Biology subjects

Tanaka, M.

Publications and source records attributed to Tanaka, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration

Why mammals cannot regenerate limbs, unlike amphibians, presents a longstanding puzzle in biology. We show that exposing ex vivo amputated embryonic mouse limbs to subatmospheric oxygen environment, or stabilizing oxygen-sensitive HIF1A enables not only rapid wound healing, but alters cellular mechanics, and reshapes the histone landscape to prime regenerative fates. Conversely, regenerative Xenopus tadpole limbs display low oxygen-sensing capacity, robust wound healing, a regenerative histone landscape, and glycolytic programs even under high oxygen. This reduced oxygen-sensing capacity, in stark contrast to mammals, associates with decreased HIF1A-regulating gene expressions. Our findings thus uncover species-specific oxygen sensing as a unifying mechanism for limb regeneration initiation across vertebrates, reveal how aquatic subatmospheric habitats may enhance regenerative capabilities, and identify targetable barriers to unlock latent limb regenerative programs in adult mammals.

developmental biology↗

bioRxiv2024

A nucleic acid prodrug activates mitochondrial respiration and extends lifespan

Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan of Caenorhabditis elegans. AXP-driven stimulation of cellular energy metabolism proposed herein represents a novel geroprotective strategy and paves the way for the development of bioenergetic-molecule therapeutics.

bioengineering↗

bioRxiv2024

Meioc-Piwil1 complexes regulate rRNA transcription for differentiation of spermatogonial stem cells

Ribosome biogenesis is vital for sustaining stem cell properties, yet its regulatory mechanisms are obscure. Herein, we show unique properties of zebrafish meioc mutants in which spermatogonial stem cells (SSCs) do not differentiate or upregulate rRNAs. Meioc colocalized with Piwil1 in perinuclear germ granules, but Meioc depletion resulted in Piwil1 accumulation in nucleoli. Nucleolar Piwil1 interacted with 45S pre-rRNA. piwil1+/-spermatogonia with reduced Piwil1 upregulated rRNAs, and piwil1+/-;meioc-/- spermatogonia recovered differentiation later than those in meioc-/-. Further, Piwil1 interacted with Setdb1 and HP1, and meioc-/- spermatogonia exhibited high levels of H3K9me3 and methylated CpG in the 45S-rDNA region. These results indicate that zebrafish SSCs maintain low levels of rRNA transcription with repressive marks similar to Drosophila piRNA targets of RNA polymerase II, and that Meioc has a unique function on preventing localization of Piwil1 in nucleoli to upregulate rRNA transcripts and to promote SSC differentiation.

developmental biology↗

bioRxiv2024

Evolution of Key Factors Influencing Performance Across Phases in Junior Short Sprints

Sprint performance plays a crucial role in various sports. Short sprints vary in court size and competitive characteristics but are common in many sports. Although the relationship between age and muscle strength has been explored in short sprints, there is limited understanding of how various physical factors interact, particularly concerning differences in the acceleration phase. This study examined the relationship between sprint times at 0-2.5 m, 2.5-5 m, and 5-10 m intervals and various factors in junior athletes. Results indicated that sprint times increased with age, and is correlated with muscle strength and flexibility. Partial correlation analysis showed that faster times in the 0-2.5 m interval were associated with higher hip flexibility; in the 2.5-5 m interval, faster times were associated with higher core flexibility; and in the 5-10 m interval, a relationship with standing long jump performance was confirmed. Furthermore, lower fat-free body weight translated to higher performance. In the acceleration phase of 10 m, flexibility immediately after the start and the subsequent horizontal propulsive force is important factors that are strongly related to performance change in each interval. The study results illuminate the mechanism behind short sprints in junior athletes and emphasize the importance of daily training, considering the sprint distance required for each sport.

