Biology subjects

Tanaka, S.

Publications and source records attributed to Tanaka, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Stabilization Mechanism of Initiator Transfer RNA in the Small Ribosomal Subunit from Coarse-Grained Molecular Simulations

Proteins play a variety of roles in biological phenomena in cells. Proteins are synthesized by a ribosome, which is a large molecular complex composed of proteins and nucleic acids. Among many molecules involved in the process of protein synthesis, transfer RNA (tRNA) is one of the essential molecules. In this study, coarse-grained molecular dynamics simulations were performed to understand how the tRNA molecule is stabilized in the ribosome, and the free energy along the dissociation path of the tRNA was calculated. We found that some ribosomal proteins, which are components of the ribosome, are involved in the stabilization of the tRNA. The positively charged amino acid residues in the C-terminal region of the ribosomal proteins are particularly important for the stabilization. These findings contribute to our understanding of the molecular evolution of protein synthesis in terms of the ribosome, which is a universal component of life. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/603193v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@180f160org.highwire.dtl.DTLVardef@671705org.highwire.dtl.DTLVardef@187fd6org.highwire.dtl.DTLVardef@70c5ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

HD-ZIP IV genes are essential for embryo initial cell polarization in the radial axis initiation in Arabidopsis

Plants develop along apical-basal and radial axes. In Arabidopsis thaliana, the radial axis becomes evident when the cells of the eight-cell proembryo divide periclinally, forming inner and outer cell layers. Although changes in cell polarity or morphology likely precede this oriented cell division, the initial events and the factors regulating radial axis formation remain elusive. Here, we report that three transcription factors belonging to class IV homeodomain-leucine zipper (HD-ZIP IV) family redundantly regulate radial pattern formation: HOMEODOMAIN GLABROUS11 (HDG11), HDG12, and PROTODERMAL FACTOR2 (PDF2). The hdg11 hdg12 pdf2 triple mutant failed to undergo periclinal division at the eight-cell stage and cell differentiation along the radial axis. Live-cell imaging revealed that this failure in radial axis formation can be traced back to the behavior of the embryo initial cell (apical cell), which is generated by zygote division. In the wild type, the apical cell grows longitudinally and then radially and its nucleus remains at the bottom of the cell, where the vertical cell plate emerges. By contrast, the mutant apical cell elongates longitudinally and its nucleus releases from its basal position, resulting in a transverse division. Computer simulations based on the live-cell imaging data confirmed the importance of the geometric rule (the minimal plane principle and nucleus-passing principle) in determining the cell division plane. We propose that HDG11, HDG12, and PDF2 promote apical cell polarization, i.e., radial cell growth and basal nuclear retention, as the initial event of radial axis formation during embryogenesis.

plant biology↗

bioRxiv2024

Dysregulated expanded endocannabinoid system as therapeutic targets of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of upper and lower motor neurons. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance. Herein, to elucidate the systemic metabolic changes related to ALS progression, we performed metabolomics analysis on the serum of ALS patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NAT) were correlated with the longitudinal change in the revised ALS functional rating scale (ALSFRS-R) rating. In vitro experiments with ALS cell models and in vivo studies with SOD1G93A transgenic mice revealed that PF-04457845, a fatty amide acid hydrolase (FAAH) inhibitor, up-regulated the expanded ECS, particularly the levels of NATs and N-acyl ethanolamine and ameliorates motor neuron degeneration through the regulation of microglial polarization, synapse plasticity, and neuronal development. Our study indicates that dysregulation of the expanded ECS is associated with ALS progression and a target for novel disease-modifying therapies.

neuroscience↗

bioRxiv2023

Impact of body image on the kinematics of gait initiation

In our daily lives, we walk naturally because we can consider our physical characteristics and formulate appropriate motor plans. However, the impact of changes in body image during motor planning on walking movements remains poorly understood. Therefore, in this study, we investigated how walking movements change when body image is altered. We included 26 participants (13 males, 13 females, aged 18.27{+/-}0.52) to perform walking movements under five conditions: open eyes (baseline), closed eyes, closed eyes while imagining their bodies becoming large, closed eyes again, and open eyes again. As a result, under the condition where participants imagined their bodies becoming large, their stride length, step completion time, and foot lift height increased. These results are attributed to the disparity between actual body size and body image, which affects motor planning. The results of this study have potential applications in rehabilitation and sports coaching settings.

