Biology subjects

Tsuda, M.

Publications and source records attributed to Tsuda, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells

Pancreatic ductal adenocarcinoma (PDAC) progression involves malignant cell state plasticity. Epigenetic changes underlie this plasticity, yet the PDAC cis-regulatory landscape remains understudied. To address this, we profiled 33 primary tumors and 7 metastases from 39 patients with single-cell ATAC-seq, paired with 10 single-cell RNA-seq profiles. We found that epigenetic GATA6+/KRT17+ co-accessibility identifies a classical-basal subtype-intermediate progenitor state (SIP) associated with better clinical outcomes. SIP cells display limited epigenetic reprogramming from premalignant epithelium and retain gastric-intestinal differentiation reminiscent of neoplastic precursors. Lineages without GATA6+/KRT17+ co-accessibility exhibit greater lineage and epithelial-mesenchymal plasticity. Classical PDACs that repress basal gene accessibility activate neural-like progenitor (NRP) and tuft lineage enhancers, whereas basal committed tumors display esophageal transdifferentiation. Compared to SIP, classical-NRP and basal committed tumors have poorer outcomes, and show distinct PD-1/PD-L1 immune proteomic phenotypes and prognostic myofibroblast epigenetic states, respectively. Our work reveals links between lineage reprogramming, EMT, and epigenetic progression in human PDAC.

cancer biology↗

bioRxiv2026

Metabolome genome-wide association study reveals hierarchical and epistatic genetic control of flavonoid metabolism in soybean

Metabolic phenotypes are often governed by complex genetic architectures involving both additive and non-additive effects. However, the extent to which epistatic interactions contribute to the pathway-level regulation of plant metabolism remains unclear. In this study, we investigated the genetic architecture of flavonoid-related metabolites using metabolomic and genomic data from 200 soybean accessions cultivated under multiple environmental conditions. Broad-sense heritability estimates revealed that many metabolites were under strong genetic control, particularly flavonoid-related metabolites. Principal component analysis-based metabolome-wide genome-wide association studies identified four major loci associated with flavonoid metabolic variation, including a locus corresponding to flavonoid 3'-hydroxylase. Conditional analyses based on multilocus genetic backgrounds demonstrated that the effects of downstream loci were highly dependent on upstream genotypes. In particular, single-nucleotide polymorphism effects were frequently detectable only in specific allelic backgrounds defined by the major flavonoid 3'-hydroxylase locus, consistent with strong epistatic interactions among loci. Bayesian network analyses further supported a hierarchical genetic structure consistent with upstream regulation of downstream loci across the flavonoid biosynthetic pathway. These results demonstrate that highly heritable metabolic phenotypes can be controlled by a few loci exhibiting both additive and context-dependent non-additive effects. Our findings provide evidence that pathway-level metabolic diversity in soybean is generated through hierarchical and epistatic genetic control involving a limited set of key loci.

plant biology↗

bioRxiv2026

Experimental SARS-CoV-2 infection using horseshoe bats

Horseshoe bats are known as the natural reservoir of sarbecoviruses. To understand how horseshoe bats coexist with sarbecoviruses in nature, experimental infection can provide direct evidence. However, in vivo infection studies using horseshoe bats have been lacking because of the difficulty of maintaining insectivorous bats in a laboratory setting. Here, we established a stable husbandry system for greater horseshoe bats (Rhinolophus ferrumequinum) and performed experimental infection with SARS-CoV-2. In contrast to Syrian hamsters which showed substantial viral replication, infected horseshoe bats exhibited low-level but persistent viral replication in the lung without overt disease. Histological analyses revealed that inflammatory lesions in the bat lungs were spatially restricted and temporally delayed compared with those in hamsters. Transcriptomic analyses further showed preferential activation of tissue repair pathways but limited inflammatory responses following infection. Notably, bats expressed several interferon-stimulated genes prior to infection. Our results suggest that a host strategy combining constitutive antiviral state, limited inflammation and enhanced tissue repair may result in controlled viral replication without overt disease, likely enabling horseshoe bats to coexist with sarbecoviruses.

microbiology↗

bioRxiv2026

Spatial proteomics reveals prefrontal circuit diversity in socioemotional behaviour

