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Ohta, S.

Publications and source records attributed to Ohta, S..

16 recordsLinked to original sources

MEG correlates of empty subjects in Japanese control and raising constructions

Empty categories are unpronounced elements with syntactic properties that play a central role in theories of sentence structure. Although there are several types within these categories, the neural basis for distinguishing among them remains unclear. Using magnetoencephalography, we investigate whether the brain distinguishes between two Japanese sentence structures: Control and raising. Although these constructions appear similar on the surface, they are argued to involve different types of empty categories. In theoretical analyses, the control-type empty category, which is called PRO, is often treated as an anaphoric element, similar to reflexives such as himself and herself, whereas the raising-type empty category is a noun phrase trace. Twenty-six native Japanese speakers participated in a reading task under three experimental conditions: Control, raising, and baseline. Source estimates were computed, and condition differences were tested using spatiotemporal cluster-based permutation t-tests. We observed late left-hemispheric differences at approximately 700-800 ms after the critical verb. The control condition elicited larger responses than the raising condition, with activity centered in the temporal cortex spanning the middle temporal gyrus and the superior temporal sulcus and gyrus and extending into the anterior insula and the supramarginal gyrus. In addition, the control condition elicited larger late responses than the baseline condition in a broader left fronto-temporal distribution, including the inferior frontal cortex, anterior temporal cortex, and insula. These results provide source-level evidence that brain activity in the left language network differs between the control and raising conditions in Japanese during online sentence comprehension. Furthermore, they suggest that we can distinguish empty category types in the brain.

neuroscience↗

Non-Canonical ERP Patterns in Second-language Sentence Processing: Evidence from Syntactic, Semantic, and Phonological Violations in Japanese Learners of English

Background/ObjectivesDespite notable advances in the neural mechanisms of second-language (L2) processing, few studies have systematically compared syntactic, semantic, and phonological processing of L2 within a single experimental design. We investigate the neurocognitive mechanisms underlying L2 sentence processing in native Japanese speakers with intermediate English proficiency. By integrating behavioral measures and event-related potentials (ERPs), we examined how syntactic, semantic, and phonological information influenced sentence comprehension. MethodsTwenty-seven participants completed an auditory sentence judgment task involving English sentences with a syntactic, semantic, or phonological error. ResultsBehavioral results revealed the highest accuracy in the control and semantic conditions, while syntactic and phonological violations led to significantly lower performance, indicating greater processing difficulty in these domains. Among the three linguistic violation types, phonological violations elicited the robust ERP negativities across both time 300-500 ms and 500-800 ms time windows, while syntactic and semantic violations evoked less consistent neural responses in this L2 auditory sentence judgment task. These results suggest that mismatches in expected phonological forms hinder lexical activation, triggering a negativity that resembles an N400 but reflects different underlying processes. ConclusionWe found non-canonical neural response patterns in L2 learners, characterized by sensitivity to phonological anomalies but minimal neural disruption for semantic or syntactic anomalies. The current study contributes to our understanding of L2 sentence processing in native Japanese speakers, particularly by aligning real-time neural responses with behavioral performance. This work offers implications for pedagogical practices and assessment strategies tailored to neurodiverse bilingual populations.

neuroscience↗

Two Sites, Two Languages: Dual-site tDCS and EEG Evidence for L1 Feature Transfer in L2

The neural bases of syntactic and semantic processing remain unclear. While prior transcranial direct current stimulation (tDCS) studies have targeted either the inferior frontal gyrus (LIFG) or left superior temporal gyrus (LSTG), we test whether dual stimulation of both alters second language (L2) anomaly based on native language (L1). Chinese and Korean participants evaluated Japanese sentence correctness; Japanese shares morpho-syntax with Korean and semantic radicals with Chinese. For the N400, dual anodal tDCS elicited a significant interaction stimulation and L1 (F (1,960.7) = 5.48, p = 0.0194), stimulation and sentence type (F (5,960.7) = 2.28, p = .0448), and L1 and sentence type (F (5, 960) = 2.28, p = 0.045). For the P600, a significant effect of stimulation and L1 interaction (F (1,1303.1) = 9.86, p = 0.0017), and stimulation x sentence type (F (5,1303.1) = 2.35, p = 0.039), suggesting L1 typology affected semantic integration during dual-stimulation tDCS.

