Biology subjects

Baba, Y.

Publications and source records attributed to Baba, Y..

16 recordsLinked to original sources

bioRxiv2026

Quantum Dot-Based Non-invasive Monitoring of Sinusoidal Endothelial Scavenger Function in Steatohepatitis

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent urgent medical challenges. Current non-invasive assessments rely on serum indices or tissue stiffness, and none visualizes functional changes within the liver, hindering drug discovery and patient management. In this study, we developed a non-invasive technique using semiconductor quantum dots, as blood-borne foreign particle mimics, to evaluate the scavenger function of liver sinusoidal endothelial cells (LSECs) via near-infrared optical imaging. Progression from MASLD to MASH induced a significant decline in the scavenger capability of LSECs, resulting in a marked reduction of intrahepatic quantum dot retention. Mechanistically, we demonstrated that quantum dots are recognized and internalized by scavenger receptor class A (SR-A) on LSECs, and that SR-A-mediated uptake progressively diminishes with increasing MASH severity. Crucially, quantum dot retention levels significantly correlated with both the progression and regression of MASH pathology. These findings demonstrate that quantum dot-based optical evaluation of LSEC scavenger function offers a highly sensitive, non-invasive diagnostic platform for staging MASH and assessing therapeutic efficacy.

bioengineering↗

bioRxiv2026

Improved recombinant protein production and scale-up fermentation of Aspergillus oryzae hyphal-dispersion hydrophobin-deficient strain

In liquid fermentation of filamentous fungi such as Aspergillus oryzae, increased broth viscosity and biomass adhesion to bioreactor surfaces remain major challenges. We previously developed a hyphal dispersion mutant lacking two hyphal adhesion factors, namely cell wall -1,3-glucan (AG) and biofilm galactosaminogalactan (GAG) (AG{Delta}-GAG{Delta} strain). The culture broth of the AG{Delta}-GAG{Delta} strain has low viscosity, which improves mixing and enzyme production. However, mycelia still extensively attach to bioreactor walls and downstream equipment, which impairs mixing and reduces product recovery. The hydrophobin RolA, a surface-active protein of A. oryzae, densely coats conidia and hyphae and contributes to cell surface hydrophobicity. In this study, we disrupted the rolA gene in AG{Delta}-GAG{Delta} (AG{Delta}-GAG{Delta}-{Delta}rolA strain) and evaluated the effects of this disruption on hyphal adhesion to the walls of culture vessels, enzyme production, and bioreactor performance. At the flask scale, the adhesion to glass surfaces was significantly reduced and recombinant enzyme activity was increased by 10%. Improved culture recovery at the end of fermentation further increased total enzyme yield. In a lab-scale stirred-tank bioreactor, both growth and enzyme production were increased. Scaling-up to a 200-L bioreactor showed reduced agitation power consumption while improving hydrodynamic properties. Fermentation of AG{Delta}-GAG{Delta}-{Delta}rolA was successfully scaled up to a 3000-L bioreactor; consistent enzyme activity and improved flow circulation in the bioreactors were confirmed by computational fluid dynamics analysis. Overall, the AG{Delta}-GAG{Delta}-{Delta}rolA strain has increased enzyme production and scalability, supporting its suitability for industrial applications.

bioengineering↗

bioRxiv2026

STING restrains calcium-dependent microglial phagocytosis and protects against neuronal loss and cognitive impairment during epileptogenesis

Epileptogenesis is accompanied by robust neuroinflammation, yet the molecular pathways linking innate immune activation to neuronal dysfunction remain incompletely defined. Given the established pro-inflammatory role of the stimulator of interferon genes (STING), we initially hypothesized that its loss would attenuate neuroinflammatory responses during epileptogenesis. Contrary to our expectation, we found that STING deficiency instead amplified microglial activation. Using a kainic acid mouse model of temporal lobe epilepsy (TLE), we show that STING-deficient microglia exhibit pronounced lysosomal expansion and enhanced phagocytic engulfment of neurons, leading to increased hippocampal neuronal loss and cognitive impairment. Mechanistically, STING deficiency increased the expression and altered the subcellular distribution of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum Ca{superscript 2} sensor that mediates store-operated calcium entry (SOCE), resulting in dysregulated intracellular calcium dynamics and elevated SOCE activity. Pharmacological inhibition of SOCE reduced microglia-neuron interactions and microglial phagocytic engulfment, improved neuronal survival in the CA3 region of the hippocampus, and rescued cognitive deficits following status epilepticus. Collectively, these findings redefine STING as a negative regulator of microglial activation and identify a previously unrecognized STING-STIM1-SOCE axis that constrains calcium-dependent microglial phagocytosis during epileptogenesis, highlighting microglial calcium signaling as a potential therapeutic target in TLE.

