Biology subjects

Umeda, S.

Publications and source records attributed to Umeda, S..

14 recordsLinked to original sources

bioRxiv2026

Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer

Pancreatic cancer (PC) is largely refractory to immune checkpoint blockade (ICB), although homologous recombination-deficient (HRD) tumors may derive benefit. In the POLAR trial of maintenance pembrolizumab plus olaparib after platinum-based chemotherapy for metastatic PC, responses remained heterogeneous. To define determinants of productive antitumor immunity, we integrated longitudinal blood TCR sequencing with tumor single-cell and spatial profiling. Durable benefit was associated with rare tumor-infiltrating, peripherally expanding (TIE) CD8+ T cell clonotypes, a subset of which were functionally neoantigen-reactive. TIE patients showed markedly prolonged survival beyond established genomic and immune biomarkers. Conversely, resistance was associated with spatial T cell exclusion, myCAF-rich stromal remodeling, basal-like/KRAS-associated malignant-cell programs, and expansion of CTLA4 regulatory T cells linked to local immunosuppressive remodeling. These findings define a clonotype-resolved framework for immune monitoring and identify complementary stromal, tumor-intrinsic, and regulatory immune barriers that may guide rational combination immunotherapy in PC.

cancer biology↗

bioRxiv2026

Heartbeat-Related Bodily Processing Shapes Transition Patterns in Self-Related Spontaneous Thought

Spontaneous thought changes over time, yet the moment-to-moment factors shaping these changes remain poorly understood. We examined whether heartbeat-related bodily processing, operating largely outside explicit awareness, is associated with the organization of ongoing thought. Forty adults performed an auditory attention task with intermittent thought probes in which auditory events were scheduled either 200 ms after each detected R peak (synch condition) or independently of ongoing cardiac timing (asynch condition), with occasional omissions in both conditions. Heartbeat-synchronous omissions in this paradigm have been shown to induce cardiac deceleration and modulate heartbeat-evoked potentials (HEPs). The score of the heartbeat counting task (HCT) served as a behavioral index related to cardiac interoceptive accuracy. The results showed that higher HCT score was associated with a stronger synch-asynch shift toward more self-related and less task/self-unrelated thought. HEPs showed a synch-related negative shift across several thought groups, although the magnitude of this condition effect did not reliably differ among thought groups. Overall thought-group distributions were similar across conditions, while transition analyses suggested a tendency in the synch condition toward more frequent transitions linking predominantly interoceptive stimulus-dependent thought with both on-task and self-related thought. Together, these findings suggest that heartbeat-related bodily processing may influence the organization of spontaneous thought, particularly in individuals with greater cardiac interoceptive accuracy. Bodily signals may therefore act as an automatic constraint on the ongoing stream of thought, biasing which thought contents and transitions become more likely over time.

neuroscience↗

bioRxiv2026

Autonomic and cortical responses to heartbeat-synchronous auditory omissions during an auditory attention task

Cardiovascular regulation depends on bidirectional communication between autonomic cardiac control and cardiac afferent signals ascending to the central nervous system, forming a heart-brain loop. Cardio-auditory omission paradigms provide a non-invasive way to probe this loop in humans by withholding scheduled tones within heartbeat-contingent auditory sequences and measuring the resulting autonomic cardiac and heartbeat-related cortical responses. Previous studies have shown omission-evoked cardiac deceleration and neural responses mainly in specific contexts such as passive listening or synchrony-judgement tasks. The present study examined whether these responses also occur under the more general condition of active responses to external stimuli. We tested 40 adults in an auditory detection task in which tones were presented either 200 ms after the ECG R-peak (synch) or at pseudo-random intervals matched to each participants resting heart rate (asynch). A five-minute no-stimulation resting recording was used to generate the asynch sequence and served as the resting comparison condition. In both auditory conditions, 10% of scheduled tones were omitted, yielding synch and asynch omissions. Heartbeat-synchronous omissions induced sustained RR-interval prolongation that exceeded responses to asynch omissions, sound-present conditions, and rest. HEP amplitude was selectively enhanced in the synch-omission condition relative to all other conditions. Reaction times to the first post-omission tone were slightly delayed, whereas overall performance remained comparable across conditions. These findings show that heartbeat-synchronous auditory omissions produce a distinct autonomic-cortical response profile under active response demands, indicating that heart-brain loop dynamics continue to shape physiological responses during ongoing behaviour.