neuroscience↗

Senotherapeutic potential against xeroderma pigmentosum

Xeroderma pigmentosum (XP) is an inherited photoaging syndrome caused by mutations in genes involved in the nucleotide excision repair (NER) pathway. XP patients exhibit hypersensitivity to ultraviolet (UV) radiation, leading to accelerated skin aging and requiring lifelong sun avoidance. Here, we demonstrate that UV-induced DNA damage triggers cellular senescence and up-regulates senescence-associated secretory phenotype (SASP) genes in melanocytes derived from an XP patient. To explore the potential therapeutics for XP, we developed a cisplatin-based drug screening system and identified JAK inhibitors and curcuminoids as promising senomorphic agents. In addition, two classes of senolytic agents, BCL-2-like protein inhibitors and HSP90 inhibitors, effectively eliminate senescent melanocytes. Further analysis demonstrates that senomorphic treatment effectively counteracts senescence and reduces SASP gene expression in XP-derived melanocytes. Moreover, genes in senescence-related pathways, including the JAK/STAT, Type I interferon (IFN-I), and PI3K/AKT pathways, which are activated by both UV irradiation and cisplatin treatment, are down-regulated by senomorphic treatment. This study highlights a potential senotherapeutic strategy for XP, which may help alleviate photoaging symptoms in XP patients.

cell biology↗

Modeling Dyslexia in Neurotypical Adults by Combining Neuroimaging and Neuromodulation Techniques: A Hypothesis Paper

Dyslexia is a prevalent developmental disorder marked by deficits in literacy skills. Given that the core deficits of dyslexia are uniquely human, animal models have not been as useful in dyslexia research as they have been in other areas of research. While significant progress has been made through behavioral and neuroimaging studies, a viable model could facilitate controlled investigations into the neural mechanisms underlying dyslexia and accelerate the development of targeted interventions. In this hypothesis article, we propose a two-pronged approach to model dyslexia in neurotypical adults using neuroimaging and neuromodulation techniques. First, we propose using functional and structural MRI data to cluster individuals into neuropathologically derived subgroups in order to facilitate the classification of dyslexia subtypes based on neuropathological characteristics. Second, we propose employing transcranial temporal interference stimulation (tTIS) to temporarily downregulate activity in brain regions specified in the clustering analysis, inducing subtype-specific dyslexic symptoms in neurotypical individuals. This approach enables the establishment of causal or probabilistic relationships between neuropathologies and dyslexia subtypes, while at the same time creating dyslexia models to facilitate investigation into subtype-specific interventions. By integrating neuroimaging and neuromodulation, we hope to offer a viable substitute for animal models in dyslexia and accelerate the development of personalized therapeutic strategies for dyslexia.

neuroscience↗

A role for condensin-mediator interaction in mitotic chromosomal organization

Eukaryotic genomes are organized by condensin into 3D chromosomal architectures suitable for chromosomal segregation during mitosis. However, molecular mechanisms underlying the condensin-mediated chromosomal organization remain largely unclear. Here, we investigate the role of newly identified interaction between the Cnd1 condensin and Pmc4 mediator subunits in fission yeast, Schizosaccharomyces pombe. We develop a condensin mutation, cnd1-K658E, that impairs the condensin-mediator interaction and find that this mutation diminishes condensin-mediated chromatin domains during mitosis and causes chromosomal segregation defects. The condensin-mediator interaction is involved in recruiting condensin to highly transcribed genes and mitotically activated genes, the latter of which demarcate condensin-mediated domains. Furthermore, this study predicts that mediator-driven transcription of mitotically activated genes contributes to forming domain boundaries via phase separation. This study provides a novel insight into how genome-wide gene expression during mitosis is transformed into the functional chromosomal architecture suitable for chromosomal segregation. O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/600663v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@488ab5org.highwire.dtl.DTLVardef@8a7a73org.highwire.dtl.DTLVardef@16d416eorg.highwire.dtl.DTLVardef@1e2d3db_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG In BriefMitotic chromosomes are organized by condensin into an architecture suitable for their segregation, although molecular mechanisms underlying how condensin assembles the functional chromosomal architecture remain unclear. This study with the fission yeast model organism shows that the protein interaction between condensin and mediator is involved in chromosomal segregation by forming a mitotic chromosomal architecture. A similar mechanism involving the condensin-mediator interaction is likely conserved in human cells, implying the evolutionary conservation of this mechanism. HighlightsO_LIThe Cnd1 condensin subunit interacts with the Pmc4 mediator component in fission yeast. C_LIO_LIThe condensin-mediator interaction is required to recruit condensin to highly transcribed and mitotically activated genes. C_LIO_LIThe condensin-mediator interaction is required to form chromatin domains during mitosis. C_LIO_LIMediator participates in the boundary formation of mitotic chromatin domains. C_LI

