Biology subjects

Goto, A.

Publications and source records attributed to Goto, A..

9 recordsLinked to original sources

bioRxiv2026

Multi-omics analysis reveals chromatin and transcriptomic remodeling in hippocampal CA1 following adolescent social isolation

Social isolation (SI) during adolescence is associated with neurobiological alterations; however, its effect on the hippocampal epigenome and transcriptome remains unclear. We performed ATAC-seq and RNA-seq of hippocampal CA1 in an adolescent mouse SI model, with single-cell RNA-seq reference mapping and cell type deconvolution. ATAC-seq identified candidate SI-associated chromatin accessibility alterations, with nominal functional enrichment linking increased enhancer-associated regions to calcium transport and decreased promoter regions to synaptic organization. Motif analysis showed enrichment of the activator protein 1 (AP-1) motif among candidate regions with reduced accessibility. RNA-seq identified 106 differentially expressed genes (DEGs), including upregulated Fosl2 and Hdac9 and downregulated Fbxw7, with enrichment of myelination-related pathways. Although global concordance between chromatin accessibility and transcriptional changes was limited, integrated analysis showed directional concordance between expression and nearby candidate accessibility changes for a subset of DEGs. Cell type analyses suggested that SI-downregulated transcriptional signatures were linked to excitatory neurons, whereas SI-upregulated signatures were enriched in non-neuronal populations, particularly oligodendrocytes. Deconvolution suggested higher estimated oligodendrocyte representation and lower estimated excitatory neuron representation in isolated mice. These findings suggest that adolescent SI is associated with significant transcriptomic remodeling and candidate chromatin accessibility changes within hippocampal CA1, accompanied by distinct neuronal- and glial-associated transcriptional signatures.

neuroscience↗

bioRxiv2025

Pathological Angiogenesis Precedes the Onset of Aortic Dissection

Aortic dissection (AD) is a severe, life-threatening disease that occurs abruptly1. Although remodeling and inherent vulnerability of the aortic media, as observed in heritable connective tissue disorders such as Marfan syndrome, have been implicated in the onset of AD, the precise pathological mechanisms underlying the non-heritable form, which accounts for most cases, remains largely unknown2. Here, using hyperacute AD patient-derived samples, we show that pathological angiogenesis within the aortic media precedes the onset of dissection. Integrating single-cell transcriptomic analysis of aortic medial endothelial cells with high-resolution imaging revealed temporal changes preceding dissection. Hypoxic alterations in the media triggered osteochondrogenic changes in smooth muscle cells, promoted hydroxyapatite deposition, and induced angiogenesis via VEGF secretion from AD-specific CD14+CD68+CD163+MRC1(CD206)neg-low macrophages. Atomic force microscopy revealed that these processes culminated in the formation of a soft capillary layer, potentially concentrating stress on this region and contributing to AD onset. H&E staining of archived specimens revealed that non-heritable AD can be classified into angiogenic or non-angiogenic subtypes, with more than half exhibiting the former. In contrast, acute AD cases associated with Marfan syndrome typically exhibit a non-angiogenic pattern, suggesting distinct underlying mechanisms. This study reports angiogenesis as a key pathological driver in non-heritable AD and highlight potential targets for early diagnosis, prevention, and treatment.

pathology↗

bioRxiv2025

Generation of iPSC-derived CD4+ Th1 cells enhancing chimeric antigen receptor-T cell cytotoxicity

CD4+ T cells are anticipated to enhance the overall immune response, including the anti-tumor activity of chimeric antigen receptor (CAR)-T cell therapy. In the past, we established a culture system to generate CD8+ T cells from iPS cells (iPSCs); however, it was challenging to generate CD4+ T cells. Drawing inspiration from the observation that adult T cell leukemia (ATL) cells are consistently CD4+ and possess Treg characteristics, we successfully generated CD4+ Treg cells by reprogramming ATL cells into iPSCs and then differentiating them into T cells. Gene expression analysis of this generation system suggested that RUNX3 serves as a key regulator in T cell differentiation within the ex vivo generation system. By knocking out RUNX3, we demonstrated the generation of antigen-specific CD4+ Th1 cells via the iPSC route, thereby enhancing the activity of CD8+ CAR-T cells against GD2-expressing lymphoma. These technologies hold significant promise for contributing to "off-the-shelf" immunotherapies against malignant tumors, including solid tumors.