neuroscience↗

bioRxiv2026

Hierarchical classification of immune cell transcriptomes at population-scale

Accurate immune cell classification is essential for interpreting single-cell RNA sequencing (scRNA-seq) data. However, progress in automating cell type annotation is constrained by the lack of independent, high-resolution benchmarks, as routine data integration introduces statistical dependencies that inflate model generalizability. Here, we present the single-cell universal classification omnibus (Suco), a resource of independent, uniform expert annotations, and Compocyte, a modular hierarchical classifier. Together, they establish a framework that substantially outperforms existing classifiers while facilitating expert review of ambiguous annotations. Applying Compocyte across 50 studies, including three newly generated datasets, we classified 15.6 million leukocytes from 3,965 patients. Within this cohort, we identified a new tumor-associated resorptive macrophage phenotype, a non-canonical monocyte subtype in subclinical cytokine release syndrome, and the programmatic erosion of T cell memory stemness across metastatic sites. Suco and Compocyte thus provide a generalizable framework to uncover the principles governing human immunity at population scale. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/728980v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@13a6e4borg.highwire.dtl.DTLVardef@11f1626org.highwire.dtl.DTLVardef@1e72bd4org.highwire.dtl.DTLVardef@1ee799b_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefThe single-cell universal classification omnibus and the modular hierarchical classifier Compocyte enable annotating single cell RNA sequencing data from 3,965 patients, revealing novel resorptive macrophage and vaccination-associated monocyte states, alongside the erosion of T cell memory stemness as a hallmark of solid tumor metastases. HighlightsO_LISuco, a benchmark enabling novel single cell artificial intelligence models C_LIO_LICompocyte, a hierarchical cell type classifier outperforming current architectures C_LIO_LIMacrophages adopt osteoclast-like gene expression states across cancer types C_LIO_LIStem-like programs erode in metastasis-infiltrating T memory cells across tumors C_LI

bioinformatics↗

bioRxiv2026

A hierarchical generative model reveals enhanced latent precision of brain-body interaction dynamics during interoceptive attention

Brain-body interactions (BBIs) are fundamental to cognition and mental health, but their continuous multimodal dynamics remain difficult to extract. Previous approaches have been largely observational, and few frameworks enable these interacting processes to be modeled within an integrated generative system. Here, we applied a Predictive-Coding-Inspired Variational RNN (PV-RNN) to simultaneous EEG, ECG, and respiration recordings obtained from 33 participants during exteroceptive and interoceptive attention. The model learned a temporal hierarchy spanning modality-specific dynamics, multimodal associative integration, and sequence-level global states, and accurately reconstructed unseen physiological sequences. Specifically, the intermediate associative layer successfully captured the core complexities of BBI by extracting multiscale, nonlinear, and bidirectional coupling dynamics with variable temporal lags. Furthermore, the estimated precision (inverse variance) of latent variables representing BBI dynamics within this multimodal associative layer increased significantly during interoceptive attention. The magnitude of this condition-dependent precision enhancement correlated positively with subjective adaptive body controllability and negatively with psychiatric vulnerabilities, including rumination and trait anxiety. These findings identify a latent physiological signature of interoceptive attention and establish hierarchical generative modeling as an interpretable framework for extracting continuous BBI dynamics and linking multimodal physiology to cognitive and clinical characteristics.

neuroscience↗

bioRxiv2026

POLQ-driven repair scars shape the immunogenic landscape of homologous recombination-deficient pancreatic cancer

Pancreatic cancer (PC) is broadly resistant to immune checkpoint blockade, although a subset of homologous recombination-deficient (HRD) tumors exhibits durable immune engagement. The genomic features that distinguish these immune-responsive tumors from immune-inert HRD tumors remain poorly understood. Here we identify a microhomology-mediated end joining (MMEJ) repair scar, the MMEJ Deletion Footprint (MDF), as a genomic readout of POLQ-associated error-prone repair that enriches for frameshift indels. Across the multi-omic discovery cohort integrating tumor genomics, single-nucleus transcriptomics and spatial immune profiling, MDF-high HRD PC exhibited increased frameshift-indel-derived neoantigens and interferon programs. MDF was further associated with remodeling of the myeloid compartment toward MHC II-high dendritic cell-like antigen-presenting macrophage states and the immune synapse architecture marked by increased spatial interaction between APC-like macrophages and cytotoxic CD8+ T cells. These tissue-level features aligned with a functional trajectory shift of CD8+ T cells, consistent with effective anti-tumor immunity and was associated with favorable clinical outcomes of patients. Together, our findings position MMEJ-linked repair scarring as actionable biology that connects an HRD genotype to immune organization and suggests rational immunotherapy combinations that may enhance antigen presentation and myeloid activation to extend durable benefit in HRD-lineage cancers.