neuroscience↗

bioRxiv2026

In vivo brain temperature measurement using quantum dot imaging temperature sensors

Temperature regulation in the brain is essential for maintaining neuronal function and preventing thermally induced damage. Here, we report the development and in vivo application of quantum dots (QDs) to high-resolution thermometry in the mouse brain using two-photon excitation microscopy. These QDs, via the red-to-green photoluminescence (PL) intensity ratios, enabled stable temperature measurements in both normal and chronically hypo-perfused cerebral tissue. Our findings show that localized neuronal activity leads to transient heat generation, which is rapidly dissipated by cerebrovascular responses. In a chronic hypoperfusion model, impaired vascular function resulted in exaggerated and prolonged brain temperature elevations. This thermometry system provides unprecedented insight into the mechanisms of cerebral thermoregulation and highlights the importance of vascular cooling in protecting the brain from heat-induced stress, particularly in pathological conditions such as stroke.

bioengineering↗

bioRxiv2026

Diversity and stability of the gut microbiome of naked mole-rat (Heterocephalus glaber), the longest-lived rodent

The naked mole-rat is a subterranean rodent adapted to extreme hypoxia and low metabolic demands, with an exceptionally long lifespan relative to its small body size, while maintaining reproductive capacity. Using 16S rRNA gene sequencing of 24 samples and whole-metagenome sequencing of 11 samples from individuals up to 15 years of age, we characterized the gut microbiota and showed its complexity and distinctiveness compared with that of other rodents, including mice, squirrels, and rabbits. Although all animals were born and raised in a laboratory setting, the gut microbiota remained taxonomically stable across ages and retained key taxa previously reported in wild naked mole-rats (e.g., Treponema and Desulfovibrio). Metagenome-assembled genomes revealed the presence of archaeal methanogens and termite-gut-associated bacteria (e.g., Methanobacteria within Euryarchaeota and Avelusimicrobium within Elusimicrobiota), together with genes involved in hydrogen metabolism and archaeal methanogenesis. Compared with mice, the naked mole-rat gut microbiota was enriched in carbohydrate-active enzymes targeting plant cell-wall polysaccharides, resembling those found in ruminants. We also detected evidence of flagellates, ciliates, and fungi, which may further contribute to polysaccharide degradation and fermentation, potentially within the enlarged cecum. Together, this comprehensive analysis provides distinctive gut microbial features of the naked mole-rat that may be associated with the naked mole-rats low metabolic rate and exceptional longevity.

microbiology↗

bioRxiv2024

A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats

The X-linked orange (O) locus in domestic cats controls an unknown molecular mechanism that causes the suppression of black-brownish pigmentation in favor of orange coloration. The alternating black-brownish and orange patches seen in tortoiseshell and calico cats are considered as classic examples of the phenotypic expression of random X-chromosome inactivation (XCI) occurring in female mammals. However, the O gene in the cat genome has not been identified, and the genetic variation responsible for the orange coloration remains unknown. We report here that a 5.1-kilobase (kb) deletion within an intron of the X-linked ARHGAP36 gene, encoding a Rho GTPase activating protein, is closely and exclusively associated with orange coloration. The deleted region contains a highly conserved putative regulatory element, whose removal presumably cause altered ARHGAP36 expression. Notably, ARHGAP36 expression in cat skin tissues is linked to the suppression of many melanogenesis genes, potentially shifting pigment synthesis from eumelanin to pheomelanin. Furthermore, we find evidence that the gene undergoes XCI in female human and mouse cells, and XCI-dependent CpG island methylation consistent with random XCI in female domestic cats. The 5.1-kb deletion seems widespread in domestic cats with orange coat coloration, suggesting a single origin of this coat color phenotype.

