Biology subjects

Nakanishi, N.

Publications and source records attributed to Nakanishi, N..

11 recordsLinked to original sources

bioRxiv2025

Kidney-specific lipid metabolism underlies stable chemical individuality in domestic cats and other felids

Domestic cats uniquely accumulate lipid droplets (LDs) in renal proximal tubular epithelial cells, but their chemical composition and biological functions remain unknown. Here, we identify a distinctive renal specialization in felids: lipid droplets enriched in branched-chain fatty acids (BFAs). These BFAs accumulate as triglyceride components and are excreted in urine as free fatty acids with stable and individually distinctive profiles. Behavioral assays show that cats discriminate urine samples based on BFA composition, even against complex volatile backgrounds, suggesting BFAs as robust, metabolically encoded olfactory signatures for individual recognition. Comparative analyses of non-domesticated felids reveal that BFA production is broadly conserved but exhibits both species-specific and individual variation. These findings demonstrate how a core metabolic pathway has been evolutionarily co-opted into a chemical signature system. This discovery highlights an unusual integration of renal physiology with social communication and expand our understanding of lipid metabolism, organ-level adaptation, and the evolution of chemical individuality in mammals. Significance statementUnique lipid droplets in felid kidneys reveal how organ-specific metabolism can be adapted for social communication.

zoology↗

bioRxiv2025

VEGF-C-mediated Cardiac Lymphangiogenesis Promotes Inflammation Resolution in Autoimmune Acute Myocarditis in Mice

BACKGROUNDAcute myocarditis is an immune-mediated inflammatory disease characterized by myocardial inflammation and edema. Cardiac lymphatic vessels are essential for fluid clearance and immune regulation; however, their role in modulating inflammation in autoimmune myocarditis remains largely unclear. METHODSWe investigated the impact of cardiac lymphangiogenesis using a murine model of experimental autoimmune myocarditis induced by cardiac myosin peptide immunization. Human autopsy samples were analyzed for lymphatic expansion. Mice were treated with VEGF-C C156S, a VEGFR3-specific agonist, beginning one week after immunization. Cardiac lymphangiogenesis, myocardial edema, inflammatory infiltration, fibrosis, and cardiac function were evaluated by immunohistochemistry, echocardiography, gene expression analysis, and water content measurements. RESULTSThe VEGF-C treatment accelerated cardiac lymphangiogenesis, enhanced lymphatic drainage, reduced myocardial edema, and attenuated inflammatory cell infiltration and fibrosis. Echocardiography showed the preservation of left ventricular function. VEGF-C selectively decreased the accumulation of iNOS inflammatory macrophages without broadly suppressing T cells or reparative macrophages. Bulk RNA sequencing confirmed the down-regulation of inflammatory gene signatures associated with macrophage activation. CONCLUSIONSThe early stimulation of cardiac lymphangiogenesis by VEGF-C promotes the resolution of inflammation, reduces myocardial injury, and preserves cardiac function in autoimmune myocarditis. Targeting the cardiac lymphatic system may represent a promising therapeutic strategy for acute myocarditis.

pathology↗

bioRxiv2024

Structural molecular and developmental evidence for cell-type diversity in cnidarian mechanosensory neurons

Deploying a conserved mechanosensory neuron known as the concentric hair cell, cnidarians have evolved diverse mechanoreceptors from hydroid filiform tentacles to jellyfish statocysts. However, it is unknown whether cnidarian mechanoreceptor evolution has relied solely on repurposing a single ancestral mechanosensory neuron type. Here we report evidence for cell-type diversity of mechanosensory neurons in sea-anemone cnidarian Nematostella vectensis. Uncovered in the ectoderm of feeding tentacles are conventional type I hair cells and previously unrecognized type II hair cells differing in the structure of apical sensory apparatus and synapses. Moreover, we identify TRP channel-encoding gene polycystin-1 as a type-II-hair-cell-specific essential mediator of gentle touch response. Ontogenically, type I and type II hair cells derive from distinct postmitotic precursors that begin forming at different phases of larval development. Taken together, our findings suggest that anatomically, molecularly, and developmentally distinct mechanosensory neurons diversified within Cnidaria, or prior to the divergence of Cnidaria and Bilateria.

