Biology subjects

Mori, C.

Publications and source records attributed to Mori, C..

12 recordsLinked to original sources

bioRxiv2026

Distribution-Constrained Optimization for Reliable ML-Guided 5'UTR Sequence Design

The 5' untranslated region (5' UTR) shapes translation initiation, so its design is central to mRNA therapeutics and to improving protein-production cell lines. Deep-learning models that predict translation efficiency, measured as mean ribosome load (MRL), from the 5' UTR sequence have been combined with genetic algorithms (GAs) for sequence optimization. However, optimizing against a model trained on offline data risks reward hacking that exploits the models estimation error outside the training distribution, yielding sequences that score highly in prediction yet fail to perform in the wet lab. Yet for 5' UTR design, few studies have systematically examined which region should be treated as untrustworthy (the definition of out-of-distribution, OOD) or which constraints keep the search away from it. We present a constrained optimization that keeps candidates within a trust region where the predictors validated accuracy holds; here "reliable" denotes keeping candidates within the training distribution over which prediction has been validated, not a guarantee of measured performance. As the OOD score, we compare the k-nearest-neighbor (KNN) distance in the predictors embedding space against a pseudo-perplexity (PPPL) from the encoder and LM head, and show that for nucleotide sequences--whose vocabulary is small--PPPL fails to separate in- vs out-of-distribution, whereas the KNN distance is an effective OOD score that can define a trust region even from unlabeled native UTR sequences. Using the KNN distance as a hard GA constraint keeps all candidates inside the trust region while maintaining predicted MRL: under unconstrained optimization most final-generation candidates (72-96% across seeds) left the trust region (self-KNN p95), whereas the hard constraint holds predicted MRL at the unconstrained level and yields about 4.3x more selectable low-risk candidates than post-hoc filtering of the unconstrained output. Comparing an output extrapolation guard, reference-sequence similarity and structural accessibility (RNAplfold), we find that the guard and the similarity constraint also suppress OOD as a side effect, whereas making accessibility a secondary objective broadens the search without suppressing OOD.

bioinformatics↗

bioRxiv2025

Why early birds sing early: rebound singing from nighttime suppression can explain dawn chorus

Many birds sing vigorously at dawn, a phenomenon widely known as the "dawn chorus." While its adaptive functions have been extensively studied, the proximate mechanisms underlying this widespread phenomenon have remained largely unexplored. Here, we demonstrate that intense morning singing resembling the dawn chorus is evoked as a rebound from singing suppression prior to dawn in captive zebra finches. Our findings indicate that when birds become hormonally aroused in darkness well before dawn, the suppression of spontaneous singing by darkness enhances their intrinsic motivation to sing. This elevated motivation subsequently triggers a rebound of intense singing immediately upon an increase in ambient light. These results reveal mechanisms by which intense morning singing arises from the interaction between the birds arousal state and ambient light, providing a plausible mechanistic explanation for the dawn chorus. Additionally, we found that rebound morning singing accelerates morning changes in song structure, supporting the existing hypothesis that the dawn chorus functions as a vocal warm-up to rapidly optimize song performance following nighttime silence. Together, our findings provide both mechanistic and functional insights into the dawn chorus and other diel vocal patterns in songbirds.

animal behavior and cognition↗

bioRxiv2023

Auditory feedback-independent maintenance of song performance through daily singing in adult songbirds

