Biology subjects

Kudo, M.

Publications and source records attributed to Kudo, M..

6 recordsLinked to original sources

bioRxiv2026

ORGANOTYPIC ENDOTHELIAL IDENTITY DETERMINES DIVERGENT MOLECULAR AND FUNCTIONAL RESPONSES TO LPS AND IL-6

ABSTRACT Endothelial cells (ECs) display marked vascular bed-specific heterogeneity, and their inflammation-induced activation is a central feature of vascular pathology. However, whether inflammatory responses are primarily shaped by intrinsic organotypic endothelial identity or by the inflammatory stimulus itself remains largely unknown. To address this question, we compared the temporal responses of brain- (hCMEC/D3), skin- (HMEC-1), and lung-derived (HuLEC-5a) human microvascular ECs to lipopolysaccharide (LPS) and interleukin-6 (IL-6/IL-6R). Across all conditions, endothelial origin was the dominant determinant of transcriptional variation, outweighing the effects of both the inflammatory stimulus and exposure time. Brain-, skin- and lung-derived ECs exhibited distinct basal inflammatory and innate immune gene expression programs and responded differently to both LPS and IL-6/IL-6R. LPS induced a rapid but largely transient response, whereas IL-6/IL-6R elicited more sustained inflammatory changes. Although transcriptional profiling identified a shared inflammatory signature across EC populations, most differentially expressed genes were vascular bed specific. These molecular differences translated into distinct functional outcomes: IL-6/IL-6R increased endothelial permeability and promoted more sustained metabolic adaptations, whereas LPS induced robust inflammatory activation without persistent barrier dysfunction. Collectively, these findings demonstrate that while inflammatory stimuli determine which signaling pathways are activated, intrinsic endothelial identity dictates the magnitude, kinetics, and functional consequences of the inflammatory response. Our results highlight the importance of incorporating vascular bed specificity into experimental models and the development of therapies targeting endothelial dysfunction and inflammation.

cell biology↗

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

Clinical and molecular characterisation of primary refractoriness to atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma.

BackgroundDespite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma (HCC), primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation following treatment, remains a significant and poorly understood clinical challenge. MethodsWe analysed 1296 patients with HCC and Child-Pugh A liver cirrhosis treated with frontline A+B (AB-real) and validated findings in 645 trial participants recruited to IMbrave150 and GO30140. PRef was defined by Society for the Immunotherapy of Cancer (SITC) criteria as progressive disease in the first 6 months after treatment initiation. Patients who achieved complete response, partial response or stable disease for [≥] 6 months were classified as responders. We performed a multi-parametric analysis of pre-treatment tumour tissue including machine learning-based quantification of tumour-infiltrating lymphocytes, imaging mass cytometry and RNA sequencing (RNAseq) to evaluate differences in the tumour microenvironment (TME) of PRef versus responding patients. We employed conditional inference tree analyses to provide a hierarchical organisation of determinants of PRef. ResultsAmong 677 AB-real and 378 trial patients evaluable by SITC criteria, PRef identified inferior median OS in comparison with responding patients (AB-real: 7.3 vs. 31.5 months, HR 3.7, 95%CI 2.8-8.5, p<0.001; Trials: 10.8 vs. NR, HR 4.6, 95%CI 3.3-6.3, p<0.001). PRef patients exhibited higher baseline systemic inflammation (neutrophil-to-lymphocyte ratio, NLR [≥]3), a distinctively immunosuppressive TME enriched in CD163+ tumour-associated macrophages and a higher Treg/Teff ratio. RNAseq of tumour tissue demonstrated lower intrinsic immunogenicity in PRef samples, characterised by repressed IFN-{gamma} and Teff signatures, with elevated myeloid infiltration. Conditional inference tree analysis identified IFN-{gamma} signature downregulation combined with NLR [≥]3 as the strongest contributor of PRef. ConclusionsPRef to A+B identifies a distinct biological entity characterised by unopposed systemic inflammation, myeloid cell infiltration and T-cell depletion. Targeting myeloid-mediated immunosuppression, particularly in patients with low IFN-{gamma} signature expression and elevated NLR might enhance responsiveness to A+B. HighlightsO_LIPrimary refractoriness to atezolizumab plus bevacizumab in hepatocellular carcinoma, as defined by SITC criteria, is associated with poor clinical outcomes. C_LIO_LITumour microenvironment profiling reveals an immunosuppressive phenotype characterized by high myeloid infiltration, reduced interferon-{gamma} signalling, and T-cell depletion. C_LIO_LIThe combination of systemic inflammation and low IFN-{gamma} signature expression strongly predicts primary refractoriness and may inform therapeutic decision-making. C_LI