animal behavior and cognition↗

bioRxiv2024

SENP2-based N-terminal truncation of α-synuclein in Lewy pathology propagation

-Synuclein (Syn) is a major component of Lewy bodies (LBs) and Lewy neurites (LNs) which are pathological features of Parkinsons disease (PD) and Dementia with Lewy bodies. In the PD brain, with disease progression, LB/LN formation is propagated from the lower brainstem to the cerebral cortex. Prion-like cell-to-cell seed-transmission has been implicated as an underlying mechanism for Lewy-pathology propagation. However, the biochemical properties and production mechanism of those pathogenic seeds are unelucidated. In this study, we ascertained that the seeds released from pathological neurons that harbour LB/LN-like aggregates have the N-terminally truncated form of Syn. This N-terminal truncation is directly catalysed by SENP2, which is a well-known deSUMOylation enzyme. After SENP2 processing of recombinant Syn, the SDS-resistant high-molecular oligomer formation was promoted in vitro. Inhibition of SENP2 activity suppressed aggregate formation and propagation in cultured neurons and mouse brains. Thus, SENP2 might be a novel therapeutic target in LB diseases.

neuroscience↗

bioRxiv2024

Mitochondrial direct repeat reduction as a strategy for enhancing human longevity: the case of the common repeat

Aging, characterized by a series of functional declines correlated with advancing chronological age, has a significant mitochondrial DNA (mtDNA) component, with somatic mtDNA deletions playing a central role. In post-mitotic or slow-dividing cells like neurons and skeletal muscles, selfish mtDNA deletions clonally expand within a cell, ultimately leading to the deterioration and death of host cells and appearence of age-related phenotypes. Thus reducing the burden of somatic deletions could have far- reaching systemic benefits for the entire human body. Given the crucial role of direct nucleotide repeats in the formation of mitochondrial deletions, we hypothesize that minimizing these repeats in the human mitochondrial genome could enhance healthspan by decreasing somatic deletions. To investigate this hypothesis, we focus on the "common repeat", a 13-base pair perfect direct repeat sequence (ACCTCCCTCACCA) located at positions 8470-8482 and 13447-13459, respectively. This perfect repeat: (i) is highly prevalent, with its potential deleterious consequences affecting the majority of humans; (ii) represents one of the most fragile sites, highly prone to forming deletions; (iii) when disrupted, is associated with a decreased somatic deletion load and enhanced human healthspan; (iv) is likely to experience positive selection in the present or near future due to indirect fitness effects, such as the "grandmother effect", and direct fitness effects, such as (v) a decreased mutation rate. These observations support the argument that reducing the mtDNA somatic deletion load through targeted disruption of these repeats, or by using naturally occurring polymorphisms with disrupted repeats in mitochondrial medicine, could be an effective approach to increasing human longevity.

genetics↗

bioRxiv2024

Disruption of ultrasonic vocalization with systemic administration of the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 in adult male mice

Objective: Social behavior and communication, including ultrasonic vocalizations (USVs), are important for survival and reproductive success across species. N-methyl-D-aspartate (NMDA) receptors contribute to the neural mechanisms underlying social behavior, and pharmacological modulation of these receptors can alter both social behavior and USVs in rodents. However, the effects of NMDA receptor blockade on dyadic USVs and social approach during male-female interactions in mice remain incompletely understood. We therefore investigated the effects of systemic administration of MK-801, a noncompetitive NMDA receptor antagonist, on dyadic vocal activity, social approach, locomotor behavior, and excretory outcomes in adult male mice. Methods: Sexually experienced male mice were tested in male-female interaction and same-sex social-preference tasks. Using VocalMat, a machine-learning-based tool, we classified the USVs recorded during male-female interactions into 11 call categories and examined their temporal relationship to the proximity of the male subject to the female stimulus. Results: Administration of MK-801 to the male dose-dependently reduced the total number of USVs recorded from the male-female dyad, with a marked reduction at the highest dose, while leaving the treated male's proximity to the female stimulus unchanged. In the same-sex social-preference task, MK-801 reduced the time spent near the social stimulus at the highest dose, although preference for the social stimulus over the non-social object remained significant under all treatment conditions. MK-801 also increased locomotor activity and reduced fecal output and estimated urine output in the open-field task. These findings demonstrate that systemic NMDA receptor blockade differentially affects dyadic vocal communication, social approach, locomotor activity, and excretory outcomes. Conclusion: Systemic MK-801 administration to the male reduced the number of USVs recorded during male-female interactions and produced distinct effects on social approach, locomotor activity, and excretory outcomes. These findings indicate that NMDA receptor blockade differentially affects multiple behavioral domains, although the mechanisms underlying the reduction in USVs remain to be determined.