Many songbirds learn to produce songs through vocal practice early in life and continue to sing numerous renditions of their learned songs daily throughout their lifetime. While it is well-known that adult songbirds sing as part of a mating ritual, the functions of singing behavior outside of reproductive contexts are not fully understood. Here, we demonstrate that adult singing outside of reproductive contexts serves to prevent passive changes in song performance. We suppressed the daily singing behavior of adult zebra finches produced in the solo context for two weeks using a reversible behavioral manipulation and examined the effect on song performance. Our results indicated that suppressing daily singing significantly decreased the pitch of song elements and both the amplitude and duration of song motifs. These findings suggest that adult song is not acoustically stable without singing, and that adult birds maintain their song performance by daily singing. Moreover, we found that the changes in song structure caused by singing suppression were substantially recovered within two weeks of free singing, even in deafened birds. Thus, the recovery of song performance does not necessarily require auditory feedback but is predominantly caused by singing behavior per se (i.e., the physical act of singing). Finally, unlike the auditory feedback-dependent song plasticity reported previously, the passive song changes caused by singing suppression were not significantly dependent on age. Taken together, our findings demonstrate that adult songbirds maintain song performance by preventing passive song changes through the physical act of daily singing throughout their life. Such daily singing likely functions as vocal training to maintain the neural and/or muscular system in optimal conditions for song performance in reproductive contexts, similar to how human singers and athletes practice daily to maintain their performance.

animal behavior and cognition↗

bioRxiv2022

Biophysical insight into protein-protein interactions in the Interleukin-11/Interleukin-11Rα/glycoprotein 130 signaling complex

Interleukin-11 (IL-11) is a member of the interleukin-6 (IL-6) family of cytokines. IL-11 is a regulator of multiple events in hematopoiesis, and IL-11-mediated signaling is implicated in inflammatory disease, cancer, and fibrosis. All IL-6 family cytokines signal through the signal-transducing receptor, glycoprotein 130 (gp130), but these cytokines have distinct as well as overlapping biological functions. To understand IL-11 signaling at the molecular level, we performed a comprehensive interaction analysis of the IL-11 signaling complex, comparing it with the IL-6 complex, one of the best-characterized cytokine complexes. Our thermodynamic analysis revealed a clear difference between IL-11 and IL-6. Surface plasmon resonance analysis showed that the interaction between IL-11 and IL-11 receptor (IL-11R) is entropy driven, whereas that between IL-6 and IL-6 receptor (IL-6R) is enthalpy driven. Our analysis using isothermal titration calorimetry revealed that the binding of gp130 to the IL-11/IL-11R complex results in entropy loss, but that the interaction of gp130 with the IL-6/IL-6R complex results in entropy gain. Our hydrogen-deuterium exchange mass spectrometry experiments suggested that the D2 domain of gp130 was not involved in n IL-6-like interactions in the IL-11/IL-11R complex. It has been reported that IL-6 interaction with gp130 in the signaling complex was characterized through the hydrophobic interface located in its D2 domain of gp130. Our findings suggest that unique interactions of the IL-11 signaling complex with gp130 are responsible for the distinct biological activities of IL-11 compared to IL-6.

biochemistry↗

bioRxiv2022

Growth, organic matter release, aggregation and recycling during a diatom bloom: A model-based analysis of a mesocosm experiment

Mechanisms terminating phytoplankton blooms are often not well understood. Potentially involved processes such as consumption by grazers, flocculation, and viral lysis each have different post-bloom consequences on the processing of the organic material, therefore it is important to develop a better understanding of the relevance of these processes, and potential interactions between them. In this study, we present a model-based analysis of a spring bloom observed in a mesocosm experiment. The intermediate-complexity (27-state variable) numerical model we extended from an earlier version to this end can resolve C, N, P and Si cycles, and relevant processes like formation of various organic material size classes (low and high molecular weight (hereafter small and large) dissolved organic carbon (DOC), transparent exopolymer particles (TEP), and small/large detritus) and their degradation by two bacterial sub-communities (free-living and particle-attached) and planktonic protists (heterotrophic flagellates and ciliates). The model can explain > 90% of the variation of a rich set of observations consisting of 11 independent variables over the course of 13 days during which a bloom largely dominated by diatoms develops, and disappears almost entirely. Fluxes estimated by the model point to the importance of coagulation (TEP formation) as a sink term for DOC, and a source term for POC. Consequently, aggregation with TEPs constitute an important loss term for phytoplankton. The flocculated phytoplankton, and detrital material, in turn become rapidly degraded by the particle attached bacteria and other protist heterotrophs. Through a scenario analysis, the relevance of nutrient-stress enhanced lysis rates; alterations between small and large DOC in phytoplankton exudates; and coagulation of smaller DOC molecules were investigated. Our results suggest that the former two processes have negligible effects in isolation, but when combined with the latter, they can synergistically cause substantial deviations in TEP formation, hence, in flocculation rates; and consequently in the peak magnitude of the diatom bloom, and in timing of its termination. Our results point to a need for better understanding of processes governing the termination of phytoplankton blooms, their inter-dependencies, and consequences on the global biogeochemical cycles.

