Biology subjects

Otsuka, T.

Publications and source records attributed to Otsuka, T..

8 recordsLinked to original sources

bioRxiv2026

Natriuretic Peptide Augmentation Attenuates Renin Cell Hyperactivation and Afferent Arteriolar Hypertrophy During Long-Term Renin-Angiotensin System Inhibition

BACKGROUNDChronic renin-angiotensin system (RAS) inhibition activates renin cells and induces afferent arteriolar hypertrophy, a maladaptive vascular response that may contribute to nephrosclerosis-like renal injury. Although genetic or cell ablation approaches have shown that renin cells are required for this remodeling, no pharmacological strategy to restrain hyperactivated renin cells while preserving RAS inhibition benefits has been established. Natriuretic peptides (NPs) counteract RAS; however, whether NP signaling modulates renin cell activation and afferent arteriolar remodeling remains unclear. METHODSWe examined direct effects of atrial natriuretic peptide (ANP) on As4.1 renin-producing cells using reverse transcription-quantitative PCR, ELISA, and RNA sequencing (RNA-seq). We established a mouse model of long-term RAS inhibition using valsartan, an angiotensin II receptor blocker (ARB), and compared it with sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI). Valsartan was matched between the ARB and ARNI groups. Renin cell activation, afferent arteriolar remodeling, and renal injury were evaluated using biochemical assays, histology, immunostaining, single-nucleus RNA-seq, and region-specific photo-isolation chemistry RNA-seq of afferent arteriolar/juxtaglomerular regions. RESULTSANP suppressed Ren1 expression and renin secretion in As4.1 cells; this effect was attenuated by a natriuretic peptide receptor A antagonist. RNA-seq demonstrated that ANP induced receptor-dependent remodeling of renin cell gene programs. In mice, long-term ARB treatment induced renin cell hyperactivation, expansion of renin-positive juxtaglomerular regions, afferent arteriolar hypertrophy, renal dysfunction, tubular injury markers, and fibrosis. ARNI increased plasma ANP levels and attenuated these pathological changes, despite a comparable blood pressure reduction. Single-nucleus transcriptomics revealed attenuation of tubular injury-associated cellular states and altered renin cell-associated mesenchymal programs with ARNI. Region-specific transcriptomics further demonstrated distinct molecular states in afferent arteriolar/juxtaglomerular regions between ARB- and ARNI-treated kidneys. Integrated transcriptomic analysis suggested that NP signaling converges on vascular regulatory programs in hyperactivated renin-expressing cells. CONCLUSIONSNP signaling acts as a pharmacologically augmentable modulator of maladaptive renin cell activation. ARNI attenuates renin cell hyperactivation, afferent arteriolar hypertrophy, and renal injury during long-term RAS inhibition, suggesting that neprilysin inhibition may preserve RAS blockade benefits while limiting renin cell-driven renal vascular remodeling.

physiology↗

bioRxiv2026

Serial dependence in duration perception reveals reliability-weighted updating of the prior

Bayesian theories of perception propose that perceptual estimates result from the integration of prior beliefs ("priors") with sensory input ("likelihood"), weighted by their reliability. While Bayesian theories assume that priors are continuously updated over time, empirical evidence for such reliability-weighted updating modulating sequential percepts remains lacking. Here, we leverage a behavioral phenomenon called serial dependence--in which perceptual judgments are attracted toward previous stimuli--to test a central prediction of Bayesian theories: that perceptual estimates are sequentially updated according to the reliability of successive stimuli. We used a duration reproduction task in which the reliability of perceived duration was manipulated via signal-to-noise ratio by embedding stimuli in dynamic white noise. Consistent with the prediction of Bayesian theories, serial dependence in perceived duration was enhanced by increased reliability of previous stimuli and attenuated by increased reliability of current stimuli. Computational modeling revealed that changes in sensory noise (i.e., the width of the likelihood) can account for the reliability-dependent modulation of serial dependence. These findings provide empirical evidence for reliability-weighted updating, supporting a central prediction of Bayesian theories that prior information and sensory input are iteratively integrated to calibrate perceptual estimates.