pharmacology and toxicology↗

bioRxiv2024

Genotype dependence of virulence-associated genes in ESBL-producing Escherichia coli isolated from the blood of patients with urinary tract infections

Approximately 80% of urinary tract infections (UTIs) are caused by uropathogenic Escherichia coli (UPEC). The prevalence of extended-spectrum {beta}-lactamase (ESBL)- producing E. coli in UPEC isolates belonging to specific multilocus sequence-type clones is a global concern. Relations between the pathogenicity of UPEC virulence factors and genotype have been discussed. However, the specific virulence factors and genotypes associated with a higher likelihood of causing UTIs remain unclear. This study analyzed the genotypes and virulence-associated genes of 46 ESBL-producing strains isolated from the blood of patients with UTIs who visited the Department of Emergency Medicine from 2017 to 2022 to elucidate the characteristics of UPEC strains associated with severe infections. Most phylogroups of clinical isolates were B2, except for D, found in three strains. The dominant multilocus sequence typing (MLST) was ST131, followed by ST73, ST95, and ST38, frequently observed in UPEC strains. ST131 strains were more resistant to levofloxacin (87.5%) than non-ST131 strains (50.0%) and caused fewer sepsis cases than non-ST131 strains. Based on in silico analysis, of 23 clinical isolates, the genes detected in all clinical strains could have important role in invasive UTIs. Clustering analysis highlighted the genotype MLST dependence of UPEC-specific virulence-associated genes. The absence of several UPEC-specific gene loci or the presence of ST38-specific indicated atypical repertories of virulence-associated genes in ST38 strains. Genes encoding secretion systems, which were found in enteropathogenic E. coli, were less detected in ST131 strains. These results suggested that the correlation of MLST and repertories should be considered to understand UPEC virulence. IMPORTANCE STATEMENTSeveral virulence genes, their diverse repertories depending on the strains, and various pathological indications complicate the pathogenicity of uropathogenic Escherichia coli (UPEC). The genes detected in all clinical isolates in this study would play a crucial role in UPEC pathogenicity. In contrast, depending on the genotype, the distribution of UPEC- specific genes and other pathogenic E. coli virulence genes in some genotype strains varied. Secretion system genes related to the pathogenicity of enteropathogenic E. coli (EPEC) were less in the strains of the most prevalent genotype, ST131; this was relevant to the number of sepsis cases. These results clearly indicated genotype dependencies on virulence-associated gene repertories and ambiguity in UPEC and EPEC. This study proposed that analyzing genotype-specific virulence factors and sharing virulence genes with EPEC will bring new insights into UPEC pathogenicity.

microbiology↗

bioRxiv2024

Exploring 3-Aminobenzoic Acid as a Therapeutic Dietary Component for Enhancing Intestinal Barrier Integrity in Ulcerative Colitis