genetics↗

bioRxiv2024

Comparative analysis of trans-chromosomic rodent models reveals improved somatic hypermutation and class-switch recombination in rats

Humanized rodent models, especially humanization of genetic/genomic components involved in immunity have significantly advanced our understanding of human immune system. Here, we utilized trans-chromosomic (Tc) technology to generate a TC-mAb rat model that stably harbors a mouse artificial chromosome carrying full-length human immunoglobulin (Ig) heavy and kappa light chain genes (IGHK-NAC) in a rat Ig knockout background. In contrast with TC-mAb mice, serum human IgG concentration was found higher than IgM. Number of lymphocytes was recovered, and B cell population in the spleen was normal. Remarkably, repertoire analysis revealed similarities between the model and human PBMCs; somatic hypermutation and class-switch recombination also more closely resembled humans. Furthermore, immunization resulted in generation of antigen-specific human antibodies. Collectively, our strategy to generate both rat and mouse models through introduction of the identical IGHK-NAC offers unprecedented opportunities to comprehensively evaluate genomic regulation and its outcomes associated with genomic sequences and host-derived protein factors.

bioengineering↗

bioRxiv2023

Microfluidic device for simple diagnosis of plant growth condition by detecting miRNAs from filtered plant extracts

Plants are exposed to a variety of environmental stress and starvation of inorganic phosphorus can be a major constraint in crop production. In plants, in response to phosphate deficiency in soil, miR399, a type of microRNA (miRNA), is upregulated. By detecting miR399, the early diagnosis of phosphorus deficiency stress in plants can be accomplished. However, general miRNA detection methods require complicated experimental manipulations. Therefore, simple and rapid miRNA detection methods are required for early plant nutritional diagnosis. For the simple detection of miR399, microfluidic technology is suitable for point-of-care applications because of its ability to detect target molecules in small amounts in a short time and with simple manipulation. In this study, we developed a microfluidic device to detect miRNAs from filtered plant extracts for the easy diagnosis of plant growth conditions. To fabricate the microfluidic device, verification of the amine-terminated glass as the basis of the device and the DNA probe immobilization method on the glass was conducted. In this device, the target miRNAs were detected by fluorescence of sandwich hybridization in a microfluidic channel. For plant stress diagnostics using a microfluidic device, we developed a protocol for miRNA detection by validating the sample preparation buffer, filtering, and signal amplification. Using this system, endogenous sly-miR399 in tomatoes, which is expressed in response to phosphorus deficiency, was detected before the appearance of stress symptoms. This early diagnosis system of plant growth conditions has a potential to improve food production and sustainability through cultivation management.

plant biology↗

bioRxiv2023

Chronic BCR signaling generates and maintains age-associated B cells from anergic B cells

Accumulation of age-associated B cells (ABCs) with autoreactive properties contributes to the pathogenesis of autoimmune diseases1-5. However, the mechanisms whereby ABCs are generated and maintained are not understood1, 2, 4. Here, we show that continuous stimulation of the B-cell receptor (BCR) with self-antigens plays a crucial role in ABC generation from anergic B cells and that this signal is vital for sustaining ABCs during aging and autoimmunity. In ABCs, BCR signaling was constitutively activated and the surface BCR was internalized in vivo, as occurs in autoreactive B cells chronically exposed to self-antigens6. With aging, ABCs were generated from autoreactive anergic B cells, but not from B cells expressing non-self-reactive BCR. In vitro stimulation of anergic B cells with self-antigen, interleukin-21, and Toll-like receptor 7/9 agonists promoted their differentiation to ABCs. Furthermore, the cellular phenotype of ABCs in Bm12-induced lupus mice7, 8 resembled that of ABCs in aged mice, showing activation of BCR signaling, expression of activation markers, and BCR internalization. Importantly, Btk was persistently activated in ABCs of aged/autoimmune mice and humans with lupus. Pharmacological Btk inhibition resulted in a marked reduction in the number of ABCs and pathogenicity in lupus mice. Our findings have implications for accumulating ABCs and developing therapies for autoimmune diseases.