cancer biology↗

bioRxiv2026

A Genetically Engineered Human Organoid Model Reveals Distinct Genetic and Epigenetic Barriers of Lineage Plasticity in Early PDAC Transformation

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro, validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

cancer biology↗

bioRxiv2025

How the Heart Shapes the Mind: The Role of Cardiac Interoception in the Interaction between Autonomic Nervous Activity and Self-related Thoughts

Our thoughts often drift away from the tasks at hand. Various factors influence this phenomenon, including changes in the external environment, individual cognitive characteristics, and fluctuations in bodily responses. This study investigated the relationship between autonomic nervous fluctuations and thought state transitions, focusing on individual differences such as cardiac interoception. First, the heartbeat counting task was conducted, and the difference between the reported and actual number of heartbeats was used as an index of interoceptive accuracy. The participants then completed an auditory attention task while their cardiac activities were monitored. During the task, thought probes were randomly presented, and participants selected their thought content from eight categories and rated aspects such as task concentration and arousal. We estimated trial-by-trial thought states in a data-driven manner and examined how the current thought state, autonomic nervous activity, and individual cardiac interoceptive accuracy influenced the thought state in the next trial. The results demonstrated a strong association between higher cardiac interoceptive accuracy and the maintenance of similar states in subsequent trials when accelerated heart rates occurred during self-related thought states. Furthermore, the participants with higher depressive tendencies and interoceptive accuracy exhibited an increased likelihood of transitioning to self-related states when experiencing decreased heart rate during task-concentrated states. These results suggest that accurately detecting heart rate changes associated with specific thought states facilitates updates in first-person conscious experience, thereby biasing the transition patterns of subsequent thought states. This study provides new insights into the cognitive and physiological mechanisms underlying the dynamics of spontaneous thought.

neuroscience↗

bioRxiv2025

Transcriptomic plasticity is a hallmark of metastatic pancreatic cancer

Metastasis is the leading cause of cancer deaths; nonetheless, how tumor cells adapt to vastly different organ contexts is largely unknown. To investigate this question, we generated a transcriptomic atlas of primary tumor and diverse metastatic samples from a patient with pancreatic ductal adenocarcinoma who underwent rapid autopsy. Unsupervised archetype analysis identified both shared and site-specific gene programs, including lipid metabolism and gastrointestinal programs prevalent in peritoneum and stomach wall lesions, respectively. We developed a probabilistic approach for inferring clonal phylogeny from single-cell and matched whole-exome data. Distantly related genetic clones in the peritoneum express the lipid metabolism program, likely due to signaling by the adipocyte-rich peritoneum environment, and cells in most clones express multiple programs, suggesting that transcriptomic plasticity is a prevalent feature of metastatic cells. These deeply annotated analyses using a patient-centric platform provide a model for investigating metastatic mechanisms and plasticity in advanced cancer.

bioinformatics↗

bioRxiv2024

Brain-Body Interactions Influence the Transition from Mind Wandering to Awareness of Ongoing Thought

Our thoughts are inherently dynamic and often wander far from our current situation (mind wandering, MW). Although previous research revealed that the ascending arousal system shapes neural dynamics to mediate awareness of ongoing thoughts, the physiological states and afferent signals altered by this activation and its effects on awareness are unknown. In this study, we examined electroencephalography (EEG), electrocardiography (ECG), and respiration data before participants were aware of MW during a task in which they focused on external or internal stimuli. We showed that the transition from MW to awareness was characterized by decreased alpha and beta activity and increased heartbeat-evoked potential (HEP) amplitudes. In addition, the participants were more likely to be in the exhalation phase becoming aware, and in the inhalation phase at the time of MW reports. Moreover, changes in cardiac activity and HEP accompanied this pattern when participants were asked to focus on respiration. Based on these findings, we suggest that the release from the increased cognitive load with sustained MW and catching these changes as physiological alterations supporting awareness of MW; moreover, the modulation of the respiratory cycle by focusing on breathing enhances these changes.

