Biology subjects

Yoshimoto, T.

Publications and source records attributed to Yoshimoto, T..

11 recordsLinked to original sources

bioRxiv2026

Inflammatory restraint and membrane lipid integrity protect hematopoietic stem cells under stress

Life-long production of blood requires the preservation of hematopoietic stem cell (HSCs) regenerative capacity during inflammation. The cytokine, Thrombopoietin (THPO), is essential for HSC maintenance yet its role during inflammatory stress remains incompletely understood. Long-term repopulating potential was rapidly depleted in THPO-deficient HSCs upon poly(I:C) administration through inflammatory pyroptosis. Transcriptomic and chromatin accessibility analyses revealed constitutive interferon (IFN) pathway activation in THPO-deficient HSCs, characterized by enhanced STAT1 signaling, increased accessibility of STAT and IRF motifs, and elevated expression of IFN-stimulated genes. Lipidomic profiling further identified selective shifts in sphingomyelin (SM) species and enrichment of features associated with increased bilayer rigidity. THPO-deficient HSCs displayed elevated membrane SM incorporation, impaired membrane fluidity and altered membrane ultrastructure. Genetic ablation of Stat1 normalized membrane lipid abnormalities and reduced pyroptotic activation and restored HSC survival and regenerative function under inflammatory stress. Together, these findings identify a STAT1 and SM metabolism as critical THPO downstream to protect HSCs from inflammatory pyroptosis. Our results reveal membrane lipid homeostasis as a fundamental mechanism through which cytokine signaling safeguards HSC function during stress.

cell biology↗

bioRxiv2026

Paired CRISPR screens identify mitochondrial metabolism and UBE2H as aneuploid-specific dependencies in human cancer cell lines

Aneuploidy is a hallmark of cancer and imposes widespread cellular stress, including proteotoxicity, transcriptional dysregulation, and increased metabolic demand. Although these stresses are predicted to create therapeutic vulnerabilities, the genetic dependencies of aneuploid cells remain incompletely characterized. Here, we performed paired CRISPR loss-of-function screens in isogenic aneuploid and near-euploid cancer cell line models to systematically identify aneuploidy-specific dependencies. Seven genome-wide paired screens identified ribosomes, rRNA processing, spliceosome-mediated RNA processing, proteasome subunits, and mitochondrial metabolism as top aneuploid-specific dependency gene groups. To identify therapeutically targetable aneuploid dependencies, we performed 18 additional paired CRISPR screens using a focused druggable genome library. This analysis identified the ubiquitin-conjugating enzyme UBE2H as a top aneuploid-selective dependency. Functional validation confirmed aneuploid cell dependency on UBE2H, and mechanistic analyses linked UBE2H to mitochondrial protein abundance, suggesting a role in maintaining mitochondrial proteostasis under aneuploid stress. Together, these findings define core cellular systems that support the viability of aneuploid cells and identify UBE2H as a potential therapeutic vulnerability connecting ubiquitin signaling to mitochondrial homeostasis.

cancer biology↗

bioRxiv2026

Marker-based CRISPR screens identify POU2F1 as a regulator of DLL3 and neuroendocrine identity in small cell lung cancer

Small cell lung cancers (SCLC) often exhibit a neuroendocrine lineage identity marked by high expression of Delta-like Ligand 3 (DLL3). Because DLL3 shows minimal expression in normal adult tissues, it serves as an SCLC-selective tumor antigen and is the basis for clinically efficacious targeted therapies. Understanding the mechanisms that regulate DLL3 expression is therefore critical for advancing therapeutic strategies in this disease. Here, we performed transcription factor-focused and genome-wide CRISPR screens to identify regulators of DLL3 expression in SCLC. Both approaches converged on POU2F1 as a top activator of DLL3 in this tumor context. Despite its ubiquitous expression, we identify an SCLC-specific role for POU2F1 in activating DLL3 and a broader set of neuroendocrine lineage genes. Epigenomic analyses reveal tandem POU2F1-ASCL1 motifs within the DLL3 promoter that underlie the strong codependency between POU2F1 and the neuroendocrine master regulator ASCL1 for high-level DLL3 expression in SCLC. We provide evidence that tandem POU2F1-ASCL1 elements are part of a cis-regulatory code for the lung neuroendocrine cell fate. Together, these findings define a previously unrecognized transcriptional logic controlling DLL3 expression and establish POU2F1 as a context-specific regulator of neuroendocrine lineage in small cell lung cancer.

cancer biology↗

bioRxiv2025

MoChia1 is a family 18 glycoside hydrolase from the rice blast fungus, Magnaporthe oryzae, that releases reducing-end GlcNAc from chitin oligosaccharides

