Biology subjects

Sato, R.

Publications and source records attributed to Sato, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Single-neuron and population contributions of hippocampal LFPs to spike prediction

Local field potentials (LFPs) contain signals generated by individual neurons and by coordinated population activity, but distinguishing these contributions remains a challenge. We examined how hippocampal LFPs at different frequencies predict single-neuron spiking during spatial navigation in male rats using two datasets. At each frequency, we assessed the spatial distribution of LFP-based prediction across the electrode array and its generalization across behavioral contexts in which a neuron remained active, but its co-active peers changed. For pyramidal cells, spatially distributed LFP features, consistent with population-level activity, contributed primarily to spike prediction at theta ([~]10 Hz) and its harmonics. In contrast, spatially localized signals, consistent with the recorded neurons activity, contributed predominantly at higher frequencies. Notably, gamma-band LFPs (30-80 Hz) provided comparatively little information about pyramidal-cell spiking, while distributed LFP features predicted interneuron spiking across a broader frequency range. Together, this predictive approach separates local and distributed correlates of spiking within the LFP. In hippocampal CA1, these correlates fell into two spatiotemporal regimes: a distributed regime expressed primarily at theta frequencies and a localized regime reflecting single-neuron activity at higher frequencies. Significance StatementBrain waves reflect the activity of neuronal populations across spatiotemporal scales. We asked which features of brain waves recorded in the hippocampus predict an individual neurons spiking activity as a rat navigated a maze. Brain waves predicted spiking activity most accurately at two different regimes: a low-frequency, spatially distributed regime and a high-frequency, local regime. The distributed regime was concentrated in the [~]10 Hz theta band, while the local regime appeared to reflect the recorded neurons activity at high frequencies (>100 Hz). Surprisingly, the gamma band, often linked to neuronal communication and cell assemblies, was the weakest predictor of place cell activity. Our work provides a way to separate individual-neuron and population-level information in hippocampal LFPs.

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↗

bioRxiv2025

Selective induction by statins of FAM134B-mediated sarcoplasmic reticulum (SR)-phagy degrades the SR calcium pump SERCA1 and contributes to myopathy

Statins, HMG-CoA reductase inhibitors, are the most prescribed medication for lowering low-density lipoprotein cholesterol. Although statin intolerance due to statin-associated muscle symptoms (SAMS) has been a clinically important issue for decades, the molecular mechanisms of statin myopathy remain incompletely understood. To seek to clarify how statins induce myopathy, here we perform transcriptome analysis and identify FAM134B short isoform (FAM134B-S), an endoplasmic reticulum (ER)-phagy receptor, as a statin-inducible gene. FAM134B-S expression is regulated by the mevalonate pathway and sterol regulatory element-binding proteins. We further show that FAM134B plays a critical role in the regulation of skeletal muscle integrity both in the steady-state and statin-treated conditions in human iPS cell-derived myocytes and mice. Mechanistically, FAM134B-S interacts with the sarcoplasmic reticulum (SR) calcium pump SERCA1 and promotes its autophagic degradation. Collectively, our work reveals a hitherto undisclosed mechanism of statin myopathy; blocking the mevalonate pathway induces SERCA1 degradation through FAM134B-mediated SR-phagy, exerting myotoxicity.

pharmacology and toxicology↗

bioRxiv2025

Functional and dysfunctional T regulatory cell states in human tissues in RA and other autoimmune arthritic diseases