evolutionary biology↗

bioRxiv2024

Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-Driven refractory vascular malformations

Congenital vascular malformations, affecting 0.5% of the population, often occur in the head and neck, complicating treatment due to the critical functions in these regions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these areas, tracing them to the cardiopharyngeal mesoderm (CPM), which contributes to the development of the head, neck, and cardiovascular system in both mouse and human embryos. In this study, we investigated the pathogenesis of these malformations by expressing Pik3caH1047R in the CPM. Mice expressing Pik3caH1047R in the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3caH1047R upregulates Vegf-a expression in endothelial cells through HIF-mediated hypoxia signaling. Human samples supported these findings, showing elevated HIF-1 and VEGF-A in malformed vessels. Notably, inhibition of HIF-1 and VEGF-A in the mouse model significantly reduced abnormal vasculature. These results highlight the role of embryonic origins and hypoxia-driven mechanisms in vascular malformations, providing a foundation for the development of therapies targeting these difficult-to-treat conditions.

molecular biology↗

bioRxiv2024

Identifying Genetic Variations in emm89 Streptococcus pyogenes Linked to Severe Invasive Infections

Streptococcus pyogenes causes mild human infections as well as life-threatening invasive diseases. Since the mutations known to enhance virulence to date account for only half of the severe invasive infections, additional mechanisms/mutations need to be identified. Here, we conducted a genome-wide association study of emm89 S. pyogenes strains to comprehensively identify pathology-related bacterial genetic factors (SNPs, indels, genes, or k-mers). Japanese (n=311) and global (n=666) cohort studies of strains isolated from invasive or non-invasive infections revealed 17 and 1,075 SNPs/indels and 2 and 169 genes, respectively, that displayed associations with invasiveness. We validated one of them, a non-invasiveness-related point mutation, fhuB T218C, by structure predictions and introducing it into a severe invasive strain and confirmed that the mutant showed slower growth in human blood. Thus, we report novel mechanisms that convert emm89 S. pyogenes to an invasive phenotype and a platform for establishing novel treatments and prevention strategies.

microbiology↗

bioRxiv2021

Cnidarian hair cell development illuminates an ancient role for the class IV POU transcription factor in defining mechanoreceptor identity

Although specialized mechanosensory cells are found across animal phylogeny, early evolutionary histories of mechanoreceptor development remain enigmatic. Cnidaria (e.g. sea anemones and jellyfishes) is the sister group to well-studied Bilateria (e.g. flies and vertebrates), and has two mechanosensory cell types - a lineage-specific sensory-effector known as the cnidocyte, and a classical mechanosensory neuron referred to as the hair cell. While developmental genetics of cnidocytes is increasingly understood, genes essential for hair cell development are unknown. Here we show that the class IV POU homeodomain transcription factor (POU-IV) - an indispensable regulator of mechanosensory cell differentiation in Bilateria and cnidocyte differentiation in Cnidaria - controls hair cell development in the sea anemone cnidarian Nematostella vectensis. N. vectensis POU-IV is postmitotically expressed in tentacular hair cells, and is necessary for development of the apical mechanosensory apparatus, but not of neurites, in hair cells. Moreover, it binds to deeply conserved DNA recognition elements, and turns on a unique set of effector genes - including the transmembrane-receptor-encoding gene polycystin 1 - specifically in hair cells. Our results suggest that POU-IV directs differentiation of cnidarian hair cells and cnidocytes via distinct gene regulatory mechanisms, and support an evolutionarily ancient role for POU-IV in defining the mature state of mechanosensory neurons.

evolutionary biology↗

bioRxiv2021

Characterization of a Novel Plasmid in Serratia marcescens Harboring blaGES-5 Isolated from a Nosocomial Outbreak in Japan

Serratia marcescens is a nosocomial pathogen with carbapenem resistance, limiting the availability of effective treatment options. In this study, we performed molecular characterization of GES-5 carbapenemase-producing S. marcescens isolated from an outbreak in Japan. Comparative genetic analysis revealed that the blaGES-5-encoding plasmid p2020-O-9 is a unique plasmid contributing towards carbapenem resistance. Furthermore, this study highlights the necessity of surveillance programs for monitoring novel, along with commonly occurring carbapenemases in clinical settings.