BackgroundDietary components and their metabolites produced by intestinal bacteria play a crucial role in maintaining intestinal epithelial integrity. Disrupted epithelial integrity increases permeability and leads to chronic inflammation in the colon, known as ulcerative colitis (UC), in genetically predisposed individuals. However, the gut microbial metabolites regulating epithelial permeability remain unexplored and their metabolism in UC patients is unclear. MethodsA library of 119 gut microbial metabolites was screened for their ability to reduce epithelial permeability in Caco2 cell monolayers. The diet containing 3-aminobenzoic acid (3-ABA) was identified using liquid chromatography with quadrupole time-of-flight mass spectrometry. The abundance of fecal 3-ABA was compared between UC patients and healthy individuals followed by 16S rRNA metagenomic analysis to estimate the gut microbial function in ABA degradation. The anti-inflammatory effect of 3-ABA was examined in a mouse model of dextran sodium sulfate-induced colitis. ResultsStimulation with 3-ABA reduced epithelial permeability and enhanced barrier integrity in Caco2 cells by modulating the tight junctional regulatory pathway. 3-ABA was abundant in beans and decreased in the feces of UC patients. Functional prediction analysis of gut microbiota revealed an accelerated degradation of ABA with significant up-regulation of mabA, a gene encoding a bacterial enzyme involved in 3-ABA degradation, in UC patients. Rectal and oral administration of 3-ABA ameliorated experimental colitis in mice. Conclusion3-ABA abundant in beans enhanced intestinal epithelial integrity and ameliorated experimental colitis in mice. Proactive intake of 3-ABA might be a novel treatment approach for UC.

molecular biology↗

bioRxiv2024

Two types of regeneration mechanism in acute liver injury

The liver has a strong regenerative capacity, but the mechanisms of liver regeneration are not well understood. Furthermore, many previous studies on liver regeneration have been conducted in partial hepatectomy models, which may differ from acute liver injury with inflammation and necrosis, as observed in many clinical cases. In this study, we conducted a single-cell RNA-seq analysis (scRNA-seq) of liver regeneration in mice treated with acetaminophen (APAP) using publicly available data. We discovered that two cell proliferation populations appeared simultaneously during a single regenerative process. The two populations differed significantly in terms of differentiation, localization, proliferation rate, and signal response. Furthermore, one of the populations was induced by contact with necrotic tissue and exhibited a higher proliferative capacity with a dedifferentiated feature. These findings can shed new light on liver regeneration and aid in the development of therapeutic strategies for liver failure.

pathology↗

bioRxiv2024

AAV delivery of GBA1 suppresses alpha-synuclein accumulation in Parkinson's disease models and restores motor dysfunction in a Gaucher's disease model

Biallelic mutations in the glucosylceramidase beta 1 (GBA1) gene are the underlying genetic cause of Gauchers disease (GD), resulting in a deficient lysosomal hydrolase and subsequent accumulation of glycosphingolipids. More recently, GBA1 mutations have been identified as the most prevalent genetic risk factor for Parkinsons disease (PD), associated with more pronounced symptoms characterized by earlier onset and accelerated cognitive decline. In these GBA-associated PD patients the -synuclein pathology is more prominent, and recent data suggest a link between -synucleinopathies and GBA1 mutations. Here, we explored the effect of GBA1 gene supplementation on the GD phenotypes and -synuclein pathology by using the adeno-associated virus (AAV) system. We have compared two AAV serotypes, AAV5 and AAV9, and two different ubiquitous promoters, and demonstrate that both promoters work efficiently albeit not the same in vitro and in vivo. GBA1 overexpression reduces the accumulation of glucosylsphingosine (GlcSph) and restores motor dysfunction in a GD mouse model. We further demonstrate that GBA1 overexpression can dissolve phospho--synuclein aggregation induced by the addition of -synuclein pre-formed fibril (PFF) in a mouse primary neuron model suggesting the direct effect of {beta}-Glucocerebrosidase (GCase) on -synuclein accumulation. In vivo, we show that GCase inhibition can induce insoluble high-molecular-weight -synuclein aggregation and that delivery of GBA1 achieves robust reduction of the -synuclein aggregates in the mouse brain. In summary, GCase expression not only reduces GlcSph, but also restores GD motor dysfunction and removes -synuclein aggregates which are the hallmark for PD and -synucleinopathies. AAV delivery of GBA1 is a powerful approach to restore glucocerebrosidase function and to resolve misfolded -synuclein protein, with applications for GD and PD.