Regulatory T cells (Tregs), characterized by FOXP3 expression, are essential for maintaining immune homeostasis by controlling inflammation. However, in autoimmune diseases such as rheumatoid arthritis (RA), impaired Treg function contributes to immune dysregulation and disease pathology. While most studies of human Tregs have focused on blood, here we analyzed Tregs in synovial tissues from RA patients using single cell RNA sequencing (scRNAseq). We identified two predominant Treg states, CD25hiCXCR6pos Tregs with strong suppressive function, and CD25loAREGpos Tregs, a dysfunctional state exclusively enriched in synovial tissues but not in blood. Computational and in vitro analyses revealed that cortisol induced AREG expression, suppressed glycolysis, and impaired the suppressive function of CD25loAREGpos Tregs. In turn, AREG promoted an IL-33+ inflammatory phenotype in synovial fibroblasts. Importantly, we found that TNFR2 engagement can prevent or reverse this dysfunctional Treg state. In contrast to CD25loAREGpos Tregs, CD25hiCXCR6pos Tregs were highly suppressive, showed coordinated abundance with macrophages in synovial tissue, and functionally interacted with membrane-bound TNF expressed by macrophages, which promoted their functional suppressive state. These two Treg subsets were similarly found in the synovial tissue in Juvenile Idiopathic Arthritis (JIA), another inflammatory arthritic disorder, indicating conserved mechanisms across arthritic diseases. Together, our findings define distinct pathways driving divergent functional and dysfunctional Treg states in inflamed tissues and point to interventions that may prevent or reverse the development of the dysfunctional state.

immunology↗

bioRxiv2025

β-III tubulin identifies anti-fibrotic state of pericytes in pulmonary fibrosis

Pericytes have been implicated in pulmonary fibrosis, yet their activated cellular states and functional roles remain largely unclear. Here, we identified {beta}-III tubulin (Tuj1) as a distinctive marker for fibrosis-associated lung pericytes. Most pericytes in fibrotic regions are Tuj1-positive and interact uniquely with multiple endothelial cells, localizing near collagen-producing fibroblasts and pro-fibrotic SPP1+/arginase+ macrophages. Tuj1 expression is predominantly induced in pericytes during the fibrotic phase, and Tuj1 gene (Tubb3) knockout in mice exacerbates lung fibrosis, accompanied by an increase in the neighboring pro-fibrotic fibroblasts and macrophages, suggesting an anti-fibrotic role for Tuj1-expressing pericytes. Mechanistically, the anti-fibrotic chemokine CXCL10 is upregulated in Tuj1-expressing pericytes, whereas this upregulation is not observed in Tubb3 knockout. Moreover, CXCL10 inhibits the pro-fibrotic differentiation of macrophages induced by lung fibroblasts in culture, implying that CXCL10 may mediate the anti-fibrotic effects of Tuj1-expressing pericytes. These findings underscore the role of lung pericytes in negatively regulating fibrotic process and their potential as therapeutic targets for pulmonary fibrosis patients. SummaryIn response to fibrotic stimuli, lung pericytes upregulate {beta}-III tubulin (Tuj1) expression, adopting an anti-fibrotic phenotype. This phenotype acts as a negative immune regulator of pro-fibrotic macrophage differentiation by releasing CXCL10, thereby counteracting the progression of pulmonary fibrosis.

pathology↗

bioRxiv2025

Excessive chondrogenesis in the blastema initiates during hypomorphic limb regeneration in Xenopus froglet, but not during patterned limb regeneration in Xenopus tadpoles and newts

Xenopus laevis tadpoles and newts regenerate a limb almost completely after amputation, with recapitulation of the patten formation of the limb. Metamorphosed Xenopus froglets form a cone-shaped regenerating blastema, similar to tadpoles and newts, but ultimately regenerate only a hypomorphic cartilaginous spike. Previous study suggested that excessive chondrogenesis, distinct from Xenopus tadpoles, may occur in the regenerating limb of a froglet and may prevent pattern formation during regeneration. However, it remains unclear whether excessive chondrogenesis actually occurs in froglet blastemas. If it does, when does it initiate and how does it progress in the blastemas? To answer these questions, we examined the extent of chondrogenesis in regenerating blastemas which have the common morphological shapes observed in newts (Pleurodeles waltl), Xenopus laevis tadpoles, and froglets. To evaluate excessive chondrogenesis, we developed a simplified procedure using immunofluorescence for cartilage markers (Sox9 or Col2a1) and quantitative image analysis. Our analysis revealed that signs of excessive chondrogenesis were detected not in newts and tadpoles but in froglets blastemas. During limb regeneration in froglets, the first sign of excessive chondrogenesis was detected in the cone-shaped blastema at the medium bud (MB) stage, and excessive chondrogenesis progressed to a more severe state as the blastema grew. These results indicate that excessive chondrogenesis initiates specifically in froglet blastemas at the MB stage at the latest and progresses in a definite spatio-temporal manner. Further elucidation of the mechanisms underlying froglet-specific excessive chondrogenesis in the blastema may lead to the recovery of patterned limb regeneration in froglets with adequate inhibition of chondrogenesis.

