioRxiv2025

The integration mechanism of the four positional cues--anterior, posterior, dorsal, and ventral--in axolotl limb regeneration

Axolotls (Ambystoma mexicanum) exhibit a remarkable ability to regenerate limbs after amputation. Classical experiments have suggested that contact between cells derived from distinct orientations--dorsal, ventral, anterior, and posterior--within the regenerating blastema is necessary for accurate limb pattern formation. However, the molecular basis for this requirement has remained largely unknown. Here, we demonstrate that both dorsal and ventral tissues are required for limb formation via induction of Shh expression, which plays a crucial role in limb patterning. Using the accessory limb model (ALM), we induced position-specific blastemas lacking cells derived from a single orientation (anterior, posterior, dorsal, or ventral). Patterned limb formation occurred only in blastemas containing both dorsal- and ventral-derived cells. We further observed that Shh expression requires dorsoventral contact within a blastema, highlighting the necessity of dorsoventral contact for inducing Shh expression. In addition, we identified WNT10B and FGF2 as dorsal- and ventral-mediated signals, respectively, that create the inductive environment for Shh expression. Our findings clarify the role of dorsal and ventral cells in inducing Shh, a mechanism that has rarely been studied in the context of limb regeneration and pattern formation. This model provides new insights into how cells with different positional identities drive the regeneration process.

developmental biology↗

bioRxiv2025

Stacked mutations disrupting syringyl and p-coumaroylated lignin biosynthesis in rice result in lignin dominated by guaiacyl units: insights into grass-specific lignin monomer biosynthesis and polymerization mechanisms

O_LIThe aromatic composition of lignin significantly impacts the usability of lignocellulosic biomass. In eudicots, transgenic and mutant lines with elevated guaiacyl (G) or syringyl (S) lignin units have been successfully generated by manipulating the expression level of CONIFERALDEHYDE 5-HYDROXYLASE (CAld5H). However, this bioengineering approach has proven less effective in grasses, implicating the potential existence of a grass-specific alternative pathway for S lignin biosynthesis. C_LIO_LIThrough characterization of genome-edited rice mutants, we demonstrated that S lignin in rice can be virtually eliminated by disrupting genes encoding CAld5H along with p- COUMAROYL-COENZYME A:MONOLIGNOL TRANSFERASE (PMT), a grass-specific enzyme essential for the biosynthesis of monolignol p-coumarate conjugates. In contrast, individual mutations in either CAld5H or PMT genes resulted in incomplete elimination of S lignin. These findings provide strong evidence that rice possesses a CAld5H-independent pathway leading to the grass-specific monolignol p-coumarate conjugates. C_LIO_LIIn-depth structural characterizations of G-dominated lignins from rice and Arabidopsis mutants, natural gymnosperm pine, and G-type synthetic lignin revealed pronounced effects of lineage-dependent cell wall environments on the linkage patterns and molecular weight distributions of the resulting lignin polymers. C_LIO_LIOverall, our findings highlight previously overlooked lineage-specific lignin monomer biosynthesis and polymerization patterns in grasses. C_LI

plant biology↗

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↗

bioRxiv2025

Bacterial pathogen deploys iminosugar galactosyrin to manipulate plant glycobiology

The extracellular space (apoplast) of plants is an important molecular battleground during infection by many pathogens. We previously found that a plant-secreted {beta}-galactosidase BGAL1 acts in immunity by facilitating the release of immunogenic peptides from bacterial flagellin and that Pseudomonas syringae suppresses this enzyme by producing a small molecule inhibitor called galactosyrin. Here, we elucidated the structure and biosynthesis of galactosyrin and uncovered its multifunctional roles during infection. Structural elucidation by cryo-EM and chemical synthesis revealed that galactosyrin is an iminosugar featuring a unique geminal diol attached to the pyrrolidine moiety that mimics galactose binding to the {beta}-galactosidase active site. Galactosyrin biosynthesis branches off from purine biosynthesis and involves three enzymes of which the first is a reductase that is unique in iminosugar biosynthesis. Besides inhibiting BGAL1 to avoid detection, galactosyrin also changes the glycoproteome and metabolome of the apoplast. The manipulation of host glycobiology may be common to plant-associated bacteria that carry putative iminosugar biosynthesis clusters.

plant biology↗

bioRxiv2025

Association of human gut microbiota with Alzheimers disease pathogenesis: An exploratory clinical study