microbiology↗

bioRxiv2021

Single-Domain SARS-CoV-2 S1 and RBD Antibodies Isolated from Immunized Llama Effectively Bind Targets of the Wuhan, UK, and South African Strains in vitro

The spreading of SARS-CoV-2 variants has become a major challenge of the current fight against the pandemic. Of particular concerns are the strains that have arisen from the United Kingdom (UK) and South Africa. The UK variant spreads rapidly and is projected to overtake the original strain in the US as early as in March 2021, while the South African variant appears to evade some effects of the current vaccines. Potential false-negative diagnosis using currently available antigen kits that may not recognize these variants could cause another wave of community infection. Therefore, it is imperative that antibodies used in the detection kits are validated for binding against these variants. Here we report that the nanoantibodies (nAbs in our terminology, also referred to as VHH fragments, single domain antibodies, nanobodies) that we have developed for rapid antigen detection test bind the receptor binding domain (RBD) of the S1 protein from the original COVID-SARS-2 virus as well as those from the UK and South African variants. This finding validates our antibodies used in our assay for the detection of these major variant strains.

immunology↗

bioRxiv2020

Aberrant gliogenesis and excitation in MEF2C autism patient hiPSC-neurons and cerebral organoids

MEF2C has been shown to be a critical transcription factor for neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Here, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found an aberrant micro-RNA-mediated gliogenesis pathway that contributes to decreased neurogenesis. We also demonstrate network-level hyperexcitability in neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the extrasynaptic NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks suggesting that our approach may lead to personalized therapy for multiple forms of ASD. One sentence summaryAutism-like MEF2C+/- patient hiPSC models show miRNA-mediated overproduction of astrocytes and hyperactivity of neurons.

neuroscience↗

bioRxiv2020

Diversification of the restriction modification system of Streptococcus pyogenes through its acquisition of mobile elements

Restriction-modification (RM) systems are typically regarded as "primitive immune systems" in bacteria. The roles of methylation in gene regulation, segregation, and mismatch repair are increasingly recognized. To analyze methyltransferase (MTase) diversity in Streptococcus pyogenes, we compared the RM system distribution in eight new complete genome sequences obtained here and in the database-deposited complete genome sequences of 51 strains. The MTase gene distribution showed that type I MTases often change DNA sequence specificity via switching target recognition domains between strains. The type II MTases in the included strains fell into two groups: a prophage-dominant one and a CRISPR-dominant one. Some highly variable type II MTases were found in the prophage region, suggesting that MTases acquired from phage DNA can generate methylome diversity. Additionally, to investigate the possible contribution of DNA methylation to phenotype, we compared the methylomes and transcriptomes from the four most closely related strains, the results of which suggest that phage-derived methylases possibly regulate the methylome, and, hence, regulate expression levels in S. pyogenes. Our findings will benefit further experimental work on the relationship between virulence genes and pathogenicity in S. pyogenes.

microbiology↗

bioRxiv2020

Genetic characterization of Streptococcus pyogenes emm 89 strains isolated in Japan from 2011 to 2019

Streptococcal toxic shock syndrome (STSS) caused by Streptococcus pyogenes emm89 strains has been increasing in several countries and reported to be linked with a recently emerged clade of emm89 strains, designated clade 3. In Japan, epidemiological and genetic information for emm89 strains remains elusive. In this study, we utilized emm89 strains isolated from both STSS (89 isolates) and non-STSS (72 isolates) infections in Japan from 2011 to 2019, and conducted whole-genome sequencing and comparative analysis, which resulted in classification of a large majority into clade 3 regardless of disease severity. In addition, STSS-associated genes and SNPs were found in clade 3 strains, including mutations of streptokinase (Ska), control of virulence sensor (CovS), serum opacity factor (SOF), sortase (SrtB), and fibronectin-binding protein F1 (PrtF1), and absence of the hylP1 gene encoding hyaluronidase. These findings provide insights into notable genetic features of emm89 strains.

microbiology↗