developmental biology↗

bioRxiv2025

Proteomic profiling of tissue extracellular vesicles (EVs) identifies tissue-specific EV markers and predicts the accessibility of tissue EVs to the circulation

Extracellular vesicles (EVs) mediate cell-to-cell communication in endocrine, paracrine, and autocrine fashions, but their roles and transport in the body remain incompletely understood. It is expected that EVs circulate in the body through the bloodstream, where EVs derived from various tissues are present. However, how much each tissue contributes to circulating EVs is largely unknown. Therefore, identifying tissue-specific EV markers is of importance for elucidating in vivo dynamics of tissue EVs. A key issue that hampers studying EVs in vivo is the lack of methodologies for collecting them from tissues. Here, we developed methods to isolate EVs from four different tissues, skeletal muscle, heart, liver, and adipose tissue, and performed proteomic analysis on their EVs. Unbiased and quantitative proteomic analysis revealed protein signatures of EVs from the four tissues and identified marker proteins specific to EVs of each tissue. Furthermore, through comprehensive comparisons of the proteome from tissue and plasma EVs, we predicted the accessibility of EVs from the four tissues to the circulation. Our data suggests that, among the four tissues, adipose tissue-derived EVs more readily enter the circulation, while skeletal muscle-derived EVs exhibit poor accessibility to the blood. Collectively, our tissue EV proteome identified tissue-specific EV markers and suggests that the accessibility of tissue EVs to circulation highly depends on the original tissues.

physiology↗

bioRxiv2025

Differential O-Glc elongation on the specific EGF repeat within a ligand binding domain regulates NOTCH1 signaling

Three types of O-linked glycosylation - O-glucose, O-fucose, and O-N-acetylglucosamine - are crucial for the function of Notch receptors, which regulates critical cell fate determination processes in a wide variety of contexts. O-Glucose glycans are added to serine residues located between the first and second conserved cysteines within the epidermal growth factor (EGF) -like repeats in the Notch extracellular domain. Previously, O-glucose glycans were shown to be extended to a trisaccharide structure with two xyloses via an 1-3 linkage. Our recent studies, however, indicated that the O-glucose glycan on NOTCH1 EGF10 can be extended by hexose and Neu5Ac. Here, we demonstrated that this hexose- and Neu5Ac-extended glycan has a 3-sialyllactose-like structure synthesized by specific members of two isoenzyme families, B4GALT1 and ST3GAL4. Using mass spectrometry, we identified this modification exclusively on NOTCH1 EGF10 and NOTCH3 EGF9 (equivalent to NOTCH1 EGF10), with no detection in any other EGF domains in NOTCH1-3. Sequence comparison and mutagenesis experiments identified one amino acid at position -2 of the fourth cysteine in the EGF domain as crucial for the galactose elongation of O-glucose glycans. We further demonstrated that this site-specific elongation of O-glucose on NOTCH1 EGF10 significantly impact ligand binding and signal transduction of NOTCH1. Our findings contribute to the understanding of the intricate regulatory mechanisms of Notch receptor function mediated by distinct positions and structures of O-glycans. Significance StatementNotch, a signaling receptor critical for development, differentiation, and homeostasis in multicellular organisms, undergoes multiple post-translational glycan modifications to regulate its function. While O-glucose glycan elongation by xylose was previously known, we identified an O-glucose glycan extended by galactose and Neu5Ac on specific epidermal growth factor (EGF) -like repeats of certain Notch paralogs, NOTCH1 and NOTCH3. As far as we know, this structure has not been reported on any other proteins. We identify the enzymes involved in the biosynthesis of this glycan and demonstrate that modifications at a specific site on Notch direct receptor functions, including ligand binding and Notch signaling.