The relationship between Alzheimers disease (AD) onset and the brain-gut axis has garnered increasing attention. This study aimed to investigate the potential role of the brain-gut axis in AD pathogenesis, with a specific focus on microbiota composition. This exploratory study enrolled 10 patients with AD and 13 healthy adults, grouped by age ([≤]30 years, 31-40 years, and [≥]41 years). Fecal samples were collected, and 16S rRNA gene sequencing was employed to analyze differences in fecal microbiota composition at the bacterial species level. Certain bacterial species appeared more abundant in the AD group (e.g., Ruminococcus inulinivorans and Ruminococcus torques), while others were relatively more abundant in healthy adults (e.g., Prevotella vulgatus 1, Bacteroides wexlerae, Clostridium butyricum, and Alistipes rectalis). However, these differences were not statistically significant, likely because of the limited sample size. These findings suggest that fecal microbiota composition may differ between patients with AD and healthy individuals, with a potential intermediate group at risk of AD development. Larger-scale clinical studies are necessary to further elucidate the bacterial species associated with AD pathogenesis, potentially enabling the use of microbiota composition as a screening tool to distinguish between healthy individuals, patients with AD, and those with preclinical AD.

neuroscience↗

bioRxiv2025

Repurposing of the RIPK1 selective benzooxazepin-4-one scaffold for the development of a type-III LIMK1/2 inhibitor

Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds as a type-III inhibitor targeting the C-out/DFG-out conformation. This inactive conformation results in a large expansion of the kinase back pocket, a conformation that has also been reported for LIM kinases. Scaffold hopping is common in the design of orthosteric kinase inhibitors, but has not been explored in the design of allosteric inhibitors, mainly due to the typically exclusive selectivity of type III inhibitors. Here, we hypothesized that the shared structural properties of LIMKs and RIPKs could lead to novel type III LIMK inhibitors using the benzoxazepinone scaffold. We report the discovery of a novel LIMK1/2 inhibitor that relies on this scaffold-based approach. The discovered compound 10 showed low nanomolar potency on LIMK1/2 and exceptional selectivity, as confirmed by a comprehensive selectivity panel with residual RIPK activity as the only off-target. The study provides one of the few examples for scaffold hopping for type-III inhibitors which are usually associated with exclusive target selectivity. Table of contents (TOC) graphics O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/636296v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@19bad48org.highwire.dtl.DTLVardef@18d8929org.highwire.dtl.DTLVardef@1280043org.highwire.dtl.DTLVardef@1296ddf_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Essential Yet Dispensable: The Role of CINNAMATE 4-HYDROXYLASE in Rice Cell Wall Lignification

A comprehensive understanding of the intricate lignin biosynthesis in grasses could contribute to enhancing our ability to utilize grass biomass. CINNAMATE 4-HYDROXYLASE (C4H), in conjunction with PHENYLALANINE AMMONIA-LYASE (PAL), initiates the entry of phenylalanine into the cinnamate/monolignol pathway, leading to the production of diverse phenylpropanoids, including lignin monomers. Despite extensive research on C4H in eudicots, genetic studies of C4H in grasses remain considerably limited. Notably, the role of C4H in the presence of PHENYLALANINE/TYROSINE AMMONIA-LYASE (PTAL), a grass-specific ammonia-lyase that can bypass the conserved PAL-C4H pathway by recruiting tyrosine into the cinnamate/monolignol pathway, remains unclear. To address this gap, a set of genome-edited rice mutants harboring knockout mutations in rice C4H genes were generated and subjected to the analysis of growth phenotype and cell wall chemotype, alongside isotopic feeding and chemical inhibitor assays to test the contributions of the PAL-C4H and PTAL pathways. The phenotype and chemotype characterizations of C4H-knockout rice mutants demonstrated that class I (OsC4H1/CYP73A38) and class II (OsC4H2a/CYP73A39 and OsC4H2b/CYP73A40) C4Hs cooperatively contribute to lignin biosynthesis in rice. Nevertheless, the impacts of C4H-deficiency on plant development and lignin formation in rice appeared to be less prominent compared to those reported in eudicots. The 13C-labeled phenylalanine and tyrosine feeding experiments demonstrated that even with the phenylalanine-derived PAL-C4H pathway completely blocked, the C4H-knockout rice can still produce significant levels of lignin and maintain sound cell walls by utilizing the tyrosine-derived PTAL pathway. Overall, this study demonstrates the essential but dispensable role of C4H in grass cell wall lignification.