neuroscience↗

bioRxiv2026

Co-targeting an AMPK--MAPK axis reprograms CAFs and suppresses PDAC

Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer characterized by limited therapeutic options and a highly treatment-resistant tumor microenvironment. Beyond tumor-intrinsic genetic alterations, growing evidence indicates that host-microbiome interactions influence cancer progression through microbial metabolites. However, how microbiome-derived metabolites influence oncogenic signaling in PDAC remains unclear. Here, integrated profiling revealed a consistent reduction of the microbial metabolite acetic acid in fecal samples from treatment-naive patients with PDAC and in a genetically defined Drosophila model recapitulating key PDAC driver alterations. Acetic acid activates AMP-activated protein kinase, and pharmacological activation of this pathway together with inhibition of mitogen-activated protein kinase signaling suppressed tumor growth in fly and mouse models. Combined pathway targeting restored AMPK activity and suppressed cancer-associated fibroblast activation. These findings identify a microbiome-associated metabolic vulnerability in PDAC and suggest that coordinated targeting of metabolic and oncogenic signaling may restrain tumor progression and improve therapeutic strategies.

cancer biology↗

bioRxiv2024

Estimating the mean: behavioral and neural correlates of summary representations for time intervals

Our behavior is guided by the statistical regularities in the environment. Prior research on temporal context effects has demonstrated the dynamic processes through which humans adapt to the environments temporal regularities. However, learning temporal regularities not only entails dynamic adaptation to traces of previous individual events but also often requires the extraction and retention of summary statistics (e.g., the mean) of temporal distributions. To investigate these summary representations for temporal distributions and to test their sensitivity to distributional changes, we explicitly asked participants to extract the mean of different distributions of time intervals, which shared the same mean but varied in their variability specifically operationalized by the width and presentation frequency of the intervals. Our findings showed that the variability of the estimated mean increased with the distributions variability, even though the actual mean remained constant. We further examined how such learning of temporal distributions modulates EEG signals during subsequent temporal judgments. Analysis revealed that the contingent negative variation (CNV), predictive of single-trial RTs, was correlated with how much individuals estimates of the mean were affected by the distributions variability. Conversely, the post-interval P2 was not modulated by the distributions but predicted participants responses, suggesting that P2 reflects the perceived duration of an interval. Taken together, our results demonstrate not only that humans can accurately estimate the mean of a temporal distribution, but also that the representation of the mean becomes more uncertain as the variability of the distribution increases, as reflected neurally in the preparation-related CNV during temporal decisions.

neuroscience↗

bioRxiv2024

Flow zoometry of Drosophila

Drosophila serves as a highly valuable model organism across numerous fields including genetics, immunology, neuroscience, cancer biology, and developmental biology. Central to Drosophila-based biological research is the ability to perform comprehensive genetic or chemical screens. However, this research is often limited by its dependence on laborious manual handling and analysis, making it prone to human error and difficult to discern statistically significant or rare events amid the noise of individual variations resulting from genetic and environmental factors. In this article we present flow zoometry, a whole-animal equivalent of flow cytometry for large-scale, individual-level, high-content screening of Drosophila. Our flow zoometer automatically clears the tissues of Drosophila melanogaster, captures three-dimensional (3D) multi-color fluorescence tomograms of single flies with single-cell volumetric resolution at an unprecedented throughput of over 1,000 animals within 48 hours (24 hr for clearing; 24 hr for imaging), and performs AI-enhanced data-driven analysis - a task that would traditionally take months or years with manual techniques. To demonstrate its broad applications, we employed the flow zoometer in various laborious screening assays, including those in toxicology, genotyping, and tumor screening. Flow zoometry represents a pivotal evolution in high-throughput screening technology: previously from molecules to cells, now from cells to whole animals. This advancement serves as a foundational platform for "statistical spatial biology", to improve empirical precision and enable serendipitous discoveries across various fields of biology.