biochemistry↗

bioRxiv2024

Universal base editing for hemophilia B

The repair of pathological gene variants is an ultimate aim for treating genetic diseases; however, it is not practical to develop different therapeutic reagents for each of the many variants that can occur in a gene. Here, we investigated whether base editing to induce a gain-of-function variant in blood coagulation factor IX (FIX) can increase FIX activity as a treatment strategy for hemophilia B. We engineered a G:C to A:T substitution at c.1151 of F9 by cytosine base editing to generate R338Q, known as the Shanghai F9 variant, which markedly potentiates coagulation factor activity. An adeno-associated virus vector harboring the base editor converted more than 60% of the target G:C to A:T and increased FIX activity in HEK293 cells harboring patient-derived F9 variants, as well as in knock-in mice harboring a human F9 cDNA. Furthermore, administration of lipid nanoparticles embedded with the base editor mRNA and gRNA increased FIX activity in mice. These data indicate that cytosine base editing to generate R338Q in FIX can become a universal genome editing strategy for hemophilia B.

bioengineering↗

bioRxiv2024

ENDOTHELIAL PROX1 INDUCES BLOOD-BRAIN BARRIER DISRUPTION IN THE CENTRAL NERVOUS SYSTEM

The central nervous system (CNS) parenchyma has conventionally been believed to lack lymphatic vasculature, likely due to a non-permissive microenvironment that hinders the formation and growth of lymphatic endothelial cells (LECs). Recent findings of ectopic expression of LEC markers including Prospero Homeobox 1 (PROX1), a master regulator of lymphatic differentiation, and the vascular permeability marker Plasmalemma Vesicle Associated Protein (PLVAP), in certain glioblastoma and brain arteriovenous malformations (AVMs), has prompted investigation into their roles in cerebrovascular malformations, tumor environments, and blood-brain barrier (BBB) abnormalities. To explore the relationship between ectopic LEC properties and BBB disruption, we utilized endothelial cell-specific Prox1 overexpression mutants. When induced during embryonic stages of BBB formation, endothelial Prox1 expression induces hybrid blood-lymphatic phenotypes in the developing CNS vasculature. This effect is not observed when Prox1 is overexpressed during postnatal BBB maturation. Ectopic Prox1 expression leads to significant vascular malformations and enhanced vascular leakage, resulting in BBB disruption when induced during both embryonic and postnatal stages. Mechanistically, PROX1 downregulates critical BBB-associated genes, including {beta}-catenin and Claudin-5, which are essential for BBB development and maintenance. These findings suggest that PROX1 compromises BBB integrity by negatively regulating BBB-associated gene expression and Wnt/{beta}-catenin signaling.

developmental biology↗

bioRxiv2024

Modeling statin-induced myopathy with human iPSCs reveals that impaired proteostasis underlies the myotoxicity and is targetable for the prevention

Statins, HMG-CoA reductase inhibitors, have been widely prescribed to lower circulating low-density lipoprotein cholesterol levels and reduce the risk of cardiovascular disease. Although statins are well tolerated, statin-associated muscle symptoms (SAMS) are the major adverse effect and cause statin intolerance. Therefore, understanding the molecular mechanisms of SAMS and identifying effective strategies for its prevention are of significant clinical importance; however, both remain unclear. Here we establish a model of statin-induced myopathy (SIM) with human induced pluripotent stem cell (hiPSC)-derived myocytes (iPSC-MCs) and investigate the effect of statins on protein homeostasis (proteostasis) that affects skeletal muscle wasting and myotoxicity. We show that treating hiPSC-MCs with statins induces atrophic phenotype and myotoxicity, establishing a hiPSC-based SIM model. We then examine whether statins impair the balance between protein synthesis and degradation. The results show that statins not only suppress protein synthesis but also promote protein degradation by upregulating the expression of the muscle-specific E3 ubiquitin ligase Atrogin-1 in a mevalonate pathway-dependent manner. Mechanistically, blocking the mevalonate pathway inactivates the protein kinase Akt, leading to the inhibition of mTORC1 and GSK3{beta} but the activation of FOXO1. These changes explain the statin-induced impairment in proteostasis. Finally, we show that pharmacological blockage of FOXO1 prevents SIM in hiPSC-MCs, implicating FOXO1 as a key mediator of SIM. Taken together, this study suggests that the mevalonate pathway is critical for maintaining skeletal muscle proteostasis and identifies FOXO1 as a potential target for preventing SIM.

