Biology subjects

Ono, R.

Publications and source records attributed to Ono, R..

8 recordsLinked to original sources

bioRxiv2026

Stressor-specific dynamic patterns of noradrenaline release in the paraventricular nucleus of the hypothalamus in freely moving mice

An organism is constantly challenged with various stressors. These stress signals ultimately converge on the hypothalamic paraventricular nucleus (PVN), where they are integrated by corticotropin-releasing hormone (CRH)-producing neurons that are primarily involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline (NA), among others, is recognized as the major transmitter that regulates the PVN-CRH neurons, and thereby is involved in the regulation of the HPA axis as well as the autonomic outflow. Previous studies have demonstrated that stress increases NA release within the PVN1 and that NA activates CRH neurons2. However, NA release patterns from the axon terminals in the PVN upon stress exposure have not yet been studied, because continuous monitoring of transmitter release became possible only recently. In the present study, we aimed to monitor stressor-dependent NA release patterns in the PVN. To continuously monitor NA release in freely moving mice, a fluorescent NA sensor (GRABNA)3,4 was expressed in the PVN, and the emitted signals were recorded via fibre photometry. Following stress exposure, NA release took place over distinct timescales ranging from seconds to hours. For example, a pulsatile NA release was observed in seconds in response to an acute nociceptive stressor. In contrast, sustained physical stressors, such as tail suspension and restraint, induced much more prolonged NA release that persists throughout the stress exposure period over tens of minutes. Intraperitoneal administration of lipopolysaccharide produced a gradual increase in NA release that persisted for several hours. These findings demonstrate that NA is released into the PVN in a stress-specific manner. In addition, elevated NA release was associated with increased behavioural activity, characteristic of each stressor. Together, these findings provide a framework for understanding how the temporal dynamics of NA release in the PVN encode diverse stress signals, and regulate neuroendocrine outputs.

neuroscience↗

bioRxiv2026

Bridge recombinase enables versatile rewriting of bacterial genomes

Bacteria drive crucial processes across ecosystems and impact human health, yet tools to rewrite microbiomes remain limited. Here, we show that bridge recombinase enables versatile and programmable genome editing across the bacterial tree of life. In Escherichia coli, we achieved 142 kb insertions at >90% efficiency, megabase-scale inversions (2.3 Mb), and pathway-scale 50 kb excisions. With a single ortholog and bridge RNA (bRNA), we edited bacterial isolates spanning five phyla and diverse members of two human gut communities. We overcame cross-reactivity between co-expressed bRNAs to establish search-and-replace Targetable Recombinase Assisted DNA Exchange (TRADE) editing and demonstrated capture and interphylum transfer of chromosomal pathways, enabling programmable horizontal gene transfer. These advances establish bridge recombinase as a foundation for reprogramming gene flow in complex microbial communities.

synthetic biology↗

bioRxiv2025

Host range and ARG dissemination are shaped by distinct survival strategies of conjugative plasmids

Horizontal gene transfer is a major driver of bacterial evolution and the global dissemination of antibiotic resistance genes (ARGs). Conjugative plasmids play a crucial role in ARG spread across hosts within their host range, yet the genetic and functional determinants shaping plasmid host range remain poorly understood. Here, we systematically analyzed the gene content of conjugative/mobilizable plasmids from public databases and found that two distinct survival strategies were enriched in different host-range groups: a "stealth" strategy, which minimizes host fitness costs by employing a global regulator h-ns, was particularly enriched in broad-host-range plasmids, whereas an "aggressive" strategy, which protects plasmids by actively inhibiting host response including SOS response by encoding the SOS inhibitor psiB, was more common in narrow-host-range plasmids. Plasmids employing either strategy constituted the majority of all conjugative plasmids analyzed, and accumulated significantly more ARGs than plasmids with neither strategy. Our data further suggested that stealth plasmids facilitate the acquisition of emerging ARGs, while aggressive plasmids amplify the copy number of established ARGs. This "stealth-first" model successfully recapitulated historical ARG dissemination patterns. These findings provide critical insights into the relationship between plasmid survival strategies and host range, advancing our understanding of the global patterns underlying plasmid-mediated ARG transmission. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/655438v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@bb692dorg.highwire.dtl.DTLVardef@1f639f1org.highwire.dtl.DTLVardef@562f75org.highwire.dtl.DTLVardef@45e1e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Targeting of retrovirus-derived Rtl8a/8b reduces social response and increases apathy-like behavior associated with GABRB2 reduction