immunology↗

bioRxiv2023

Upregulated Fcrl5 disrupts B cell anergy and causes autoimmunity

B cell anergy plays a critical role in maintaining self-tolerance by inhibiting autoreactive B cell activation to prevent autoimmune diseases. Here, we demonstrated that Fc receptor-like 5 (Fcrl5) upregulation contributes to autoimmune disease pathogenesis by disrupting B cell anergy. Fcrl5--a gene whose homologs are associated with human autoimmune diseases--is highly expressed in age/autoimmunity-associated B cells (ABCs), an autoreactive B cell subset. By generating B cell-specific Fcrl5 transgenic mice, we demonstrated that Fcrl5 overexpression in B cells caused systemic autoimmunity with age. Furthermore, Fcrl5 upregulation in B cells exacerbated the systemic lupus erythematosus-like disease model and increased the levels of ABCs and activated T cells. Mechanistically, an increase in Fcrl5 expression broke B cell anergy, activating autoreactive B cells in the presence of a self-antigen. Fcrl5 facilitated toll-like receptor signaling, reactivating anergic B cells. Thus, Fcrl5 is a potential regulator of B cell-mediated autoimmunity by regulating B cell anergy. This study provides important insights into the role of Fcrl5 in breaking B cell anergy and its effect on the pathogenesis of autoimmune diseases.

immunology↗

bioRxiv2023

Exploratory mass cytometry analysis reveals immunophenotypes of cancer treatment-related pneumonitis

Anti-cancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

immunology↗

bioRxiv2023

Mass cytometry identifies characteristic immune cell subsets in bronchoalveolar lavage fluid from interstitial lung diseases

Immune cells have been implicated in interstitial lung diseases (ILDs), although their phenotypes and effector mechanisms remain poorly understood. To better understand these cells, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), connective-tissue disease (CTD)-related ILD, and sarcoidosis, using two panels including 64 markers. Among myeloid cells, we observed the expansion of CD14+ CD36hi CD84hi monocyte populations in IPF. These CD14+ CD36hi CD84hi subsets were also increased in ILDs with a progressive phenotype, particularly in a case of acute exacerbation (AEx) of IPF. Analysis of B cells revealed the presence of cells at various stages of differentiation in BALF, with a higher percentage of IgG memory B cells in CTD-ILDs and a trend toward more FCRL5+ B cells. These FCRL5+B cells were also present in the patient with AEx-IPF and sarcoidosis with advanced lung lesions. Among T cells, we found increased levels of IL-2R+TIGIT+ LAG3+ CD4+T cells in IPF, increased levels of CXCR3+ CD226+ CD4+ T cells in sarcoidosis, and increased levels of PD1+ TIGIT+ CD57+ CD8+ T cells in CTD-ILDs. Together, these findings underscore the diverse immunopathogenesis of ILDs.

immunology↗

bioRxiv2023

Evolutionarily acquired activity-dependent transformation of the CaMKII holoenzyme

Ca2+/calmodulin-dependent protein kinase II (CaMKII) has long been central in synaptic plasticity research. CaMKII is a dodecameric serine/threonine kinase that has been essentially conserved across metazoans for over a million years. While the mechanisms of CaMKII activation are well studied, its "behavior" at the molecular level has remained unobserved. Here, high-speed atomic force microscopy was used to visualize the activity-dependent structural dynamics of rat/hydra/C. elegans CaMKII in various states at nanometer resolution. Among the species, rat CaMKII underwent internal kinase domain aggregation in an activity-dependent manner and showed a higher tolerance to dephosphorylation by phosphatase. Our findings suggest that mammalian CaMKII has evolutionarily acquired a new structural form and a tolerance to phosphatase to maintain robust CaMKII activity for proper neuronal function. One-Sentence SummaryHigh-speed atomic force microscopy reveals the activity-dependent structural dynamics of rat/hydra/C. elegans CaMKII

neuroscience↗

bioRxiv2021

Stem cell therapy for skin regeneration using mesenchymal stem cells derived from the progeroid Werner syndrome-specific iPS cells