genomics↗

Chemo-senolytic therapeutic potential against angiosarcoma

Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype (SASP) genes are activated in senescent angiosarcoma cells and that ABT-263 treatment eliminates senescent cells expressing genes in the type-I interferon (IFN-I) pathway. Moreover, we show that cisplatin treatment alone requires a high dose to remove angiosarcoma cells, whereas a lower dose of cisplatin is sufficient to induce senescence, followed by the elimination of senescent cells by senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.

cancer biology↗

Causal evidence for the involvement of Broca's area in second language acquisition: A longitudinal HD-tDCS study

A wealth of correlational evidence suggests that Brocas area (the left inferior frontal gyrus) plays a role in second language acquisition. With the use of highly focal non-invasive brain stimulation, evidence for a targeted brain regions causal role in some cognitive behavior can be assessed. Over three sessions, each one week apart, we used online anodal high-definition transcranial direct current stimulation (HD-tDCS) over Brocas area during a novel foreign grammar training session. During training, participants who were naive to Spanish were tasked with acquiring present tense conjugation rules for the three Spanish verb endings. In Session 1, we observed significant improvement in performance in two linguistic (reception and production) tasks but not in a non-linguistic (working memory) task. Sessions 2 and 3 were subject to a ceiling effect, which obscured any potentially long-lasting effects of the stimulation. We interpret these results as support for the idea that Brocas area has languagelike specificity that is not limited to receptive or productive processes and as evidence that Brocas area plays a causal role in foreign grammar acquisition.

neuroscience↗

The Neurophysiological Modality Effect in Native and Second Language Processing: An ERP Study

Experimental psychology has long discussed the modality effect, whereby the stimulus modality significantly affects retention of the information presented. In neurolinguistics, however, the effect of stimulus modality on language processing has gained little attention. We conducted a multi-modal event-related potential (ERP) experiment on both native and non-native Spanish speakers to investigate the possibility of a neurophysiological modality effect in language processing. Using morphosyntactically violated and orthographically/phonologically violated stimuli, we elicited a robust N400 and P600 in native speakers. We showed that the N400 has consistent features across modalities, while the P600 has modality-specific features. Specifically, the auditory evoked P600 was characterized by a more gradual slope and a later peak than the visual evoked P600. We discuss this in detail along with other modality effects observed post sensory perception. Among second language (L2) learner groups, those with higher proficiency exhibited more nativelike neurophysiological responses in both modalities when compared to those with lower proficiency. We additionally observed fewer modality-specific differences in low proficiency learners than in higher proficiency learners suggesting that modality-specific specialization in language processing comes with increased proficiency. We further discuss the question of modality-specific differences in the process of neurophysiological nativization, whereby L2 learners ERPs become increasingly on nativelike.

neuroscience↗

Formation of pericentromeric heterochromatin via ZNF518 that links satellite DNA to heterochromatin