animal behavior and cognition↗

bioRxiv2023

Virological characteristics of the SARS-CoV-2 Omicron EG.5.1 variant

In middle-late 2023, a sublineage of SARS-CoV-2 Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. Here, we performed multiscale investigations to reveal virological features of newly emerging EG.5.1 variant. Our phylogenetic-epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T, are critical to the increased viral fitness. Experimental investigations addressing the growth kinetics, sensitivity to clinically available antivirals, fusogenicity and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 is comparable to that of XBB.1.5. However, the cryo-electron microscopy reveals the structural difference between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible at least in our experimental setup. Our multiscale investigations provide the knowledge for understanding of the evolution trait of newly emerging pathogenic viruses in the human population.

microbiology↗

bioRxiv2023

Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection

Monitoring in vivo viral dynamics can improve our understanding of pathogenicity and tissue tropism. For positive-sense, single-stranded RNA viruses, several studies have attempted to monitor viral kinetics in vivo using reporter genomes. The application of such recombinant viruses can be limited by challenges in accommodating bioluminescent reporter genes in the viral genome. Conventional luminescence also exhibits relatively low tissue permeability and thus less sensitivity for visualization in vivo. Here we show that unlike NanoLuc bioluminescence, the improved method, termed AkaBLI, allows visualization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Syrian hamsters. By successfully incorporating a codon-optimized Akaluc luciferase gene into the SARS-CoV-2 genome, we visualized in vivo infection, including the tissue-specific differences associated with particular variants. Additionally, we could evaluate the efficacy of neutralizing antibodies and mRNA vaccination by monitoring changes in Akaluc signals. Overall, AkaBLI is an effective technology for monitoring viral dynamics in live animals.

microbiology↗

bioRxiv2023

Low-latency extracellular spike assignment for high-density electrodes at single-neuron resolution

Real-time neural signal processing is essential for brain-machine interfaces and closed-loop neuronal perturbations. However, most existing applications sacrifice cell-specific identity and temporal spiking information for speed. We developed a hybrid hardware-software system that utilizes a Field Programmable Gate Array (FPGA) chip to acquire and process data in parallel, enabling individual spikes from many simultaneously recorded neurons to be assigned single-neuron identities with 1-millisecond latency. The FPGA assigns labels, validated with ground-truth data, by comparing multichannel spike waveforms from tetrode or silicon probe recordings to a spike-sorted model generated offline in software. This platform allowed us to rapidly inactivate a region in vivo based on spikes from an upstream neuron before these spikes could excite the downstream region. Furthermore, we could decode animal location within 3 ms using data from a population of individual hippocampal neurons. These results demonstrate our systems suitability for a broad spectrum of research and clinical applications.

neuroscience↗

bioRxiv2023

Virological characteristics of the SARS-CoV-2 XBB.1.5 variant

Circulation of SARS-CoV-2 Omicron XBB has resulted in the emergence of XBB.1.5, a new Variant of Interest. Our phylogenetic analysis suggests that XBB.1.5 evolved from XBB.1 by acquiring the F486P spike (S) mutation, subsequent to the acquisition of a nonsense mutation in ORF8. Neutralization assays showed similar abilities of immune escape between XBB.1.5 and XBB.1. We determined the structural basis for the interaction between human ACE2 and the S protein of XBB.1.5, showing similar overall structures between the S proteins of XBB.1 and XBB.1.5. The intrinsic pathogenicity of XBB.1.5 in hamsters is lower than that of XBB.1. Importantly, we found that the ORF8 nonsense mutation of XBB.1.5 resulted in impairment of MHC expression. In vivo experiments using recombinant viruses revealed that the XBB.1.5 mutations are involved with reduced virulence of XBB.1.5. Together, these data suggest that the mutations in ORF8 and S could enhance spreading of XBB.1.5 in humans.

microbiology↗

bioRxiv2023

Upregulated Fcrl5 disrupts B cell anergy and causes autoimmunity

B cell anergy plays a critical role in maintaining self-tolerance by inhibiting autoreactive B cell activation to prevent autoimmune diseases. Here, we demonstrated that Fc receptor-like 5 (Fcrl5) upregulation contributes to autoimmune disease pathogenesis by disrupting B cell anergy. Fcrl5--a gene whose homologs are associated with human autoimmune diseases--is highly expressed in age/autoimmunity-associated B cells (ABCs), an autoreactive B cell subset. By generating B cell-specific Fcrl5 transgenic mice, we demonstrated that Fcrl5 overexpression in B cells caused systemic autoimmunity with age. Furthermore, Fcrl5 upregulation in B cells exacerbated the systemic lupus erythematosus-like disease model and increased the levels of ABCs and activated T cells. Mechanistically, an increase in Fcrl5 expression broke B cell anergy, activating autoreactive B cells in the presence of a self-antigen. Fcrl5 facilitated toll-like receptor signaling, reactivating anergic B cells. Thus, Fcrl5 is a potential regulator of B cell-mediated autoimmunity by regulating B cell anergy. This study provides important insights into the role of Fcrl5 in breaking B cell anergy and its effect on the pathogenesis of autoimmune diseases.