neuroscience↗

bioRxiv2024

Music-related Bodily Sensation Map in Individuals with Depressive Tendencies

Music has the power to influence peoples emotions. Therefore, music is also used as an intervention to reduce the stress in mental disorders such as depression and anxiety. Recent research has suggested that the body plays a key role in the connection between music and emotion with a correlation between the head sensations and negative emotions while listening to music. Additionally, strong sensations in the head have been suggested as a bodily perception associated with depression. In this study, we investigated the bodily sensations experienced by people with depressive tendencies when listening to music and their association with specific emotional states, using body mapping and musical chord progression. Our results revealed that individuals with depressive tendencies experience strong head sensations, with unpleasantness and low aesthetics, particularly for chord progression with a high level of surprise and uncertainty. This study sheds light on the intricate relationship between music, bodily sensations, and emotional states, providing valuable insights for research on the body and for developing musical therapeutic interventions targeting depression and related conditions.

physiology↗

bioRxiv2023

Development of a high throughput system to screen compounds that revert the activated hepatic stellate cells to a quiescent-like state

Chronic liver injury induces fibrosis that often proceeds to cirrhosis and hepatocellular carcinoma, indicating that prevention and/or resolution of fibrosis is a promising therapeutic target. Hepatic stellate cells (HSCs) are the major driver of fibrosis by expressing extracellular matrices (ECM). HSCs, in the normal liver, are quiescent and activated by liver injury to become myofibroblasts that proliferate and produce ECM. It has been shown that activated HSCs (aHSCs) become a "quiescent-like" state by removal of liver insults. Therefore, deactivation agents can be a therapeutic drug for advanced liver fibrosis. Using aHSCs prepared from human induced pluripotent stem cells, we found that aHSCs were reverted to a quiescent-like state by a combination of chemical compounds that either inhibit or activate a signaling pathway, Lanifibranor, SB431542, Dorsomorphin, retinoic acid, palmitic acid and Y27632, in vitro. Based on these results, we established a high throughput system to screen agents that induce deactivation and demonstrate that a single chemical compound can induce deactivation.

cell biology↗

bioRxiv2023

Activity-regulated micro-exon splicing programs underlie late-onset plasticity at the axon initial segment

The axon initial segment (AIS) is a specialized neuronal compartment located at the proximal end of axons and initiates action potentials. AIS undergoes plastic changes with aging, disease, and activity levels; however, the molecular mechanisms underlying their plasticity remain unclear. We discovered that depolarization induces diffuse elongation of the AIS in cerebellar granule cells over the span of days via the Ca2+-dependent ERK/MAP kinase pathway. These structural changes were accompanied by a decrease in voltage-gated Na+ channel density, resulting in a homeostatic attenuation in neuronal excitability. Notably, we found that the late-onset AIS plasticity is associated with depolarization-induced alternative splicing of smaller exons (<100 nt) of transcripts encoding AIS-enriched proteins. In addition, depolarization-induced the skipping of the 53-nt exon19 from the transcript of the splicing protein Rbfox1. CRISPR-mediated removal of exon 19 from Rbfox1 promoted its nuclear localization and sequentially induced a series of downstream micro-exon splicing changes in several AIS proteins, recapitulating cerebellar AIS plasticity. In a Rbfox1-independent mechanism, depolarization-induced insertion of the developmentally regulated micro-exon 34 into the key AIS scaffolding protein Ankyrin G (AnkG). The constitutive insertion of exon 34 into AnkG disrupted its interaction with the AIS cytoskeletal protein {beta}IV spectrin and induced plastic changes in the AIS. Our findings provide fundamental mechanistic insights into the activity-mediated late-onset plasticity of AIS, highlighting the power of micro-scale splicing events in the homeostatic regulation of axonal remodeling.