plant biology↗

bioRxiv2024

Peristaltic pump-triggered amyloid formation suggests shear stresses are in vivo risk factors of amyloid nucleation

Amyloid fibrils, crystal-like fibrillar aggregates of denatured proteins, are formed linked with the breakdown of supersaturation, causing a series of amyloidosis including Alzheimers and Parkinsons diseases. Although varying in vitro factors are known, in vivo factors breaking supersaturation are unclear. We found that flowing by a peristaltic pump effectively triggers amyloid formation of hen egg white lysozyme, a model amyloidogenic protein, and, moreover, amyloidosis-associated proteins (i.e. -synuclein, amyloid {beta} 1-40, and {beta}2-microglobulin). The peristaltic pump-dependent amyloid formation was visualized by a fluorescence microscope with looped flow system, revealing dynamic motions under flow. Among them, amyloid fibrils of amyloid {beta} 1-40 were stickier than others, self-associating, absorbing to loop surfaces, and surging upon flicking the loop, implying early stages of cerebral amyloid angiopathy. On the other hand, {beta}2-microglobulin at a neutral pH showed unique two-step amyloid formation with an oligomeric trapped intermediate, which might mimic amyloid formation in patients. Peristalsis-caused strong shear stresses were considered to mechanically break supersaturation. Shearing stresses occur in vivo at varying levels, suggesting that they break otherwise persistent supersaturation, thus triggering amyloid formation and ultimately leading to amyloidosis. (182 words <200 words)

biophysics↗

bioRxiv2024

Age-related alterations in functional and structural networks in the brain in macaque monkeys

Resting-state networks (RSNs) have been used as biomarkers of brain diseases and cognitive performance. However, age-related changes in the RSNs of macaques, a representative animal model, are still not fully understood. In this study, we measured the RSNs in macaques aged 3-20 years and investigated the age-related changes from both functional and structural perspectives. The proportion of structural connectivity in the RSNs significantly decreased, whereas functional connectivity showed an increasing trend with age. Additionally, the amplitude of low-frequency fluctuations tended to increase with age, indicating that resting-state neural activity may be more active in the RSNs may increase with age. These results indicate that structural and functional alterations in typical RSNs are age-dependent and can be a marker of aging in the brain.

neuroscience↗

bioRxiv2024

Genetic diversity and differentiation of a mycoheterotrophic orchid (Cymbidium macrorhizon) under urbanization

Urbanization exerts substantial pressures on genetic diversity of plant species. However, depending on species-specific life history, the direction/magnitude of urbanization impacts can vary. To elucidate relationships between life history and urbanization effects, there are needs to accumulate the knowledge on genetic diversity/differentiation along urban-rural gradients for species with unique traits. We examined these facets based on genome-wide single nucleotide polymorphisms of a mycoheterotrophic and vegetative-dormant orchid, Cymbidium macrorhizon, for eleven populations in remnant forests along an urban gradient within the Tokyo metropolitan area, Japan. The reduced inbreeding coefficient and increased genetic differentiation were observed with increased proportion of surrounding urban land-use 50 years ago rather than in recent years. This pattern might reflect lowest heterozygosity under intensive urbanization due to population bottleneck and genetic drift due to habitat shrinkage and fragmentation. The significant impacts of past landscape on the indices might indicate time lags of genetic erosion, namely intra-specific extinction debt, due to longevity and dormancy. Therefore, 30% increase of urban land-use since 1970s has not yet affected genetic erosion, resulting in its progression in the future. We emphasize the importance not only to assess genetic diversity but also to connect the assessments with life history and spatiotemporal urbanization impacts.

ecology↗

bioRxiv2024

Glucose uptake in pigment glia suppresses tau-induced inflammation and photoreceptor degeneration in Drosophila