pharmacology and toxicology↗

bioRxiv2024

Directed evolution of hyperactive integrases for site specific insertion of transgenes

The ability to deliver large transgenes to a single genomic sequence with high efficiency would accelerate biomedical interventions. Current methods suffer from low insertion efficiency and most rely on undesired double-strand DNA breaks. Serine integrases catalyze the insertion of large DNA cargos at attachment (att) sites. By targeting att sites to the genome using technologies such as prime editing, integrases can target safe loci while avoiding double-strand breaks. We developed a method of phage-assisted continuous evolution we call IntePACE, that we used to rapidly perform hundreds of rounds of mutagenesis to systematically improve activity of PhiC31 and Bxb1 serine integrases. Novel hyperactive mutants were generated by combining synergistic mutations resulting in integration of a multi-gene cargo at rates as high as 80% of target chromosomes. Hyperactive integrases inserted a 15.7 kb therapeutic DNA cargo containing Von Willebrand Factor. This technology could accelerate gene delivery therapeutics and our directed evolution strategy can easily be adapted to improve novel integrases from nature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/598370v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@438582org.highwire.dtl.DTLVardef@f242f9org.highwire.dtl.DTLVardef@10ae9eborg.highwire.dtl.DTLVardef@183543f_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

ABCA1 deficiency causes tissue-specific dysregulation of the SREBP2 pathway in mice

The ATP-binding cassette transporter ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL) by mediating phospholipid and cholesterol efflux to apolipoprotein A-I. In humans, loss-of-function mutations in the ABCA1 gene cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients and Abca1-/- mice exhibit the cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others have shown that ABCA1 deficiency causes hyperactivation of the sterol regulatory element-binding protein 2 (SREBP2) pathway in vitro. In this work, we investigate whether ABCA1 deficiency affects SREBP2-dependent cholesterol homeostatic responses in vivo. We show that SREBP2 response gene expression is partly downregulated in the liver of Abca1-/- mice compared to wild-type mouse livers in the steady-state condition. In contrast, we find that in fasted or refed condition, the expression of SREBP2 target genes is upregulated in multiple tissues of Abca1-/- mice. Correspondently, SREBP2 processing is also increased in select tissues of these mice. Altogether, our results suggest that ABCA1 deficiency is associated with the tissue-specific dysregulation of the SREBP2 pathway in a manner dependent on nutritional status. Lack of ABCA1 thus causes not only HDL deficiency but also dysregulation of the SREBP2 pathway in multiple tissues, which may underlie the pathophysiology of TD.

physiology↗

bioRxiv2023

Engineered Active Zymogen of Microbial Transglutaminase

Microbial transglutaminase (MTG) has shown to be a powerful biocatalytic glue for site-specific crosslinking of a range of biomolecules and synthetic molecules, those handled with an MTG-reactive moiety. The preparation of active recombinant MTG requires the posttranslational proteolytic digestion of propeptide working as an intramolecular chaperon to assist the correct folding of MTG zymogen (MTGz) in the biosynthesis. Herein, we propose an engineered active zymogen of MTG (EzMTG) that is expressed as soluble form in the host E. coli cytosol and exhibits the cross-linking activity without limited proteolysis. Based on the 3D structure of MTGz and serendipitous findings, saturated mutagenesis of K10 or Y12 in propeptide domain leads to generate several active MTGz mutants. In particular, K10D/Y12G mutant exhibited the catalytic activity comparable with a mature form. However, the expression level was low possibly due to the reduction of chaperone activity and/or the promiscuous substrate specificity of MTG, which is potentially harmful to the host cells. By contrast, soluble K10R/Y12A mutant is expressed in the cytosol of host E. coli and exhibited unique substrate-dependent reactivity toward peptidyl substrates. The quantitative analysis of the binding affinity of mutated propeptide to the active site suggested the trade-off relationship of EzMTGs between the binding affinity and the catalytic activity. Our proof-of-concept study provides insights into the design of a new biocatalyst by using the zymogen as a scaffold and will convey a potential route to the high-throughput screening of MTG mutants for bioconjugation applications.