Understanding how molecular diversity across long-range neural circuits governs brain function remains a central challenge in neuroscience. Here, we developed a projection-specific spatial proteomics approach and revealed robust presynaptic molecular divergence across six projection-defined pathways of the medial prefrontal cortex (mPFC), including efferent projections to the basolateral amygdala (BLA), nucleus accumbens (NAc), thalamus (Thal), hypothalamus (HT) and cortex (CTX), as well as the afferent projection from the BLA to the mPFC. Among these pathways, we identify BLTP2 (KIAA0100), a previously uncharacterized transmembrane protein, as highly enriched in the projection from the mPFC to the BLA. BLTP2 localizes to excitatory presynaptic terminals and is enriched at synapses that are activated during memory formation. Loss of BLTP2 impairs synaptic structure and transmission, and reduces activity-dependent remodelling, resulting in selective deficits in contextual fear memory, anxiety-related behavior, and social behavior. Mechanistically, BLTP2 promotes presynaptic assembly by recruiting Neurexin 1. These findings reveal projection-specific presynaptic molecular diversity and provide mechanistic insights into circuit-level vulnerabilities in neuropsychiatric disorders.

neuroscience↗

bioRxiv2025

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

cancer biology↗

bioRxiv2025

Myc and Kras cooperate in adult acinar cells to drive phenotypic heterogeneity, metastasis, and therapeutic resistance in a novel pancreatic cancer mouse model

Pancreatic ductal adenocarcinoma (PDAc) is a deadly malignancy, most commonly diagnosed in advanced stages when no curative treatments are available. The development of new models that aid ongoing investigation into the mechanisms by which it initiates, disseminates, and evades treatment is of the utmost importance. In vivo models that accurately recapitulate the features and spectrum of human pancreatic cancer are paramount to make a dent in this disease as two decades of the standard-of-care have failed to substantially improve survival. Here, we take advantage of our finding that post-translational stabiliziation of MYC downstream of the canonical PDAc driver, mutant KRAS, is an early event in PDAc progression to design a novel mouse model of PDAc progression based on deregulated, constituitive expression of Myc and mutant Kras in adult pancreatic acinar cells. Tumors from this KMC model histologically and molecularly recapitulate heterogeneity seen in human PDAc, with a high rate of metastasis to the liver. Cell lines derived from KMC autochthonous PDAc provide new models for orthotopic primary tumors that reliably metastasize to the liver and lung, providing important new tools to efficiently study the metastatic cascade and aid in the develoment of new therapeutics addressing metastatic disease. Cell lines represent distinct molecular subtypes with corresponding differential drug sensitivity. Toghether, this model provides a new and additional tool in the study of pancreatic cancer and the means by which it so deftly evades our best efforts at treatment.

cancer biology↗

bioRxiv2025

Induction of meningioma stem signature via hydrogel reprogramming and application of meningioma stem cell marker CXCR4 to pathological diagnosis and treatment.

BackgroundsMeningioma accounts for about 40% of brain tumors, but there was no effective treatment for recurrent or inoperable cases. We have previously found that when cancer cells are cultured on certain hydrogels, cancer stem cells are efficiently induced in various cancer types and we named this process as hydrogel activated reprogramming (HARP) phenomenon. In this study, we aimed to identify a key molecule that induced meningioma stem cells via hydrogels. MethodsMeningioma cells cultured on hydrogels were analyzed for expression of regular stem cell markers and their tumor genericity. Microarray analysis was performed to identify meningioma stem cell specific markers and to examine the application of such marker molecules as a therapeutic targets or pathological diagnosis for grading. ResultsRegular stem cell markers such as Nanog, and Oct3/4 were induced by culturing meningioma cells on hydrogels, and comprehensive gene expression analysis identified molecules involved in cancer stem cell activity. Among them, CXCR4 was selected as a therapeutic target molecule. Stimulation of CXCR4 via CXCL12 led to an increase in stem cell markers. In human meningioma pathological specimens and cultured cell lines, there was a correlation between CXCR4 expression levels and NF2 mutations and/or deletions. CXCR4 immunohistochemistry also detected along with the brain invasion. Thus, CXCR4 immunohistochemistry may be useful to suggest typical CNS WHO grade 1 meningioma, that do not require molecular analysis. ConclusionsWe have defined meningioma stem cell signature via HARP phenomenon and identified CXCR4 with biological significance as being diagnostic target. Key PointsO_LIWe induce meningioma stem signature via Hydrogel activated reprogramming (HARP) phenomena. C_LIO_LIWe identified CXCR4 as a candidate molecule as stemness marker and therapeutic target. C_LIO_LITranslational research using pathological specimens reveal CXCR4 immunohistochemistry has been shown to play an auxiliary role in the diagnosis of meningiomas. C_LI Importance of the StudyIn addition to morphology, immunohistochemistry and gene alteration are being adopted as diagnostic criteria for CNS tumors. From CNS5 onwards, epigenetic changes such as methylation analysis are being adopted as diagnostic criteria. We induced epigenetic changes in meningioma cells and induced cancer stemness, and this technique will be of great importance in the research and diagnosis of meningioma. In addition, microarray analysis was used to select CXCR4 from the molecules that increased simultaneously during stem cell induction on the three hydrogels, and further analysis revealed that CXCR4 immunostaining may indicate the distribution of meningioma stem cells, also making it useful for diagnosis. This report will contribute to the advancement of meningioma research and diagnosis by conducting basic research and using histopathological specimens.