neuroscience↗

bioRxiv2024

Genomic evolution of pancreatic cancer at single-cell resolution

We adapted a previously developed targeted single-nucleus DNA sequencing (snDNA-seq) method and constructed a new suite of computational analysis tools to study 137,491 single-nucleus DNA libraries from 24 pancreatic cancers collected under a variety of clinical scenarios including early and late diagnoses, different metastatic sites and before- and after-treatment. We refined the mutational landscape of pancreatic cancer by capturing events missed by bulk sequencing, and validated the evolution pattern of early fixation of driver single-nucleotide variants (SNVs) followed by generation of intratumoral heterogeneity for copy number variations (CNVs). Intertumoral convergent evolution was common, including subclonal inactivation of TGF-{beta} pathway by mutating various components of it; intratumoral convergence was rarely observed, likely due to strong selective force in pancreatic cancer development. Continuous evolution was frequently seen manifesting as CNVs. In the context of non-targeted treatments, no particular pattern was found across metastases or through treatment. In six pancreatic cancers with germline BRCA2 mutation, we discovered varied timing of biallelic inactivation of BRCA2, which sculpted different evolutionary trajectories and could presumably contribute to differential response to treatment. As the first large-scale application of targeted snDNA-seq on pancreatic cancer, this work provides a sample processing and computational analysis pipeline that warrants further clinical utility.

cancer biology↗

bioRxiv2024

The Body Mirroring Thought: The Relationship Between Thought Transitions and Fluctuations in Autonomic Nervous Activity Mediated by Interoception

Our thought states change unconsciously. This study verified that the transference of thought states varies with fluctuations in autonomic nervous activity, and that this effect is modulated by interoceptive accuracy. The participants completed the heartbeat counting task (HCT) and vigilance task (VT). We assessed the participants interoceptive accuracy based on their performance on the HCT. The VT is a simple attention task, and during this task, we asked the participants to report the content and contemplation of their thoughts. Consequently, participants with accurate interoception were more likely to remain in a highly contemplative thought state when sympathetic activity was activated. In contrast, the dominance of parasympathetic activity facilitated transitions to different thought states or experiences of less contemplative thought states in them. The results suggest that even subtle changes in bodily responses at rest can affect thought transitions in people with accurate interoception.

neuroscience↗

bioRxiv2024

Effects of unconscious tactile stimuli on autonomic nervous activity and afferent signal processing

Autonomic nervous system (ANS) is a mechanism that regulates our internal environment. In recent years, the interest in how tactile stimuli presented directly to the body affect ANS function and cortical processing in humans has been renewed. However, it is not yet clear how subtle tactile stimuli below the level of consciousness affect human heart rate and cortical processing. To examine this, subthreshold electrical stimuli were presented to the left forearm of 43 participants during an image-viewing task, and electrocardiogram (ECG) and electroencephalogram (EEG) data were collected. The changes in the R-wave interval of the ECG immediately after the subthreshold electrical presentation and heartbeat-evoked potential (HEP), the afferent signal processing of cardiac activity, were measured. The results showed that heart rate decelerated immediately after the presentation of subthreshold electrical stimuli. The HEP during stimulus presentation was amplified for participants with greater heart rate acceleration immediately after this deceleration. The magnitude of these effects depended on the type of the subthreshold tactile stimuli. The results suggest that even with subthreshold stimulation, the changes in autonomic activity associated with orienting response and related afferent signal processing differ depending on the clarity of the tactile stimuli.

neuroscience↗

bioRxiv2022

Application of high-throughput, high-depth, targeted single-nucleus DNA sequencing in pancreatic cancer

Despite insights gained by bulk DNA sequencing of cancer it remains challenging to resolve the admixture of normal and tumor cells, and/or of distinct tumor subclones; high throughput single-cell DNA sequencing circumvents these and brings cancer genomic studies to higher resolution. However, its application has been limited to liquid tumors or a small batch of solid tumors, mainly because of the lack of a scalable workflow to process solid tumor samples. Here we optimized a highly automated nuclei extraction workflow that achieved fast and reliable targeted single-nucleus DNA library preparation of 38 samples from 16 pancreatic adenocarcinoma (PDAC) patients, with an average library yield per sample of 2867 single nuclei. We demonstrate that this workflow not only performs well using low cellularity or low tumor purity samples but reveals novel genomic evolution patterns of PDAC as well.

cancer biology↗