Retrotransposon Gag-like (RTL) 8A, 8B and 8C are eutherian-specific genes derived from a certain retrovirus. They clustered as a triplet of genes on the X chromosome, but their function remains unknown. Here, we demonstrate that Rtl8a and Rtl8b play important roles in the brain: their double knockout (DKO) mice not only exhibit reduced social responses and increased apathy-like behavior, but also become obese from young adulthood. Mouse RTL8A/8B proteins are expressed in the prefrontal cortex and hypothalamus and localize to both the nucleus and cytoplasm of neurons, presumably due to the N-terminal nuclear localization signal-like sequence at the N-terminus. An RNAseq study in the cerebral cortex revealed reduced expression of several GABA type A receptor subunits, in particular the {beta}2 subunit of Gabrb2, in DKO. We confirmed the reduction of GABRB2 protein in the DKO cerebral cortex by Western blotting. As GABRB2 has been implicated in the etiology of several neurodevelopmental disorders, it is likely that the reduction of GABRB2 is one of the major causes of the neuropsychiatric defects in the DKO mice.

molecular biology↗

bioRxiv2023

Targeting retrovirus-derived Rtl8a and 8b causes late onset obesity and neurodevelopmental defects

Retrotransposon Gag-like (RTL) 8A, 8B and 8C are triplet genes of uncertain function that form a cluster on the X chromosome. They are eutherian-specific genes presumably derived from a certain retrovirus. Here, we demonstrate that Rtl8a and Rtl8b play an important role in growth and behavior via brain functions in the hypothalamus and prefrontal cortex. Rtl8a and Rtl8b double knockout (DKO) mice exhibited overgrowth due to hyperphagia from young adulthood and reduced social responses, increased apathy-like behavior. RTL8A and RTL8B proteins are localized to both the nucleus and cytoplasm of neurons presumably due to an N-terminal nuclear localization signal-like sequence. An increment in nucleus size was also detected in the neurons in the prefrontal cortex, suggesting neuronal dysfunction. These data give another strong evidence that retrovirus-derived acquired genes contributed to the establishment of the current eutherian developmental system in a wide variety of ways. Summary statementRtl8a and Rtl8b double knockout mice exhibited late onset obesity and neurodevelopmental defects, demonstrating that these eutherian specific retrovirus-derived acquired genes encoding proteins with only 113 amino acids play important roles in the brain presumably via their functions in the hypothalamus and prefrontal cortex.

molecular biology↗

bioRxiv2022

Oncolytic adenovirus serotype 35 mediated tumor growth suppression via efficient activation and tumor infiltration of natural killer cells