microbiology↗

bioRxiv2021

Arousal-dependent auditory response in the brain of Bengalese finches as measured by gene expression

Songbirds use auditory feedback to maintain their own songs. Juveniles also memorize a tutor song and use memory as a template to make up their own songs through auditory feedback. A recent electrophysiological study revealed that HVC neurons respond to BOS playback only in low arousal, sleeping, or anesthetized conditions. One outstanding question is how does auditory suppression occur in the brain? Here, we determined how arousal affects auditory responses simultaneously in the whole brain and over the song neural circuit in Bengalese finches, using the immediate early gene egr-1 as a marker of neural activity. Our results showed that auditory responses in the low-arousal state were less susceptible to gating, which was also confirmed by gene expression, and that the suppression may be weaker than observed in previous zebra finch studies. This may be because the Bengalese finch is a domesticated species. In addition, our results suggest that information may flow from the MLd.I of the midbrain to higher auditory regions. Altogether, this study presents a new attempt to explore the auditory suppression network by simultaneously investigating the whole brain using molecular biology methods.

neuroscience↗

bioRxiv2021

Microtubule inhibitors enhance DNA transfection efficiency through autophagy receptor p62/SQSTM1

Ectopic gene expression is an indispensable tool in biology and medicine, but is often limited by the low efficiency of DNA transfection. We previously reported that depletion of the autophagy receptor p62/SQSTM1 enhances DNA transfection efficiency by preventing the degradation of transfected DNA. Therefore, p62 is a potential target for drugs to increase transfection efficiency. To identify such drugs, a non-biased high-throughput screening was applied to over 4,000 compounds from the Osaka University compound library, and their p62-dependency was evaluated. The top-scoring drugs were mostly microtubule inhibitors, such as colchicine and vinblastine, and all of them showed positive effects only in the presence of p62. To understand the p62-dependent mechanisms, the time required for p62-dependent ubiquitination, which is required for autophagosome formation, was examined using polystyrene beads that were introduced into cells as materials that mimicked transfected DNA. Microtubule inhibitors caused a delay in ubiquitination. Furthermore, the level of phosphorylated p62 at S405 was markedly decreased in the drug-treated cells. These results suggest that microtubule inhibitors inhibit p62-dependent autophagosome formation. Our findings demonstrate for the first time that microtubule inhibitors suppress p62 activation as a mechanism for increasing DNA transfection efficiency and provide solutions to increase efficiency.

cell biology↗

bioRxiv2021

Decreased synthesis and variable gene transcripts of oxytocin in a domesticated avian species

The Bengalese finch was domesticated more than 250 years ago from the wild white-rumped munia. Similar to other domesticated species, Bengalese finches show a reduced fear response and have lower corticosterone levels, compared to white-rumped munias. Bengalese finches and munias also have different song types. Since oxytocin (OT) has been found to be involved in stress coping and auditory processing, we tested whether the OT sequence and brain expression pattern and content differ in wild munias and domesticated Bengalese finches. We identified intra-strain variability in the untranslated regions of the OT sequence in Bengalese finches in comparison to the munia OT. Several of these changes fall in specific transcription factor binding sites, which show either a conserved or a relaxed evolutionary trend in the avian lineage, and in vertebrates in general. Although in situ hybridization in several hypothalamic nuclei did not reveal significant differences in the number of cells expressing OT between the two strains, real-time quantitative PCR showed significantly lower OT mRNA expression in the diencephalon of the Bengalese finches relative to munias. Our study thus points to a decreased OT synthesis in the domestic strain compared with the wild strain in birds. This is an opposite pattern from that found in some domesticated mammals, suggesting that different processes of OT function might have occurred in mammals and birds under domestication.