immunology↗

bioRxiv2024

Neutralizing antibody evasion of SARS-CoV-2 JN.1 derivatives KP.3, KP.3.1.1, LB.1, and XEC

The emergence of SARS-CoV-2 variants poses ongoing challenges to vaccine efficacy. We evaluated neutralizing antibody responses against JN.1 and its derivatives (KP.3, KP.3.1.1, LB.1, and XEC) in healthcare workers who received seven doses of BNT162b2, including XBB.1.5 monovalent vaccine. In COVID-19-naive individuals, KP.3.1.1 and LB.1 showed substantial immune escape, while previously infected individuals maintained neutralization activity against all variants. We also demonstrated that JN.1-based immunization induces robust cross-neutralizing activity against emerging variants. A single amino acid deletion at position 31 in the spike protein significantly impacted immune evasion. These findings support the potential effectiveness of JN.1-based vaccines while highlighting the need for continued surveillance and vaccine optimization.

immunology↗

bioRxiv2024

Spatial ciliary signaling regulates the dorsal/ventral regionalization of human brain organoids

Regionalization of the brain is a fundamental question in human developmental biology. Primary cilia are known for a critical organelle for dorsal/ventral fate of brain formation in mice, but little is known about how signaling in the primary cilia regulate regionalization of the human brain. Here, we found that signaling in the primary cilia function in regionalization of the brain using brain organoids derived from human induced pluripotent stem (iPS) cells. Deletion of a ciliary GTPase, ARL13B, induced partially ventralized neural stem cells in the dorsal cortical organoids, despite using a guided dorsal cortical organoid differentiation protocol. Mechanistically, ARL13B knockout (KO) neural stem cells decreased ciliary localization of GPR161, a negative regulator of SHH signaling in primary cilia and increased SONIC HEDGEHOG (SHH) signaling. GPR161 deletion also induced ventralized neural stem cells in the dorsal cortical organoids, despite using the guided differentiation protocol. GPR161 deletion increased SHH signaling mediated by decreased GLI3 repressor formation. Pharmacological treatment to increase cAMP levels rescued GLI3 repressor formation and the differentiation of dorsal neural stem cells in GPR161 KO brain organoids. Importantly, elevating the amount of ciliary cAMP by optogenetics restored the generation of dorsal neural stem cells in GPR161 KO brain organoids. These data indicate that spatial ciliary signaling, the ARL13B-GPR161-cAMP axis in primary cilia, is a fundamental regulator of the dorsal/ventral regionalization of the human brain.

developmental biology↗

bioRxiv2023

Latent taste diversity revealed by a vertebrate-wide catalogue of T1R receptors

Taste is a vital chemical sense for feeding behavior. In mammals, the umami and sweet taste receptors are composed of three members of the taste receptor type 1 (T1R/TAS1R) family: T1R1, T1R2, and T1R3. Because their functional homologs exist in teleosts, only three TAS1R genes generated by gene duplication are believed to have been inherited from the common ancestor of bony vertebrates. Here, we report five previously uncharacterized TAS1R members in vertebrates, named TAS1R4, 5, 6, 7, and TAS1Rcf, through a genome-wide survey of diverse taxa. For TAS1R2 and TAS1R3, mammalian and teleost fish genes were found to be paralogous. Phylogenetic analysis suggests that the bony vertebrate ancestor had nine TAS1Rs due to multiple gene duplications, and some TAS1Rs were lost independently in each lineage; ultimately, mammals and teleosts have retained only three TAS1Rs, whereas other lineages have retained more TAS1Rs. Functional assays and expression analysis in non-teleost fishes suggest that the novel T1Rs form heterodimers in taste receptor cells and contribute to the recognition of a broad range of ligands such as essential amino acids, including branched-chain amino acids, which were not previously considered as T1R ligands. These results highlight an unexpected diversity of taste sensations in both modern and the ancestors of vertebrates. The complex evolution of the taste receptor family might have enabled vertebrates to adapt to diverse habitats on Earth.