neuroscience↗

bioRxiv2023

Spatio-temporal Coordination of Active Deformation Forces and Wnt / Hippo-Yap Signaling in Hydra Regeneration

Ample evidence suggests that Wnt signaling and tissue deformation are key determinants for pattern formation in animals. The coordination of these biochemical and biomechanical spatio-temporal asymmetries is often unknown or controversial. We investigated this relationship by studying regeneration in the freshwater polyp Hydra. In both reaggregates of dissociated cells and tissue regenerates, we found significant tissue contraction waves and upregulation of Wnt signaling. Applying a simple mechanical model to the mode analysis of the active deformations, we quantitatively defined the phase reversal of size change and axial deformation in those oscillations as the time point of "biomechanical" symmetry breaking. Moreover, overexpression and inhibition of canonical Wnt signaling modulated the timing of this biomechanical symmetry breaking. A direct comparison with the RNAseq data indicates that the biomechanical symmetry breaking occurs only after the upregulation of canonical Wnt signaling. Further data suggest that biochemical signaling and biomechanical active deformation synergistically stabilize the body axis and hence the following head structure formation by Hippo-Yap signaling. The symmetry breaking mechanism identified here in Hydra most likely represents a patterning module that is evolutionary conserved from early metazoan to bilaterian animals.

biophysics↗

bioRxiv2023

Body Maps of Uncertainty and Surprise in Musical Chord Progression and its individual differences in Depression and Body Perception Sensitivity

Music has profoundly shaped the human experience across diverse cultures and generations, yet the mechanisms that it influences our minds and bodies remain elusive. This study examined how the perception of music chords elicits bodily sensations and emotions through predictive processing of the brain. By deploying body-mapping tests and emotional evaluations on 527 participants exposed to chord progressions, we unveil the intricate interplay between musical uncertainty, prediction error, and temporal dynamics in eliciting specific bodily sensations and emotions. Our results demonstrated that the chord progressions characterized by low uncertainty coupled with high surprise or predictability evoke bodily sensations closely associated with interoception including the cardiac and abdominal regions. Notably, these sensations are associated with aesthetic appreciation, with the intensity of cardiac sensations being positively correlated with valence in chord progressions with low uncertainty and high surprise. These results highlight the pivotal role of uncertainty and prediction error in shaping emotional responses and also suggest a hypothesis for emotion generation through predictive processing and sound embodiment. This study offers a tantalizing glimpse into the potential nexus between interoception by music and mental well-being, underscoring the importance of recognizing diverse forms of musical pleasure and their unique effects on our minds and bodies.

neuroscience↗

bioRxiv2023

Ran-GTP assembles a specialized spindle structure for accurate chromosome segregation in medaka early embryos

Despite drastic cellular changes during cleavage divisions, a mitotic spindle is assembled in each blastomere to accurately segregate duplicated chromosomes. Recent studies indicate that early embryonic divisions are highly error-prone in bovines and humans. However, processes and mechanisms of embryonic spindle assembly remain little understood in vertebrates. Here, we established live functional assay systems in medaka fish (Oryzias latipes) embryos by combining CRISPR knock-in with an auxin-inducible degron technology. In contrast to mammals, mitoses during cleavage divisions are very rapid (<12 min), but segregation errors are rarely observed. Importantly, we found that the Ran-GTP gradient assembles a specialized, dense microtubule network at the spindle midplane during metaphase, which is essential for faithful chromosome segregation in early embryos. In contrast, Ran-GTP becomes dispensable for chromosome segregation in later stages, where spindles are morphologically remodeled into short, somatic-like spindles lacking the dense microtubule network. We propose that the specialized Ran-based spindle structure ensures high fidelity of chromosome segregation in large, vertebrate early embryos.

developmental biology↗

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↗