BackgroundOncolytic adenoviruses (OAds) mediate superior antitumor effects both by inducing direct oncolysis and activating antitumor immunity. Previously, we developed a novel OAd fully composed of human adenovirus serotype 35 (OAd35). OAd35 efficiently killed a variety of human tumor cells; however, OAd35-mediated activation of antitumor immunity remains to be evaluated. In this study, we examined whether OAd35-induced activation of immune cells contributes to the antitumor effects of OAd35. MethodsTumor infiltration and activation of immune cells following intratumoral administration of OAd35 in tumor-bearing immune-competent and nude mice were analyzed. The involvement of natural killer (NK) cells in the tumor growth-suppression effects of OAd35 was evaluated in NK cell-depleted mice. The key signals for the OAd35-mediated tumor infiltration of NK cells were examined in interferon (IFN) alpha and beta receptor subunit 1 (IFNAR1) knockout and toll-like receptor 9 (TLR9) knockout mice. ResultsOAd35 efficiently induced tumor infiltration of activated NK cells. NK cell depletion apparently hindered the OAd35-mediated tumor growth suppression. In IFNAR1 knockout mice, OAd35-induced tumor infiltration of activated NK cells was significantly attenuated. OAd35 did not induce tumor infiltration of NK cells in TLR9 knockout mice, although OAd35 significantly activated NK cells and showed tumor growth suppression in TLR9 knockout mice. ConclusionsOAd35 significantly promoted activation and tumor infiltration of NK cells, leading to OAd35-mediated efficient tumor growth suppression. The type-I IFN signal was crucial for the OAd35-mediated tumor infiltration and activation of NK cells. The TLR9 signal was highly related to tumor infiltration of NK cells, but not NK cell activation and antitumor effects of OAd35. These findings suggest that OAd35 becomes a promising cancer immunotherapy agent via its enhancement of the antitumor activities of NK cells.

cancer biology↗

bioRxiv2021

Ancient genomes from the last three millennia support multiple human dispersals into Wallacea

Previous research indicates that the human genetic diversity found in Wallacea - islands in present-day Eastern Indonesia and Timor-Leste that were never part of the Sunda or Sahul continental shelves - has been shaped by complex interactions between migrating Austronesian farmers and indigenous hunter-gatherer communities. Here, we provide new insights into this regions demographic history based on genome-wide data from 16 ancient individuals (2600-250 yrs BP) from islands of the North Moluccas, Sulawesi, and East Nusa Tenggara. While the ancestry of individuals from the northern islands fit earlier views of contact between groups related to the Austronesian expansion and the first colonization of Sahul, the ancestry of individuals from the southern islands revealed additional contributions from Mainland Southeast Asia, which seems to predate the Austronesian admixture in the region. Admixture time estimates for the oldest individuals of Wallacea are closer to archaeological estimates for the Austronesian arrival into the region than are admixture time estimates for present-day groups. The decreasing trend in admixture times exhibited by younger individuals supports a scenario of multiple or continuous admixture involving Papuan- and Asian-related groups. Our results clarify previously debated times of admixture and suggest that the Neolithic dispersals into Island Southeast Asia are associated with the spread of multiple genetic ancestries.

genomics↗

bioRxiv2021

PEG10 viral aspartic protease domain is essential for the maintenance of fetal capillary structure in the mouse placenta

The therian-specific gene paternally expressed 10 (Peg10) plays an essential role in placenta formation: Peg10 knockout (KO) mice exhibit early embryonic lethality due to severe placental defects. The PEG10 protein exhibits homology to long terminal repeat (LTR) retrotransposon GAG and POL proteins, therefore mice harboring a mutation in its highly conserved viral aspartic protease motif in the POL-like region were generated because it is essential for LTR retrotransposons/retroviruses. Intriguingly, frequent perinatal lethality, not early embryonic lethality, was observed with fetal and placental growth retardation starting mid-gestation. In the mutant placentas, severe defects were observed in the fetal vasculature, where PEG10 is expressed in the three trophoblast cell layers that surround fetal capillary endothelial cells. Thus, Peg10 has essential roles not only in early placenta formation, but also in placental vasculature maintenance from mid- to late-gestation. This implies that along the feto-maternal placenta interface an interaction occurs between two retrovirus-derived genes, Peg10 and retrotransposon Gag like 1 (Rtl1, also called Peg11), that is essential for the maintenance of fetal capillary endothelial cells. Summary statementDisruption of the highly conserved viral aspartic protease domain in PEG10 causes placental abnormality leading to perinatal lethality in mice.

developmental biology↗