neuroscience↗

bioRxiv2020

Fast retrograde access to projection neuron circuits underlying vocal learning in songbirds

Understanding the structure and function of neural circuits underlying speech and language is a vital step towards better treatments for diseases of these systems. Songbirds, among the few animal orders that share with humans the ability to learn vocalizations from a conspecific, have provided many insights into the neural mechanisms of vocal development. However, research into vocal learning circuits has been hindered by a lack of tools for rapid genetic targeting of specific neuron populations to meet the quick pace of developmental learning. Here, we present a new viral tool that enables fast and efficient retrograde access to projection neuron populations. In zebra finches, Bengalese finches, canaries, and mice, we demonstrate fast retrograde labeling of cortical or dopaminergic neurons. We further demonstrate the suitability of our construct for detailed morphological analysis, for in vivo imaging of calcium activity, and for multicolor brainbow labeling.

neuroscience↗

bioRxiv2019

Angiocrine factors from HUVECs amplify erythroid cells

Erythropoiesis is regulated by microenvironmental factors from the vasculature. Enhanced erythropoiesis, which occurs under stress or during development, amplifies erythroid cells to meet the demand of red blood cells. This process uncouples cell division and differentiation, thus the accumulated erythroid cells remain undifferentiated in the vasculature. However, little is known about how vascular endothelial cells (ECs) regulate erythropoiesis. Here we identified that human umbilical vein endothelial cells (HUVECs) keep erythroid cells undifferentiated and amplify their number. We determined that HUVECs amplify erythroid cells via secreted angiocrine factors. The expression profile of these factors suggested that they resemble macrophage-crines for enhanced erythropoiesis. Molecularly, HUVECs mediate the activation of ERK signaling. These data indicate that angiocrine factors from HUVECs enhance erythropoiesis via the amplification of undifferentiated erythroid cells. Our study contributes to the ultimate goal of harnessing erythropoiesis to replace blood transfusions.

developmental biology↗

bioRxiv2019

Biomimetic Aorta-Gonad-Mesonephros on-a-Chip to Study Human Developmental Hematopoiesis

We established a multilayer microfluidic Aorta-Gonad-Mesonephros (AGM)-on-a-chip to emulate developmental hematopoiesis from human pluripotent stem cells. We show that the AGM-chip efficiently derives endothelial-to-hematopoietic transition (EHT) in the presence of mesenchymal stroma and endothelial cells. The AGM-chip could dissect the cellular and molecular mechanisms of human developmental hematopoiesis.

bioengineering↗

bioRxiv2017

Compositionally distinct nuclear pore complexes of functionally distinct dimorphic nuclei in ciliate Tetrahymena

SUMMARY STATEMENTOur study demonstrates compositional and structural differences of the nuclear pore complex between the functionally differentiated macronucleus and micronucleus within a single cytoplasm of ciliated protozoa.\n\nABSTRACTThe nuclear pore complex (NPC), a gateway for nucleocytoplasmic trafficking, is composed of about 30 different proteins called nucleoporins. It remains unknown whether the NPCs within a species are homogeneous or vary depending on the cell type, or physiological condition. Here, we present evidence for compositionally distinct NPCs that form within a single cell in a binucleated ciliate. In Tetrahymena thermophila, each cell contains both a transcriptionally-active macronucleus (MAC) and a germline micronucleus (MIC). By combining in silico analysis, mass spectrometry analysis for immuno-isolated proteins, and subcellular localization analysis of GFP fused proteins, we identified numerous novel components of MAC and MIC NPCs. Core members of the Nup107-160 scaffold complex were enriched in MIC NPCs. Strikingly, two paralogs of Nup214 and of Nup153 localized exclusively to either MAC or MIC NPCs. Furthermore, the transmembrane components Pom121 and Pom82 localize exclusively to MAC and MIC NPCs, respectively. Our results argue that functional nuclear dimorphism in ciliates is likely to depend on compositional and structural specificity of NPCs.

cell biology↗