Adult progeria, Werner syndrome (WS), is an autosomal recessive disorder that develops accelerated aging-associated symptoms after puberty. Refractory skin ulcer of limbs, which is one of the symptoms specific to WS, is seriously painful and sometimes results in amputation. In recent years, cell therapy using mesenchymal stem cells (MSCs) has been attracting attention; however, the effect of WS-derived MSCs on skin ulcers is still unclear. In this study, we generated iPS cells from a patient with WS and a normal subject, differentiated them into MSCs (WS- and NM-iMSC, respectively), and performed cell therapy to a refractory skin ulcer mouse model. As a result, WS-iMSC recapitulated premature senescence phenotypes in vitro. Upon subcutaneous injection around the wounds of mice, WS-iMSC was significantly inferior in wound healing effect compared to NM-iMSC. Proteome and transcriptome analysis revealed altered expression of genes related to angiogenesis, inflammation, and proliferation in WS-iMSC with remarkable downregulation of VEGF, a potent angiogenic factor. In addition, simultaneous administration of recombinant human VEGF and WS-iMSC improved the wound healing effect in vivo. These results indicate that the expression of angiogenic factors is reduced in WS-iMSC, and its supplementation restores the wound healing ability. This finding may pave the way to develop the treatment of intractable skin ulcers of WS.

cell biology↗

bioRxiv2019

Physiological determinants of the increase in oxygen consumption during exercise in individuals with stroke

BackgroundUnderstanding the physiological limitations of the increase in oxygen consumption ([V]O2) during exercise is essential to improve cardiorespiratory fitness in individuals with stroke. However, the physiological determinants of the increase in [V]O2 during exercise have not been examined using multivariate analysis in individuals with stroke. This study aimed to identify the physiological determinants of the increase in [V]O2 during a graded exercise in terms of the respiratory function, cardiac function, and ability of skeletal muscles to extract oxygen.\n\nMethodsEighteen individuals with stroke (60.1 {+/-} 9.4 years of age, 67.1 {+/-} 30.8 days poststroke) underwent a graded exercise test for the assessment of cardiorespiratory response to exercise. The increase in [V]O2 from rest to ventilatory threshold and that from rest to peak exercise were measured as a dependent variable. The increases in respiratory rate, tidal volume, heart rate, stroke volume, and arterial-venous oxygen difference from rest to ventilatory threshold and those from rest to peak exercise were measured as independent variables.\n\nResultsFrom rest to ventilatory threshold, the increases in heart rate ({beta} = 0.546) and arterial-venous oxygen difference ({beta} = 0.398) were significant determinants of the increase in [V]O2 (adjusted R2 = 0.703, p < 0.001). From rest to peak exercise, the increases in tidal volume ({beta} = 0.611) and heart rate ({beta} = 0.353) were significant determinants of the increase in [V]O2 (adjusted R2 = 0.702, p < 0.001).\n\nConclusion[V]O2 is well-known to increase nearly linearly with increasing heart rate; however, our results suggest that arterial-venous oxygen difference and tidal volume are also significant physiological determinants of the increase in [V]O2 from rest to ventilatory threshold and that from rest to peak exercise, respectively. Our findings could potentially contribute to the development of appropriate therapies to improve cardiorespiratory fitness in individuals with stroke.

physiology↗

bioRxiv2019

Identification of bacteria involved in the decomposition of lignocellulosic biomass treated with cow rumen fluid by metagenomic analysis

Previously, pretreatment of plant biomass using rumen fluid systems was developed to decompose cell wall. However, microbes which involved in plant cell wall decomposition in this system have not been identified, because the conditions of this system are different from the in situ rumen environment. We investigated the bacteria involved in the decomposition of cellulose and hemicellulose in a waste paper with the rumen pretreatment system using shotgun metagenomic analysis with next generation sequencing. After pretreatment of waste paper, about a half of the cellulose and hemicellulose content was decomposed. Genes encoding for cellulase and hemicellulase were mainly found to belonging to Ruminococcus, Clostridium, and Exiguobacterium. This study shows that Clostridium and Exiguobacterium, which have not been identified as predominant genus involved in cellulose and hemicellulose decomposition, might be categorized as the main fibrolytic bacteria in this system.

microbiology↗