immunology↗

bioRxiv2023

Diurnal variation of brain activity in the human suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, the SCN was localized, and its activity was investigated using perfusion imaging. We scanned each participant four times a day, every six hours, and higher activity was observed at noon while lower activity was recorded in the early morning. The SCN activity was then measured every thirty minutes for six hours from midnight to dawn and showed a decreasing trend and was comparable with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of mammals and is modulated by physical lights rather than the local time.

neuroscience↗

bioRxiv2023

Intratumoral administration of recombinant murine interleukin-12 prevents tumor progression and bone invasion

BackgroundOral squamous cell carcinoma (OSCC) progression is accompanied by bone invasion. Therefore, maintaining oral function is necessary to regulate tumor progression. Also, interleukin-12 (IL-12), a well-known anti-tumor cytokine, can suppress osteoclast differentiation in vitro. Accordingly, this study evaluated the therapeutic effects of locally administered IL-12 in an immunocompetent mouse model with mandibular bone invasion mimicking clinical features. MethodsWe investigated anti-bone resorption effects using SCCVII subcutaneous and bone invasion models both in immunocompetent and athymic mice. Furthermore, we measured bone resorption using micro-computed tomography. ResultsIntratumoral injection of recombinant murine IL-12 (r-mIL-12) significantly prolonged immunocompetent mouse survival and suppressed tumor growth and bone resorption. Real-time PCR analysis revealed that interferon-gamma (IFN-{gamma}) and Fas ligand (FasL) were upregulated after r-mIL-12 administration, compared to control levels. However, when the athymic mouse bone invasion model was evaluated, r-mIL-12-mediated suppression of tumor growth and bone resorption were equivalent to those observed in the control group, highlighting the key role of T cells in the bone invasion. Conclusionsr-mIL-12 may represent a potent therapeutic agent for OSCC accompanied by bone invasion. SUMMARYIntratumoral injection of recombinant murine IL-12 showed anti-tumor and anti-bone resorption effects in an immunocompetent mouse bone invasion model through a T cell-dependent mechanism.

cancer biology↗

bioRxiv2023

Mental navigation and telekinesis with a hippocampal map-based brain-machine interface

The hippocampus is critical for recollecting and imagining experiences. This is believed to involve voluntarily drawing from hippocampal memory representations of people, events, and places, including the hippocampus map-like representations of familiar environments. However, whether the representations in such "cognitive maps" can be volitionally and selectively accessed is unknown. We developed a brain-machine interface to test if rats could control their hippocampal activity in a flexible, goal-directed, model-based manner. We show that rats can efficiently navigate or direct objects to arbitrary goal locations within a virtual reality arena solely by activating and sustaining appropriate hippocampal representations of remote places. This should provide insight into the mechanisms underlying episodic memory recall, mental simulation/planning, and imagination, and open up possibilities for high-level neural prosthetics utilizing hippocampal representations.

neuroscience↗

bioRxiv2023

Senescence triggers intracellular acidification and lysosomal alkalinization via ATP6AP2 attenuation in breast cancer cells

Several chemotherapy drugs induce the senescence of cancer cells; however, the mechanism underlying intracellular pH dysregulation in senescent cells remains unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. We here report a new function of ATP6AP2 in senescent breast cancer cells induced by doxorubicin and abemaciclib treatment. ATP6AP2 expression was significantly downregulated in senescent cells, leading to aberrant pH levels that impaired lysosome function and caused immune response changes. The drugs caused cell cycle arrest and proliferation suppression through the upregulation of senescence-related genes. Additionally, senescent cells showed altered inflammatory and immune transcriptional profiles by reprogramming the senescence-associated secretory phenotype. These findings suggest that ATP6AP2-mediated pH regulation during therapy-induced senescence may be linked to immune changes in senescent cancer cells. These findings provide novel insights into understanding the cellular mechanisms underlying the response to anti-cancer drugs.

cancer biology↗

bioRxiv2023

Anesthetic-Binding Induced Motion of GABA A Receptors Revealed by Coarse-Grained Molecular Dynamics Simulations