Aneuploidy is caused by chromosomal missegregation and is frequently observed in cancers and hematological diseases. Pericentromeric heterochromatin formation is essential for proper chromosome segregation; however, it is unclear how heterochromatin is targeted to pericentromeres. In this study, we investigated the involvement of two homologous zinc-finger proteins (ZNF518A and ZNF518B) in heterochromatin formation at pericentromeres by determining the cellular localization of ZNF518, centromeric proteins such as CENP-A and CENP-B, and heterochromatin factors, including HP1 and histone H3K9 trimethylation. The results showed that various segments in ZNF518 interact with CENP-B, HP1, and G9a histone H3K9 methyltransferase. In conclusion, we identified a novel mechanism underlying pericentromeric heterochromatin formation mediated by ZNF518.

cell biology↗

CCDC86/Cyclon is a novel Ki-67 interacting protein important for cell division

The chromosome periphery is a network of proteins and RNAs that coats the outer surface of mitotic chromosomes. Despite the identification of new components, the functions of this complex compartment are poorly characterised. In this study we identified a novel chromosome periphery-associated protein CCDC86/cyclon. Using a combination of RNAi (RNA interference), microscopy and biochemistry, we studied the functions of CCDC86/cyclon in mitosis. CCDC86/cyclon depletion resulted in partial disorganisation of the chromosome periphery with partial alterations in the localization of Ki-67 and Nucleolin and the formation of abnormal cytoplasmic aggregates. Furthermore, CCDC86/cyclon-depleted cells displayed errors in chromosome alignment, altered spindle length and increased apoptosis. These results suggest that, within the chromosome periphery, different subcomplexes that include CCDC86/cyclon, Nucleolin and B23 are required for mitotic spindle regulation and correct kinetochore-microtubule attachments, thus contributing to chromosome segregation in mitosis. Moreover, we have identified CCDC86/cyclon as a MYC-N regulated gene whose expression levels represent a powerful marker for prognostic outcomes in neuroblastoma. Summary statementHere we report the identification of CCDC86/cyclon as novel component of the perichromosomal layer. CCDC86 is important for chromosome segregation and represents a strong prognostic marker for neuroblastoma patients.

cell biology↗

Heterozygous loss of ZBTB38 leads to early embryonic lethality in mice via suppressing Nanog and Sox2

Mammalian DNA methylation is an epigenetic modification which is involved in various biological processes, including gene expression regulation. In mice, methyltransferases are responsible for DNA methylation, which are critical for early embryogenesis. However, the significance of methyl-CpG binding proteins (MBPs) that bind methylated CpG remains largely unknown. We previously demonstrated that ZBTB38/CIBZ-a zinc finger type of MBP-is required for ES cell proliferation by positively regulating Nanog expression. However, the physiological function of ZBTB38 remains unclear. In this study, we generated conditional ZBTB38 knockout mice using Cre-loxP technology. Unexpectedly, our results showed that germline loss of the ZBTB38 single allele resulted in decreased epiblast cell proliferation and increased apoptosis shortly after implantation, leading to early embryonic lethality. We found that heterozygous loss of ZBTB38 reduced the expression of Nanog, Sox2, and the genes responsible for epiblast proliferation, differentiation, and cell viability. Despite this lethal phenotype, ZBTB38 is dispensable for ES cell establishment and identity. Together, these findings indicate that ZBTB38 is essential for early embryonic development, providing new insights into the roles of MBP in implantation.

developmental biology↗

Cooperation among c-subunits of FoF1-ATP synthase in rotation-coupled proton translocation

In FoF1-ATP synthase, proton translocation through Fo drives rotation of the c-subunit oligomeric ring relative to the a-subunit. Recent studies suggest that in each step of the rotation, key glutamic acid residues in different c-subunits contribute to proton release to and proton uptake from the a-subunit. However, no studies have demonstrated cooperativity among c-subunits toward FoF1-ATP synthase activity. Here, we addressed this using Bacillus PS3 ATP synthase harboring c-ring with various combinations of wild-type and cE56D, enabled by genetically fused single-chain c-ring. ATP synthesis and proton pump activities were decreased by a single cE56D mutation and further decreased by double cE56D mutations. Moreover, activity further decreased as the two mutation sites were separated, indicating cooperation among c-subunits. Similar results were obtained for proton transfer-coupled molecular simulations. Simulations revealed that prolonged proton uptake in mutated c-subunits is shared between two c-subunits, explaining the cooperation observed in biochemical assays.