Brain inflammation contributes to the pathogenesis of neurodegenerative diseases such as Alzheimers disease (AD). Glucose hypometabolism and glial activation are pathological features seen in AD brains; however, the connection between the two is not fully understood. Using a Drosophila model of AD, we identified that glucose metabolism in glia plays a critical role in neuroinflammation under disease conditions. Expression of human Tau in the retinal cells, including photoreceptor neurons and pigment glia, causes photoreceptor degeneration accompanied by inclusion formation and swelling of the lamina cortex. We found that inclusions are formed by glial phagocytosis, and swelling of the laminal cortex correlates with the expression of antimicrobial peptides. Co-expression of human glucose transporter 3 (GLUT3) with Tau in the retina does not affect tau levels but suppresses these inflammatory responses and photoreceptor degeneration. We also found that expression of GLUT3, specifically in the pigment glia, is sufficient to suppress inflammatory phenotypes and mitigate photoreceptor degeneration in the tau-expressing retina. Our results suggest that glial glucose metabolism contributes to inflammatory responses and neurodegeneration in tauopathy. Summary StatementGlucose uptake into pigment glia suppresses inflammatory responses and photoreceptor degeneration in the fly model of tauopathy.

neuroscience↗

bioRxiv2024

An eye-tracking study of visual attention in chimpanzees and bonobos when viewing different tool-using techniques

Chimpanzees and bonobos are excellent tool users and can socially learn various skills. Previous studies on social learning mainly measure success/failure in acquiring new techniques, with less direct measurement of proximate mechanisms like visual attention during the process. This study investigates how apes observe tool-using demonstrations through eye-tracking. After checking initial techniques, six chimpanzees and six bonobos were shown video demonstrations of human demonstrators using a tube to dip (low-efficiency) or suck (high-efficiency) juice, and then tried the task themselves. Attention to each video was compared to participants knowledge. Although no individuals acquired the high-efficiency technique through video demonstrations, eye-tracking results revealed attentional differences between individuals familiar with different techniques. Compared with individuals already familiar with both techniques, individuals knowing only the dipping technique showed less attention to the unfamiliar sucking technique. This result indicates that apes may not attend much to what they do not know well, which aligns with reported interplay of action observation and understanding. Attentional patterns to specific areas was similar between species, though there was a tendency towards more attention to faces in bonobos and food in chimpanzees. This study emphasizes the importance of detailed investigation into social learning process using eye-tracking.

animal behavior and cognition↗

bioRxiv2024

Latent mitotic vulnerability of AML cells induced by therapeutic agents

Acute myeloid leukemia (AML) is a hematopoietic malignancy with a poor prognosis. Understanding the unidentified properties of AML cells is beneficial for the identification of novel therapeutic strategies for AML. In this study, we uncover the vulnerabilities of AML cells in mitosis when exposed to therapeutic agents. Through comparative analysis of large-scale data quantifying drug effects on cancer cell proliferation, the drug targeting the cell cycle and mitosis are predicted to possess high cytotoxicity against AML cell lines. Consistently, live-cell imaging with microwell devices demonstrates that clinical drugs targeting the cell cycle processes, such as idarubicin, pevonedistat and vincristine, potently induce mitotic cell death in AML cells. While these therapeutic agents also induce cell death through S/G2 phase arrest, the cytotoxic effects during mitosis are notably more pronounced. Furthermore, by employing additional inhibition of Chk1 to override the G2/M checkpoint, the AML cells stalled in the S/G2 phase prematurely enter mitosis, resulting in a significant increase in cell death. Collectively, these results unveiled the latent mitotic vulnerabilities of AML cells, providing a basis for developing novel therapeutic interventions.

cancer biology↗

bioRxiv2024

Comprehensive analysis of end-modified long dsDNA donors in CRISPR-mediated endogenous tagging

CRISPR-mediated endogenous tagging is a powerful gene editing technique for studying protein dynamics and function in their native cellular environment. While the use of 5 modified DNA donors has emerged as a promising strategy to improve the typically low efficiency of knock-in gene editing, the underlying mechanisms remain poorly understood. In this study, we conducted a comprehensive analysis of end-modified long linear dsDNA donors in CRISPR-mediated endogenous tagging in human non-transformed cells. In-depth analysis of repair patterns reveals that 5 biotinylation of dsDNA donors significantly reduces imprecise insertions, thereby enhancing homology-directed repair (HDR)-mediated precise insertion efficiency. Notably, the impact of biotinylation on repair patterns resembles that of non-homologous end joining (NHEJ) pathway inhibition, suggesting its role in preventing NHEJ-mediated mis-integration. Moreover, combining biotin modification with NHEJ inhibitor treatment further improves bi-allelic knock-in efficiency. Overall, this study provides novel insights into the mechanisms by which 5 modifications enhance precise knock-ins and demonstrates their potential for achieving high-efficient, prercise endogenous tagging in human cells.

cell biology↗