bioengineering↗

bioRxiv2025

A non-spike nucleocapsid R204P mutation in SARS-CoV-2 Omicron XEC enhances inflammation and pathogenicity

The global circulation of SARS-CoV-2 in human populations has driven the emergence of Omicron subvariants, which have become highly diversified through recombination. In late 2024, SARS-CoV-2 Omicron XEC variant emerged from the recombination of two JN.1 progeny, KS.1.1 and KP.3.3, and became predominant worldwide. Here, we investigated virological features of the XEC variant. Epidemic dynamics modeling suggested that spike substitutions in XEC mainly contribute to its increased viral fitness. Additionally, four licensed antivirals were effective against XEC. Although the fusogenicity of XEC spike is comparable to that of the JN.1 spike, the intrinsic pathogenicity of XEC in hamsters was significantly higher than that of JN.1. Notably, we found that the nucleocapsid R204P mutation of XEC enhanced inflammation through NF-{kappa}B activation. Recent studies suggest that the evolutionary potential of spike protein is reaching its limit. Indeed, our findings highlight the critical role of non-spike mutations in the future evolution of SARS-CoV-2.

microbiology↗

bioRxiv2025

PIN1 Drives Cellular Plasticity and Immune Modulation in Chronic Pancreatitis

Background and AimsChronic pancreatitis (CP) is characterized by inflammation, fibrosis, and acinar-to-ductal metaplasia (ADM). PIN1, known to drive oncogenic signaling and cellular plasticity in cancer, has an unexplored role in CP. This study investigates PIN1s expression and function in CP pathogenesis using human tissues and mouse models. MethodsPIN1 expression was assessed in human CP tissue microarrays (TMAs) via immunohistochemistry (IHC) and cyclic immunofluorescence (CyCIF). Acute and chronic pancreatitis were induced in wild-type (WT) and PIN1 knockout (PIN1KO) mice using caerulein. Disease progression was monitored histologically, and immune profiling was conducted using flow cytometry. Pharmacological inhibition was performed using a small molecule PIN1 inhibitor-Sulfopin, and effects were evaluated by histology, qPCR, and cytokine analysis. Single-cell RNA sequencing (scRNA-seq) was performed on pancreatic tissues to perform pathway analysis and intercellular communication. ResultsPIN1 expression was elevated in human CP tissues, correlating with disease severity and ADM. In mice, both acute and chronic pancreatitis increased PIN1 expression, but only in our chronic PIN1KO mice displayed reduced pancreatic injury, fibrosis, ADM, and modulated immune infiltration. Pharmacological PIN1 inhibition mimicked the protective effects of genetic knockout, dampening inflammatory pathways. scRNA-seq revealed that PIN1 inhibition altered the intercellular communication networks between epithelial, immune, and stromal cells. ConclusionPIN1 drives cellular plasticity, immune modulation, and disease progression in CP. Targeting PIN1 may offer a therapeutic strategy to mitigate CP. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/653850v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@67f9fcorg.highwire.dtl.DTLVardef@4d4c1forg.highwire.dtl.DTLVardef@c099d7org.highwire.dtl.DTLVardef@b41aa5_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender. Shah, V. (2025) https://BioRender.com/undefined

cell biology↗

bioRxiv2025

Human TIMELESS, a potential circadian clock regulator, plays an essential role in survival and reawakening of metastasis-initiating cells in bone