bioengineering↗

bioRxiv2024

Extracellular disposal of nuclear waste by APP: a protective mechanism impaired in Alzheimer's disease

Although the amyloid beta (A{beta}) hypothesis1 has long been central to Alzheimers disease (AD) research, effective therapeutic strategies remain elusive2,3. Here we re-evaluate the functions of amyloid precursor protein (APP) and reveal its critical function in protecting against nuclear impairment-induced cell death and inflammation4,5. Overexpression of APP mitigated etoposide or lamin A knockdown-induced nuclear damage, while APP removal or mutations exacerbated these effects. Interestingly, neurons differentiated from induced pluripotent stem cells (iPSCs) exhibited similar patterns, and notably, familial AD-associated mutant APP failed to confer protection against nuclear impairment. We identify APPs interaction with a cytoplasmic structure of nuclear origin, termed "nuclear waste", and propose its role in extracellular waste disposal. Intriguingly, cells lacking APP showed impaired nuclear waste clearance, leading to abnormal cytoplasmic accumulation of the nuclear waste. Similarly, neuron-specific APP overexpression using adeno-associated virus (AAV) in mice reduced neuronal death and inflammation caused by nuclear damage. Conversely, shRNA-mediated APP exacerbated these effects, and mutant APP associated with familial AD lacked protective effects. Moreover, postmortem analysis of AD brains revealed accumulation of abnormal nuclear waste in the neurocytoplasm, irregular nuclear morphology, and reduced APP levels per neuron. Our data underscore APPs crucial role in disposing of nuclear waste, maintaining cellular homeostasis, and suggest its dysregulation as a potential contributor to AD pathogenesis. Restoring APP waste clearance in AD could be a promising target for disease-modifying therapies.

neuroscience↗

bioRxiv2023

Near-optimal integration of the magnitude Information of time and numerosity

Magnitude information is often correlated in the external world, providing complementary information about the environment. As if to reflect this relationship, the perceptions of different magnitudes (e.g., time and numerosity) are known to influence one another. Recent studies suggest that such magnitude interaction is similar to cue integration, such as multisensory integration. Here, we tested whether human observers could integrate the magnitudes of two quantities with distinct physical units (i.e., time and numerosity) as abstract magnitude information. The participants compared the magnitudes of two visual stimuli based on time, numerosity, or both. Consistent with the predictions of the maximum likelihood estimation (MLE) model, the participants integrated time and numerosity in a near-optimal manner; the weights for numerosity increased as the reliability of the numerosity information increased, and the integrated estimate was more reliable than either the time or numerosity estimate. Furthermore, the integration approached a statistical optimum as the temporal discrepancy of the acquisition of each piece of information became smaller. These results suggest that magnitude interaction arises through a similar computational mechanism to cue integration. They are also consistent with the idea that different magnitudes are processed by a generalized magnitude system.

neuroscience↗

bioRxiv2022

Castration alters the circadian clock and Ucp1 expression in subcutaneous white adipose tissue of mice

Castration increases the risk of metabolic syndromes in mammals. In addition, recent studies have demonstrated that castration increases the expression of Ucp1 in subcutaneous white adipose tissue (scWAT). However, how castration leads to thermogenic aberration remains poorly understood. Here, we found that castrated mice showed elevated Ucp1 expression in scWAT in response to cold exposure with an increase in body temperature in the light phase and a reduction in body weight gain with fat reduction despite showing no alterations in food intake, locomotor activity in a novel environment, and gastrocnemius muscle weight. We also analyzed the circadian behavioral rhythm and the expression rhythm of clock genes in the suprachiasmatic nucleus (SCN) and scWAT. We found that castrated mice showed fluctuations in circadian locomotor activity and a decrease in the expression rhythm of clock genes in the SCN (clock) and scWAT (Bmal1 and Per2). Moreover, the expression of Ucp1 in scWAT was rhythmic, and it was increased in castrated mice, while the expression of clock genes was decreased. These results indicate that castration may impact browning in scWAT through variations in the circadian clock and Ucp1 expression.

physiology↗