MoChia1, a family 18 glycoside hydrolase from the rice blast fungus Magnaporthe oryzae, was identified as an enzyme that binds chitin oligosaccharide elicitor to suppress the chitin-induced rice immune response. It hydrolyzed chitin oligosaccharides with a degree of polymerization of at least 3 [(GlcNAc)n (n[≥]3)] in an exo-splitting manner with anomeric retention. HPLC analysis of (GlcNAc)n cleavage by MoChia1 revealed that it specifically recognizes the {beta}-anomer of the substrate at the + 1 subsite and cleaves the terminal glycosidic linkage at the reducing end. It also hydrolyzed the partially deacetylated chitotrisaccharide GlcN-(GlcNAc)2 to GlcN-GlcNAc and GlcNAc, but not (GlcN)2-GlcNAc, indicating the requirement of the N-acetyl group at the -1 subsite for the hydrolytic reaction. MoChia1 released p-nitrophenol from pNP-(GlcNAc)2, p-nitrophenyl di-N-acetyl-{beta}-chitotrioside. Furthermore, it hydrolyzed the chitotriose derivatives with a modified GlcNAc residue on the reducing end, (GlcNAc)2-G, 4-O-{beta}-di-N-acetylchitobiosyl-2-acetamido-2-deoxy-2,3-anhydro-glucopyranose and (GlcNAc)2-L, 4-O-{beta}-di-N-acetylchitobiosyl-2-acetamido-2-deoxy-2,3-anhydro-glucono-{delta}-lactone, to (GlcNAc)2 and the modified GlcNAc, respectively. However, it did not hydrolyze 4-O-{beta}-di-N-acetylchitobiosyl moranoline [(GlcNAc)2-M], reduced chitotriose (chitotriitol), and -(GlcNAc)2 fluoride [(-(GlcNAc)2-F]. MoChia1 did not bind to chitin and barely hydrolyzed the polymeric substrate, glycol chitin. Taken together, we concluded that MoChia1 is a GH18 reducing end GlcNAc-releasing exo-oligochitinase with the {beta}-anomer selectivity. Allosamidin, a potent inhibitor of GH18 chitinases, was found to bind to MoChia1 and inhibit its hydrolytic activity with an IC50 of 54.4 {+/-} 6.91 M, indicating that allosamidin may be a potential candidate for a pesticide to prevent rice blast infection by inhibiting the chitinase activity of MoChia1.

biochemistry↗

bioRxiv2025

Tongue-Palate Electromyographic Synchronization Related to Swallowing, Mastication, and Speech

The specific oscillatory dynamics of intermuscular coupling involved in swallowing, mastication, speech production, and respiration have not been elucidated. This study aimed to explore intermuscular coupling between the tongue and palate that underlies oral functions by analyzing the event-related coherence (ERC) of electromyography (EMG) signals before swallowing, mastication, and speech production. Twenty-two healthy participants performed three oral tasks: swallowing, speech production, and mastication. Sixteen of these participants also completed a combined task involving swallowing immediately after speech. EMG signals were recorded from the tongue and palate, and ERC between tongue and palate EMG was analyzed. Peak ERC was compared across tasks for alpha (8-14 Hz), beta (16-30 Hz), and gamma (32-46 Hz) frequency bands. In all participants, ERC showed significant peaks in all frequency bands before the onset of swallowing, mastication, and speech. Only the ERC values in the beta band were significantly larger for swallowing than for mastication, but not for speech. Moreover, the ERC values for the combined task of swallowing after speech production were significantly smaller than those for the simple swallowing task in the alpha, beta, and gamma bands. The intermuscular oscillatory regulation is more critical for swallowing than for mastication.

neuroscience↗

bioRxiv2024

Enhancing Prediction of Human Traits and Behaviors through Ensemble Learning of Traditional and Novel Resting-State fMRI Connectivity Analyses

Recent efforts in cognitive neuroscience have focused on leveraging resting-state functional connectivity (RSFC) data from fMRI to predict human traits and behaviors more accurately. Traditional methods typically analyze RSFC by correlating averaged time-series data between regions of interest (ROIs) or networks, a process that may overlook critical spatial signal patterns. To address this limitation, we introduced a novel linear regression technique that estimates RSFC by predicting spatial brain activity patterns in a target ROI from those in a seed ROI. We applied both traditional and our novel RSFC estimation methods to a large-scale dataset from the Human Connectome Project, analyzing resting-state fMRI data to predict sex, age, personality traits, and psychological task performance. Additionally, we developed an ensemble learner that integrates these methods using a weighted average approach to enhance prediction accuracy. Our findings revealed that hierarchical clustering of RSFC patterns using our novel method displays distinct whole-brain grouping patterns compared to the traditional approach. Importantly, the ensemble model outperformed the traditional RSFC method in predicting human traits and behaviors. Notably, the predictions from the traditional and novel methods showed relatively low similarity, indicating that our novel approach captures unique and previously undetected information about human traits and behaviors through fine-grained local spatial patterns of neural activation. These results highlight the potential of combining traditional and innovative RSFC analysis techniques to enrich our understanding of the neural basis of human traits and behaviors.