Bone metastasis is becoming increasingly common globally. In such cases, cancer cells disseminate from the primary site to bone, subsequently entering a dormant state. Following a certain incubation period, the cells reawaken and grow, forming a metastatic mass. These dormant cells are called metastasis-initiating cells (MICs), but their survival and reawakening are poorly understood. Here, we established an in vivo MIC-reawakening mouse model in bone. Microarray analysis demonstrated enrichment for mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid synthesis in isolated MICs. In addition, transcriptional regulator TIMELESS was identified as an independent poor prognostic factor by using clinical transcriptomic datasets, which was validated by immunostaining on 209 breast cancer cases. TIMELESS-deficient breast, prostate, and bladder cancer cell lines exhibited reduced viability and MIC reawakening in bone. Single-cell analysis on the epigenetic landscape of MICs revealed that motif activities of CLOCK and BMAL1/ARNTL were enhanced in a cluster with increased TIMELESS accessibility scores. As TIMELESS regulates stemness through the OXPHOS metabolic state, an inhibitor targeting the metabolic pathway, MP-A08, was identified to suppress MIC reawakening and growth in bone more efficiently than cisplatin. These results suggest that TIMELESS regulates survival and reawakening in MICs and MP-A08 could contribute to adjuvant therapeutic strategies.

cancer biology↗

bioRxiv2025

Integration of Proxy Intermediate Omics traits into a Nonlinear Two-Step model for accurate phenotypic prediction

Intermediate omics traits, which mediate the effects of genetic variation on phenotypic traits, are increasingly recognised as valuable components of genetic evaluation. In particular, rhizosphere microbiota play a crucial role in plant health and productivity; however, their complex interactions with host genetics remain challenging to model. Although two-step modeling frameworks have been proposed to integrate intermediate omics traits into phenotype prediction, existing approaches do not incorporate nonlinear relationships between different omics layers. To address this, we have proposed a two-step phenotype prediction framework that integrates genomic, rhizosphere microbiome, and metabolome (meta-metabolome) data, while explicitly capturing omicsomics nonlinearities. The first step is to predict meta-metabolome traits from genetic and microbial features, thus effectively isolating them from the environmental noise. In this process, intermediate "proxy" omics traits are generated as general biological information to provide robust models. The second step utilises this "proxy" to enhance the accuracy of the phenotype prediction. We compared the linear model (Best Linear Unbiased Prediction, BLUP) and the nonlinear model (Random Forest, RF) at each step, as demonstrated through simulations and empirical analysis of a multi-omics soybean dataset in which nonlinear modeling captures intricate omics interactions. Notably, our approach enables phenotype prediction without requiring the original meta-metabolome data used in model training, thereby reducing reliance on costly omics measurements. This framework integrates intermediate omics traits into genomic prediction to improve prediction accuracy and provide solutions for deeper insights into plant-microbiome interactions.

bioinformatics↗

bioRxiv2025

Evolution of BA.2.86 to JN.1 reveals functional changes in non-structural viral proteins are required for fitness of SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19), is still circulating among humans, leading to the continuous evolution. SARS-CoV-2 Omicron JN.1 evolved from a distinct SARS-CoV-2 lineage, BA.2.86, spread rapidly worldwide. It is unclear why BA.2.86 did not become dominant and was quickly replaced by JN.1, which possesses one amino acid substitution in the spike protein (S:L455S) and two in the non-spike proteins NSP6 and ORF7b (NSP6:R252K and ORF7b:F19L) compared to BA.2.86. Here, we utilized recombinant viruses to elucidate the impact of these mutations on the virological characteristics of JN.1. We found that the mutation in the spike attenuated viral replication, but the non-spike mutations enhanced replication, suggesting the mutations in the non-spike proteins compensate for the one in the spike to improve viral fitness, as the mutations in the spike contribute to further immune evasion. Our findings suggest that functional changes in both the spike and non-spike proteins are necessary in the evolution of SARS-CoV-2 to enable evasion of adaptive immunity within the human population while sustaining replication. IMPORTANCEBecause the spike protein is strongly associated with certain virological properties of SARS-CoV-2, such as immune evasion and infectivity, most previous studies on SARS-CoV-2 variants have focused on spike protein mutations. However, the non-spike proteins also contribute to infectivity, as observed throughout the evolution of Omicron subvariants. In this study, we demonstrate a "trade-off" strategy in SARS-CoV-2 Omicron JN.1 in which the reduced infectivity caused by spike mutation is compensated by non-spike mutations. Our results provide insight into the evolutionary scenario of the emerging virus in the human population.

microbiology↗

bioRxiv2025

Clonal Heterogeneity in Human Pancreatic Ductal Adenocarcinoma and Its Impact on Tumor Progression