cancer biology↗

bioRxiv2025

Multimodal Analysis of Sepsis-induced Cardiomyopathy in a Baboon Model

Sepsis-induced cardiomyopathy (SIC) significantly contributes to sepsis-related morbidity and mortality, necessitating a deeper understanding of its mechanisms. This study used a post-hoc, multimodal approach--including single-nucleus RNA sequencing (snRNA-seq), echocardiography, mitochondrial function, and histopathology--to characterize SIC in a non-human primate model. Archived data and samples from six baboons challenged with 37.5 mg/kg of purified peptidoglycan were analyzed. Vital signs and echocardiography were monitored for 8 hours; the endpoint was survival at 168 hours or euthanasia for irreversible organ failure. Septic shock--defined by hypotension, tachycardia, and elevated lactate--was associated with poor outcomes. Echocardiography showed reduced intravascular volume, contraction, stroke volume, and cardiac index. SnRNA-seq revealed distinct transcriptomic profiles: non-survivors exhibited inflammation, mitochondrial dysfunction, and maladaptive remodeling; survivors showed activation of pathways supporting contraction, metabolism, and repair. Cell-type analysis highlighted metabolic dysfunction in cardiomyocytes, TNF/NF-{kappa}B-driven inflammation in endothelial cells, and stress responses in fibroblasts and pericytes. Mitochondrial analysis showed impaired electron transport and disrupted metabolism. Histopathology revealed inflammation and myofibrillar damage, more severe in non-survivors. This model recapitulates key SIC features and supports mechanistic and therapeutic discovery.

pathology↗

bioRxiv2025

Establishment of a second-generation transgenic marmoset model of polyglutamine disease recapitulating neurological symptoms and pathology

Neurodegenerative diseases, including polyglutamine diseases, remain a major clinical challenge, partly because of limited animal models that recapitulate human disease. Here, we describe a second-generation transgenic marmoset model of spinocerebellar ataxia 3 (SCA3), a polyglutamine disease, which stably expresses expanded CAG repeats in ATXN3. All five offspring of the founder marmoset harbored the transgene with reduced transgene integration sites and without repeat instability or genetic mosaicism, offering improved construct validity. Three of the five marmosets developed progressive motor impairments that segregated into two distinct phenotypes: early onset with rapid progression and late onset with mild progression, accompanied by corresponding patterns in body weight gain and grip strength. Pathological analysis revealed cerebellar Purkinje cell loss, spinal cord neurodegeneration, and widespread intranuclear inclusions. The severity of motor phenotypes correlated with transgene expression levels in disease-relevant brain regions, including the cerebellum, spinal cord, and striatum. By overcoming the common translational limitations of rodent systems, our second-generation model offers a powerful platform for investigating disease mechanisms and testing potential therapeutic interventions. Our results advance the utility of transgenic marmosets as clinically relevant models of neurodegenerative diseases. Summary StatementSecond-generation transgenic marmoset models of spinocerebellar ataxia 3 replicated the progressive motor deficits and neuropathology of the founder marmoset, providing a powerful platform for studying disease mechanisms and developing therapies.

neuroscience↗

bioRxiv2024

Probing nanomechanics by direct indentation using Nanoendoscopy-AFM reveals the nuclear elasticity transition in cancer cells

The assessment of nuclear structural changes is considered a potential biomarker of metastatic cancer. However, accurately measuring nuclear elasticity remains challenging. Traditionally, nuclear elasticity has been measured by indenting the cell membrane with a bead-attached atomic force microscopy (AFM) probe or aspirating isolated nuclei with a micropipette tip. However, indentation using a bead-attached probe is influenced by the cell membrane and cytoskeleton, while measurements of isolated nuclei do not reflect their intact state. In this study, we used Nanoendoscopy-AFM, a technique in which a nanoneedle probe is inserted into a living cell to directly measure nuclear elasticity and map its distribution. Our findings show that nuclear elasticity increases under serum depletion but decreases when serum-depleted cells are treated with TGF-{beta}, which induces epithelial-mesenchymal transition (EMT). Furthermore, we found that changes in nuclear elasticity correlate positively with trimethylation levels of histone H4 at lysine 20, rather than with nuclear lamins expression levels. These findings suggest that alterations in chromatin structure underlie changes in nuclear elasticity during cancer progression.

biophysics↗