biochemistry↗

NFκB dynamics determine stimulus-responsive epigenomic reprogramming in macrophages

The epigenome defines the cell type, but also shows plasticity that enables cells to tune their gene expression potential to the context of extracellular cues. This is evident in immune sentinel cells such as macrophages, which can respond to pathogens and cytokines with phenotypic shifts that are driven by epigenomic reprogramming1. Recent studies indicate that this reprogramming arises from the activity of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF{kappa}B), which binds not only to available enhancers but may produce de novo enhancers in previously silent areas of the genome2. Here, we show that NF{kappa}B reprograms the macrophage epigenome in a stimulus-specific manner, in response only to a subset of pathogen-derived stimuli. The basis for these surprising differences lies in the stimulus-specific temporal dynamics of NF{kappa}B activity. Testing predictions of a mathematical model of nucleosome interactions, we demonstrate through live cell imaging and genetic perturbations that NF{kappa}B promotes open chromatin and formation of de novo enhancers most strongly when its activity is non-oscillatory. These de novo enhancers result in the activation of additional response genes. Our study demonstrates that the temporal dynamics of NF{kappa}B activity, which encode ligand identity3, can be decoded by the epigenome through de novo enhancer formation. We propose a mechanistic paradigm in which the temporal dynamics of transcription factors are a key determinant of their capacity to control epigenomic reprogramming, thus enabling the formation of stimulus-specific memory in innate immune sentinel cells.

molecular biology↗

TGF-β inhibitor accelerates BMP4-induced cochlear gap junction formation during in vitro differentiation of embryonic stem cells

Mutations in the connexin 26 (CX26)/gap junction beta-2 (GJB2) gene are the most frequent cause of hereditary deafness worldwide. Using mouse induced pluripotent stem cells (iPSCs) and a BMP4 signal-based floating and adherent culture system, we recently produced in vitro responsible for GJB2-related deafness (CX26-gap junction plaque-forming cells, CX26GJCs). However, to use these cells as a disease model platform for high-throughput drug screening or regenerative therapy, cell yields must be substantially increased. In addition to BMP4, presently uncharacterized factors may also induce CX26 gap junction (GJ) formation. A floating culture with embryonic stem cell (ESC) treatment and BMP4/TGF-{beta} inhibitor (SB431542:SB) has been shown to result in greater production of isolatable CX26-positive small vesicles (CX26+ vesicles) and higher Gjb2 mRNA levels than BMP4 treatment alone, suggesting that SB may promote BMP4-mediated production of CX26+ vesicles in a dose-dependent manner, thereby increasing the yield of highly purified CX26GJCs. In the present study, we first demonstrated that SB accelerates BMP4 induced GJ formation during stem cell differentiation. By controlling the concentration and timing of SB supplementation with CX26+ vesicle purification, large-scale production of highly purified CX26GJCs suitable for high-throughput drug screening or regenerative therapy for GJB2-related deafness may be possible.

cell biology↗

Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells

BackgroundEndothelial cells (ECs) make up the innermost layer throughout the entire vasculature. Their phenotypes and physiological functions are initially regulated by developmental signals and extracellular stimuli. The underlying molecular mechanisms responsible for the diverse phenotypes of ECs from different organs are not well understood.\n\nResultsTo characterize the transcriptomic and epigenomic landscape in the vascular system, we cataloged gene expression and active histone marks in nine types of human ECs (generating 148 genome-wide datasets) and carried out a comprehensive analysis with chromatin interaction data. We identified 3,765 EC-specific enhancers, some of which were associated with disease-associated genetic variations. We also identified various candidate marker genes for each EC type. Notably, reflecting the developmental origins of ECs and their roles in angiogenesis, vasculogenesis and wound healing.\n\nConclusionsWhile the importance of several HOX genes for early vascular development and adult angiogenesis in pathological conditions has been reported, a systematic analysis of the regulation and roles of HOX genes in mature tissue cells has been lacking. These datasets provide a valuable resource for understanding the vascular system and associated diseases.

genomics↗