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by profound desmoplasia and cellular heterogeneity, which cannot be fully resolved using traditional bulk sequencing approaches. To understand the contribution of this heterogeneity to PDAC biology, we analyzed a large cohort of primary human PDAC samples (n = 62), profiling 443,451 single cells and 53,236 spatial transcriptomic spots using a combined single-cell RNA sequencing and spatial transcriptomics approach. Our analysis revealed significant intratumoral heterogeneity, with multiple genetically distinct neoplastic clones co-existing within individual tumors. These clones exhibited diverse transcriptional states and subtype profiles, challenging the traditional binary classification of PDAC into basal and classical subtypes; instead, our findings support a transcriptional continuum influenced by clonal evolution and spatial organization. Additionally, these clones each interacted uniquely with surrounding cell types in the tumor microenvironment. Phylogenetic analysis uncovered a rare but consistent classical-to-basal clonal transition associated with MYC amplification and immune response depletion, which were validated experimentally, suggesting a mechanism driving the emergence of a more aggressive basal clonal phenotype. Spatial analyses further revealed dispersed clones enriched for epithelial-to-mesenchymal transition (EMT) activity and immune suppression, correlating with metastatic potential and colonization of lymph node niches. These dispersed clones tended to transition toward a basal phenotype, contributing to disease progression. Our findings highlight the critical role of clonal diversity, transcriptional plasticity, and TME interactions in shaping human PDAC biology. This work provides new insights into the molecular and spatial heterogeneity of PDAC and offers potential avenues for therapeutic intervention targeting clonal evolution and the mechanisms driving metastasis.

cancer biology↗

bioRxiv2025

Type I partition-related proteins enhance conjugative transfer through transcriptional activation and oriT region binding

Plasmid partitioning and bacterial conjugation are critical processes ensuring plasmid maintenance and dissemination, respectively, within bacterial populations. Although traditionally regarded as distinct phenomena, these two processes are increasingly recognized as interconnected. While partitioning ensures plasmid inheritance during cell division, its potential influence on conjugative transfer remains poorly understood. A major impediment to understanding their interplay is that partition systems are often essential for plasmid stability, making it difficult to distinguish their direct effects on conjugation. In this study, we addressed this challenge using a mini-conjugative plasmid derived from the Pseudomonas putida NAH7 plasmid. This engineered plasmid, containing all conjugation-related genes, was cloned into an E. coli-compatible vector. Additionally, the par genes from NAH7 were expressed from a separate plasmid to investigate their roles in conjugative transfer. Our results revealed that the par gene cluster plays a significant role in enhancing the conjugative transfer of the mini-conjugative plasmid. Specifically, ParB, a centromere-binding protein, functions as a transcriptional activator of conjugation-related genes with binding parSNAH site. In contrast, ParR, a KorA homolog, was not found to enhance transcription directly but binds extensively to the oriT region. This binding probably facilitates the recruitment or stabilization of the relaxosome, thereby enhancing conjugation efficiency. Together, these findings unveil a previously unappreciated role for partition proteins in stimulating bacterial conjugation, providing new insights into how plasmids coordinate vertical and horizontal dissemination, highlighting that these processes can occur simultaneously within bacterial communities. IMPORTANCEPlasmid partition systems are classified into three types. While some systems have been reported to influence conjugative transfer, this study uncovers a novel mechanism utilized by a Type I system to enhance DNA transfer. Strikingly, repeat sequences perfectly matching the parSNAH site--bound by ParB to activate downstream conjugative transfer genes--were identified on both plasmids and chromosomes across diverse proteobacterial taxa. Furthermore, many of these repeat sequences were localized near genes involved in conjugative transfer and partitioning, suggesting the presence of a conserved regulatory mechanism mediated by these repeats. This study provides important insights into how plasmid partition systems coordinate both vertical and horizontal dissemination. Such knowledge is essential for understanding and mitigating the spread of antibiotic resistance and other plasmid-encoded traits, and it offers a foundation for developing strategies to manage plasmid-associated genetic exchange.

microbiology↗

bioRxiv2024

Interleukin-4 induces CD11c+ microglia leading to amelioration of neuropathic pain in mice