biochemistry↗

bioRxiv2023

Fruitless mating with the exes: the irreversible parthenogenesis in a stick insect

Parthenogenetic lineages, common in many animals, have sparked debate about their evolutionary persistence. While asexuality is expected to ensure reproductive assurance and provide a demographic advantage, parthenogens should suffer from the lack of gene shuffling with other individuals. On the other hand, occasional sexual reproduction has been theoretically predicted to be enough to mitigate the long-term costs of parthenogenesis. Recent studies have revealed instances of cryptic sex in some old parthenogenetic lineages, which is most likely mediated by rarely occurring males. Unlike female traits that rapidly become vestigial under asexuality, traits in males have been predicted to slowly decay due to the accumulation of neutral mutations over long evolutionary times. In fact, rare males often retain sexual functions, raising questions about the asexuality of these long-standing parthenogenetic lineages. Here, we intensively examined the possibility of sexual reproduction in the Japanese common stick insect, Ramulus mikado, which was also suggested to be an old parthenogen in our previous work. While asexual female reproduction appears to be quite predominant throughout Japan, we fortunately obtained the rare males from the field. These males exhibited typical stick insect male morphology and engaged in mating behaviors with conspecific females. However, no paternal-specific alleles were detected in the offspring; all embryos showed genotypes identical to their mothers. Our histological observations on a few males revealed that they had no sperm in their reproductive organs, although the degree of decay may be different among the lineages. We also found that females have sexual organs with signs of degeneration. All these results demonstrate the irreversible asexual reproduction of R. mikado and indicate their long history as a parthenogenetic species. Our present study provides unique insights into the maintenance of parthenogenesis and degenerative evolution of sexual traits in ancient asexual lineages.

evolutionary biology↗

bioRxiv2023

Microbiome ssRNA as an environmental cue to activate TLR13-dependent tissue-protective programs in CD5Lhi hepatic macrophages

Hepatic macrophages maintain liver homeostasis, but little is known about the signals that activate the hepatoprotective programs within macrophages. Here, we show that toll-like receptor 13 (TLR13), a sensor of bacterial 23S ribosomal RNA (rRNA), senses microbiome RNAs to drive tissue-protective responses in CD5Lhi hepatic macrophages. Splenomegaly and hepatomegaly developed in the absence of the endosomal RNase, RNaseT2, via TLR13-dependent macrophage proliferation. Furthermore, TLR13 in hepatic Ly6Clo macrophages activated the transcription factors LXR and MafB, leading to expression of tissue-clearance molecules, such as CD5L, C1qb, and Axl. Consequently, Rnaset2-/- mice developed resistance to acute liver injury caused by challenges with acetaminophen and lipopolysaccharide + D-galactosamine. TLR13 responses in Rnaset2-/- mice were impaired by antibiotics, suggesting that TLR13 were activated by microbiome rRNAs, which was detected in the sera and hepatic macrophages. Repeated administration of wild-type mice with the TLR13 ligand, rather than other TLR ligands, selectively increased the number of Kupffer cells, which expressed immunoregulatory and tissue-clearance genes as hepatic macrophages in Rnaset2-/- mice did. Our results suggest that microbiome ssRNA serves as an environmental cue for initiating tissue-protective TLR13 responses in hepatic macrophages. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/540294v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@69614eorg.highwire.dtl.DTLVardef@737c69org.highwire.dtl.DTLVardef@1ecd9eforg.highwire.dtl.DTLVardef@d7e10d_HPS_FORMAT_FIGEXP M_FIG In the absence of an endosomal RNase, RNase T2, microbiome RNAs circulating in the vasculature activate TLR13 in hepatic macrophages to drive hepatoprotective responses through expression of immunoregulatory and tissue-clearance molecules. Consequently, mice lacking RNase T2 are resistant against acute liver injuries caused by acetaminophen and LPS + D-galactosamine. C_FIG