General anesthetics are indispensable in modern medicine because they induce a reversible loss of consciousness and sensation in humans. On the other hand, their molecular mechanisms of action have not yet been elucidated. Several studies have identified the main targets of some general anesthetics. The structures of {gamma}-aminobutyric acid A (GABAA) receptors with the intravenous anesthetics such as propofol and etomidate have recently been determined. Although these anesthetic-binding structures provide essential insights into the mechanism of action of anesthetics, the detailed molecular mechanism of how the anesthetic binding affects the Cl- permeability of GABAA receptors remains to be elucidated. In this study, we performed coarse-grained molecular dynamics simulations for GABAA receptors and analyzed the resulting simulation trajectories to investigate the effects of anesthetic binding on the motion of GABAA receptors. The results showed large structural fluctuations in GABAA receptors, correlations of motion between the amino-acid residues, large amplitude motion, and autocorrelated slow motion, which were obtained by advanced statistical analyses. In addition, comparison of the resulting trajectories in the presence or absence of the anesthetic molecules revealed a characteristic pore motion related to the gate-opening motion of GABAA receptors.

biophysics↗

bioRxiv2023

Nutrient-regulated dynamics of chondroprogenitors in the postnatal murine growth plate

Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone. The chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate. Malnutrition is a leading cause of growth retardation in children; however, after recovery from nutrient deprivation, bone growth is accelerated beyond the normal rate, a phenomenon termed catch-up growth. Though nutritional status is a known regulator of long bone growth, it is largely unknown if and how chondroprogenitor cells respond to deviations in nutrient availability. Here, using fate-mapping analysis in Axin2CreERT2 mice, we showed that dietary restriction increased the number of Axin2+ chondroprogenitors in the resting zone and simultaneously inhibited their differentiation. Once nutrient deficiency was resolved, the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns, contributing to accelerated growth. Furthermore, we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone, and that exogenous IGF-1 canceled this reduction and stimulated differentiation of the pooled chondroprogenitors, decreasing their numbers. Our study of Axin2CreERT2 revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate, and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of the chondroprogenitor cells.

developmental biology↗

bioRxiv2022

Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants

In late 2022, the SARS-CoV-2 Omicron subvariants have highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged by recombination of two co-circulating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022 around India. In vitro experiments revealed that XBB is the most profoundly resistant variant to BA.2/5 breakthrough infection sera ever and is more fusogenic than BA.2.75. Notably, the recombination breakpoint is located in the receptor-binding domain of spike, and each region of recombined spike conferred immune evasion and augmented fusogenicity to the XBB spike. Finally, the intrinsic pathogenicity of XBB in hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provided evidence suggesting that XBB is the first documented SARS-CoV-2 variant increasing its fitness through recombination rather than single mutations.

microbiology↗

bioRxiv2022

Deleterious mutations in a heterozygous chromosome result in recessive lethality in silkworm semiconsomic strains

In this study, we found two embryonic lethal mutations, t04 lethal (l-t04) and m04 lethal (l-m04), in semiconsomic strains T04 and M04, respectively. In these semiconsomic strains, the entire diploid genome, except for one chromosome 4 of the wild silkworm Bombyx mandarina, is substituted with chromosomes of the domesticated silkworm B. mori, and l-t04 and l-m04 mutations are located on B. mandarina-derived chromosome 4. The mutations responsible for the l-t04 and l-m04 were identified as the Bombyx homolog of imaginal discs arrested (Bmida) and TATA Box Binding Protein-associated factor 5 (BmTaf5), respectively. These findings indicate that both mutations were independently introduced during or after the development of semiconsomic strains. We conclude that the recessive embryonic lethality in the T04 and M04 strains is due to deleterious mutations produced in B. mandarina-derived chromosome 4. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/521575v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1c59ea3org.highwire.dtl.DTLVardef@131fbf0org.highwire.dtl.DTLVardef@93515borg.highwire.dtl.DTLVardef@1c23afe_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2022

End-to-end protein-ligand complex structure generation with diffusion-based generative models

Three-dimensional structures of protein-ligand complexes provide valuable insights into their interactions and are crucial for molecular biological studies and drug design. However, their high-dimensional and multimodal nature hinders end-to-end modeling, and earlier approaches depend inherently on existing protein structures. To overcome these limitations and expand the range of complexes that can be accurately modeled, it is necessary to develop efficient end-to-end methods. We introduce an equivariant diffusion-based generative model that learns the joint distribution of ligand and protein conformations conditioned on the molecular graph of a ligand and the sequence representation of a protein extracted from a pre-trained protein language model. Benchmark results show that this protein structure-free model is capable of generating diverse structures of protein-ligand complexes, including those with correct binding poses. Further analyses indicate that the proposed end-to-end approach is particularly effective when the ligand-bound protein structure is not available. The present results demonstrate the effectiveness and generative capability of our end-to-end complex structure modeling framework with diffusion-based generative models. We suppose that this framework will lead to better modeling of protein-ligand complexes, and we expect further improvements and wide applications.

bioinformatics↗