Neuropathic pain, a debilitating chronic pain condition, is a major clinical challenge. The pleiotropic cytokine interleukin-4 (IL-4) has been shown to suppress neuropathic pain in rodent models, but its underlying mechanism remains unclear. Here, we show that intrathecal administration of IL-4 to mice with spinal nerve transection (SpNT) increased the number of CD11c+ microglia (a microglia subset important for pain remission) in the spinal dorsal horn (SDH) and that this effect of IL-4 was essential for its ameliorating effect on SpNT-induced pain hypersensitivity. Furthermore, in mice with spared nerve injury (SNI), another model in which pain remission does not occur, the emergence of CD11c+ SDH microglia was curtailed, but intrathecal IL-4 increased their emergence and ameliorated pain hypersensitivity in a CD11c+ microglia-dependent manner. Our study reveals a mechanism by which intrathecal IL-4 ameliorates pain hypersensitivity after nerve injury and provides evidence that IL-4 increases CD11c+ microglia with a function that ameliorates neuropathic pain.

pharmacology and toxicology↗

bioRxiv2024

Descending locus coeruleus noradrenergic signaling to spinal astrocyte subset is required for stress-induced pain facilitation

It is known that stress powerfully alters pain, but its underlying mechanisms remain elusive. Here, we identified a circuit, locus coeruleus descending noradrenergic neurons projecting to the spinal dorsal horn (LC[->]SDH-NA neurons), that is activated by acute exposure to restraint stress and is required for stress-induced mechanical pain hypersensitivity in mice. Interestingly, the primary target of spinal NA released from descending LC[->]SDH-NAergic terminals causing the stress-induced pain hypersensitivity was 1A-adrenaline receptors (1ARs) in Hes5-positive (Hes5+) astrocytes located in the SDH, an astrocyte subset that has an ability to induce pain sensitization. Furthermore, activation of Hes5+ astrocytes reduced activity of SDH-inhibitory neurons (SDH-INs) that have an inhibitory role in pain processing. This astrocytic reduction of IN activity was canceled by an A1-adenosine receptor (A1R)-knockdown in SDH-INs, and the A1R-knockdown suppressed pain hypersensitivity caused by acute restraint stress. Therefore, our findings suggest that LC[->]SDH-NA neuronal signaling to Hes5+ SDH astrocytes and subsequent astrocytic reduction of SDH-IN activity are essential for mechanical pain facilitation caused by stress.

neuroscience↗

bioRxiv2024

Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder

Anxiety disorders are accompanied by changes in brain plasticity, stress vulnerability and heightened risk of depression. Here, we found that serum LPA16:0 abundance increased with trait anxiety in both human and mice and was sufficient to reduce the proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor, LPA1, bears single nucleotide polymorphism variants associated with anxiety. In mice, LPA16:0 decreased hippocampal neurogenesis and stress resilience, whereas LPA1 antagonism or the reduction of platelets, the main source of circulating LPA16:0, increased adult neurogenesis and resilience to acute stress. Finally, the inhibition of adult neurogenesis abolished the beneficial effect of LPA1 antagonism on resilience against both acute and chronic stress. Together, these findings identify LPA16:0-LPA1 signaling as a regulation mechanism of adult neurogenesis and a potential therapeutic target for mood disorders.

neuroscience↗

bioRxiv2024

High-throughput Phenotyping of Soybean Biomass: Conventional Trait Estimation and Novel Latent Feature Extraction Using UAV Remote Sensing and Deep Learning Models

High throughput phenotyping serves as a framework to reduce chronological costs and accelerate breeding cycles. In this study, we developed models to estimate the phenotypes of biomass-related traits in soybean (Glycine max) using unmanned aerial vehicle (UAV) remote sensing and deep learning models. In 2018, a field experiment was conducted using 198 soybean germplasm accessions with known whole genome sequences under two irrigation conditions: drought and control. We used a convolutional neural network (CNN) as a model to estimate the phenotypic values of five conventional biomass-related traits: dry weight, main stem length, numbers of nodes and branches, and plant height. We utilized manually measured phenotypes of conventional traits along with RGB images and digital surface models from UAV remote sensing to train our CNN models. The accuracy of the developed models was assessed through 10-fold cross-validation, which demonstrated their ability to accurately estimate the phenotypes of all conventional traits simultaneously. Deep learning enabled us to extract features that exhibited strong correlations with the output (i.e., phenotypes of the target traits) and accurately estimate the values of the features from the input data. We considered the extracted low-dimensional features as phenotypes in the latent space and attempted to annotate them based on the phenotypes of conventional traits. Furthermore, we validated whether these low-dimensional latent features were genetically controlled by assessing the accuracy of genomic predictions. The results revealed the potential utility of these low-dimensional latent features in actual breeding scenarios.

plant biology↗