immunology↗

bioRxiv2023

Downregulation of CYP7B1 caused by lipotoxicity associates with the progression of non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with an incidence of >25% of the adult population. NAFLD ranges from benign simple steatosis to non-alcoholic steatohepatitis (NASH). However, its transition mechanisms underlying the pathogenesis remain to be clarified. The expression of Cyp7b1 gene is downregulated in the liver of leptin-deficient mice and methionine and choline-deficient diet-fed mice based on previous microarray data. Thus, in this study, we investigated the effect of CYP7B1 restoration on the progression of NASH in mice fed MCD diet and its association with oxidative and lipid stresses. Our results suggest that restoration of CYP7B1 expression attenuates hepatitis and fibrosis and that lipid and oxidative stresses observed in the early stage of NASH suppresses Cyp7b1 transcription in hepatocytes.

biochemistry↗

bioRxiv2022

Opponent Learning with Different Representations in the Cortico-Basal Ganglia Pathways Can Develop Obsession-Compulsion Cycle

Obsessive-compulsive disorder (OCD) has been suggested to be associated with impairment of model-based behavioral control. Meanwhile, recent work suggested shorter memory trace for negative than positive prediction errors (PEs) in OCD. We explored relations between these two suggestions through computational modeling. Based on the properties of cortico-basal ganglia pathways, we modeled human as an agent having a combination of successor representation (SR)-based system that enables model-based-like control and individual representation (IR)-based system that only hosts model-free control, with the two systems potentially learning from positive and negative PEs in different rates. We simulated the agents behavior in the environmental model used in the recent work that describes potential development of obsession-compulsion cycle. We found that the dual-system agent could develop enhanced obsession-compulsion cycle, similarly to the agent having memory trace imbalance in the recent work, if the SR- and IR-based systems learned mainly from positive and negative PEs, respectively. We then simulated the behavior of such an opponent SR+IR agent in the two-stage decision task, in comparison with the agent having only SR-based control. Fitting of the agents behavior by the model weighing model-based and model-free control developed in the original two-stage task study resulted in smaller weights of model-based control for the opponent SR+IR agent than for the SR-only agent. These results reconcile the previous suggestions about OCD, i.e., impaired model-based control and memory trace imbalance, raising a novel possibility that opponent learning in model(SR)-based and model-free controllers underlies obsession-compulsion. Our model cannot explain the behavior of OCD patients in punishment, rather than reward, contexts, but it could be resolved if opponent SR+IR learning operates also in the recently revealed non-canonical cortico-basal ganglia-dopamine circuit for threat/aversiveness, rather than reward, reinforcement learning, and the aversive SR + appetitive IR agent could actually develop obsession-compulsion if the environment is modeled differently. Author summaryObsessive-compulsive disorder (OCD) is one of the major psychiatric disorders diagnosed in 2.5%-3% of the population, and is characterized as an enhanced cycle of obsessive thought, e.g., whether the door was locked, and compulsive action, e.g., checking door lock. It remains elusive why such an apparently maladaptive behavior could be enhanced. A prevailing theory proposes that humans use two control systems, flexible yet costly goal-directed system and inflexible yet costless habitual system, and impairment of the goal-directed system leads to OCD. On the other hand, recent work proposed a new theory that shorter memory trace for credit-assignment of negative, than positive, prediction errors can induce OCD. Relation between these two theories remains unclear. We show that opponent learning of particular type of goal-directed(-like) system, suggested to be implemented in the brain, and habitual system from positive versus negative prediction errors could exhibit an (apparent) overall decrease in goal-directed control and also develop enhanced obsession-compulsion cycle similar to the one developed by memory-trace imbalance, thereby bridging the two theories. Such an opponent learning of the two systems was actually suggested to be advantageous in certain dynamic environments, and could thus be evolutionarily selected at the cost of possible development of OCD.

neuroscience↗