neuroscience↗

bioRxiv2024

Healthy dietary choices involve prefrontal mechanisms associated with long-term reward maximization but not cognitive control

Taste and health are critical factors to be considered when choosing foods. Prioritizing healthiness over tastiness requires self-control. It has also been suggested that self-control is guided by cognitive control. We then hypothesized that neural mechanisms underlying healthy food choice are associated with both self-control and cognitive control. Human participants performed a food choice task and a working memory (WM) task during functional MRI scanning. Their degree of self-control was assessed behaviorally by the value discount of delayed monetary rewards in intertemporal choice. Prioritizing healthiness in food choice was associated with greater activity in the superior, dorsolateral, and medial prefrontal cortices. Importantly, the prefrontal activity was greater in individuals with smaller delay discounting (i.e., high self-control) who preferred a delayed larger reward to an immediate smaller reward in intertemporal choice. On the other hand, WM activity did not show a correlation with delay discounting or food choice activity, which was further supported by supplementary results that analyzed data from the Human Connectome Project. Our results suggest that the prefrontal cortex plays a critical role in healthy food choice, which requires self-control, but not cognitive control, for maximization of reward attainments in a remote future.

neuroscience↗

bioRxiv2022

Subjectivity of time perception alters choice preference for future rewards through fronto-striatal value signal dynamics

Our preference for a reward depends on the time of delay for its delivery. Here we show that changes in the external environment can manipulate the perceived duration of time, which alters the formation of the choice preference through value signals in the cortical and subcortical brain regions. Humans anticipated a real liquid reward delayed by tens of seconds, during which colors of visually presented panels gradually changed. The color-change delay was perceived as shorter than a control color-constant delay. Interestingly, participants with greater perceptual bias of the delay showed stronger preference for rewards with the color-change delay. The ventrolateral prefrontal cortex (vlPFC) and ventral striatum (VS) showed dynamic neural signatures of value components that were modulated by subjectively perceived duration. Crucially, these effects were specifically observed while a future reward was anticipated, and moreover, the vlPFC activity was weaker in participants with greater bias in the duration perception. These results demonstrate that subjective time experience leads to biased choice preference of delayed rewards, which is regulated by dynamic value signals of future rewards and accurate perception of the external world in the vlPFC-VS systems.

neuroscience↗

bioRxiv2021

Anticipatory dynamics in the human brain guide foraging for primary rewards

Deciding whether to wait for a future reward is crucial for acquiring rewards in an uncertain world and involves anticipating future reward attainment. While seeking for a reward in natural environments, behavioral agents constantly face a trade-off between staying in their current environment or leaving it. It remains unclear, however, how humans make continuous decisions in such situations. Here we show that anticipatory brain activity in the anterior prefrontal cortex (aPFC) and hippocampus underpins continuous stay-leave decision making. Human participants awaited for real liquid rewards available after tens of seconds, and continuous decision was tracked by monitoring dynamic patterns of brain activity. Participants stopped waiting more frequently and sooner after they experienced longer delays and received smaller rewards. When dynamic activity reflecting the anticipation of a future reward was enhanced in the aPFC, participants remained in their current environment, but when this activity diminished, they left the environment for a new one. The anticipatory activity in the aPFC and hippocampus was associated with distinct decision strategies; aPFC activity was enhanced in participants adopting a leave strategy, whereas those remaining stationary showed enhanced activity in the hippocampus. Our results suggest that fronto-hippocampal anticipatory dynamics underlie continuous decision making while anticipating a future reward.

neuroscience↗

bioRxiv2021

Vision-to-value transformations in artificial network and human brains

Humans and now computers can derive subjective valuations from sensory events although such transformation process is essentially unknown. In this study, we elucidated unknown neural mechanisms by comparing convolutional neural networks (CNNs) to their corresponding representations in humans. Specifically, we optimized CNNs to predict aesthetic valuations of paintings and examined the relationship between the CNN representations and brain activity via multivoxel pattern analysis. Primary visual cortex and higher association cortex activities were similar to computations in shallow CNN layers and deeper layers, respectively. The vision-to-value transformation is hence proved to be a hierarchical process which is consistent with the principal gradient that connects unimodal to transmodal brain regions (i.e. default mode network). The activity of the frontal and parietal cortices was approximated by goal-driven CNN. Consequently, representations of the hidden layers of CNNs can be understood and visualized by their correspondence with brain activity-facilitating parallels between artificial intelligence and neuroscience.

neuroscience↗

bioRxiv2020

Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice

Retinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.

neuroscience↗