evolutionary biology↗

bioRxiv2021

Understanding the Genetics of Viral Drug Resistance by Integrating Clinical Data and Mining of the Scientific Literature

Drug resistance caused by mutations is a public health threat for existing and emerging viral diseases. A wealth of evidence about these mutations and their clinically-associated phenotypes is scattered across the literature, but a comprehensive perspective is usually lacking. This work aimed to produce a clinically-relevant view for the case of Hepatitis B virus (HBV) mutations by combining a chronic HBV clinical study with a compendium of genetic mutations systematically gathered from the scientific literature. We enriched clinical mutation data by systematically mining 2,472,725 scientific articles from PubMed Central in order to gather information about the HBV mutational landscape. By performing this analysis, we were able to identify mutational hotspots for each HBV genotype (A-E) and gene (C, X, P, S), as well as the location of disulfide bonds associated with these mutations. Through a modelling study, we also identified a mutational position common in both the clinical data and the literature that is located at the binding pocket for a known anti-HBV drug, namely entecavir. The results of this novel approach shows the potential of integrated analyses to assist in the development of new drugs for viral diseases that are more robust to resistance. Such analyses should be of particular interest due to the increasing importance of viral resistance in established and emerging viruses, such as for newly-developed drugs against SARS-CoV-2.

bioinformatics↗

bioRxiv2021

Shared and unique properties of place cells in anterior cingulate cortex and hippocampus

Hippocampal sharp-wave ripples (SWRs) and the associated replay of neuronal sequences are well-established as the primary physiological substrates for memory consolidation. While the local transformations they induce within the hippocampus are well-characterized, their impact on the downstream cortical representations remains unknown. Here, we identify a distinct functional class of neurons in the anterior cingulate cortex "spatial context cells" that emerge through the multi-day integration of discrete hippocampal inputs. Using closed-loop disruption of SWRs and longitudinal calcium imaging, we demonstrate that formation of this global spatial framework depends on SWRs during offline periods. Whereas standard cortical place maps remain intact following SWR disruption, the emergence of spatial context cells is selectively abolished. These cells preferentially express c-Fos, identifying them as constituents of the cortical memory engram, and exhibit broad receptive fields that develop through an experience-dependent process of field convergence. Collectively, these findings establish SWR-mediated replay as a computational bridge transforming high-resolution, fragmented hippocampal spatial codes into generalized, stable cortical schemas. This work reveals a bifurcated consolidation process, identifying SWR-dependent synaptic remodeling as a fundamental mechanism for the ontogeny of remote memory.

neuroscience↗

bioRxiv2018

Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila

One Sentence SummaryUpon microbial infection in Drosophila, the E3-ubiquitin ligase Hyd ubiquitinylates the NF-{kappa}B co-factor Akirin for its efficient binding to the NF-{kappa}B factor Relish and subsequent activation of immune effectors genes.\n\nABSTRACTThe Drosophila IMD pathway is activated upon microbial challenge with Gramnegative bacteria to trigger the innate immune response. In order to decipher this NF-{kappa}B signaling pathway, we undertook an ex-vivo RNAi screen targeting specifically E3 ubiquitin ligases and identified the HECT E3 ubiquitin ligase Hyperplastic Discs \"Hyd\" as a new actor of the IMD pathway. We showed that Hyd targets the NF-{kappa}B cofactor of Akirin. The K63-polyubiquitination chains deposited by Hyd decorate Akirin for its efficient binding to the NF-{kappa}B transcription factor Relish. We showed that this Hyd-mediated interaction is critical to activate immune-induced genes that depend on both Relish and Akirin, but is dispensable for those that depend solely on Relish. Therefore Hyd is key in operating a NF-{kappa}B transcriptional selectivity downstream of the IMD pathway. Drosophila depleted for Hyd or Akirin failed to express the full set of immune-induced anti-microbial peptide coding genes and succumbed to immune challenges. We showed further that Ubr5, the mammalian homolog of Hyd, is also required downstream of the NF-{kappa}B pathway for the IL1{beta}-mediated IL6 activation. This study links the action of a E3-ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases.

immunology↗