Biology subjects

Morita, K.

Publications and source records attributed to Morita, K..

35 records · Page 2Linked to original sources

bioRxiv2023

Investigation of the usefulness of liver-specific deconvolution method toward legacy data utilization

BackgroundImmune responses in the liver are related to the development and progression of liver failure, and precise prediction of their behavior is important. Deconvolution is a methodology for estimating the immune cell proportions from the transcriptome, and it is mainly applied to blood-derived samples and tumor tissues. However, the influence of tissue-specific modeling on the estimation results has rarely been investigated. In this study, we constructed a system to evaluate the performance of the deconvolution method on liver transcriptome data. ResultsWe prepared seven mouse liver injury models using small-molecule compounds with known hepatotoxicity and established a dataset with corresponding liver bulk RNA-Seq and immune cell proportions, covering various immune responses. RNA-Seq expression for nine leukocyte subsets and four liver-associated cell types were obtained from the Gene Expression Omnibus (GEO) to provide a reference covering liver component cells. Here, we found that the combination of reference cell sets affects the estimation results of reference-based deconvolution methods. We established a liver tissue-specific deconvolution by optimizing the reference cell set for each cell to be estimated. We applied this model to independent datasets and showed that liver-specific modeling focusing on reference cell sets is highly extrapolatable. ConclusionsWe provide an approach of liver-specific modeling when applying reference-based deconvolution to bulk RNA-Seq data and show its importance. It is expected to enable sophisticated estimation from rich tissue data accumulated in public databases and to obtain information on aggregated immune cell trafficking.

bioinformatics↗

bioRxiv2023

Rainbow trout in the inlet tributaries of Lake Chinishibetsu, Shiretoko Peninsula

Rainbow trout, Oncorhynchus mykiss, is one of the most widely introduced fish species in the world, and its impacts on native fishes and ecosystems are of considerable concern. One of the rivers inhabited by rainbow trout in the Shiretoko Peninsula is the Chinishibetsu River, and the origin of rainbow trout in this river is thought to be Lake Chinishibetsu in the upper reaches of the system, where the private stocking of rainbow trout was conducted in the 1960s. However, the basic biology of rainbow trout in the Lake Chinishibetsu area is currently unknown. This study addresses this knowledge gap by examining the biology of rainbow trout in the inlet tributaries of Lake Chinishibetsu based on sampling conducted during the rainbow trout spawning season. A total of 104 rainbow trout, ranging in age from 1+ to 8+ years, were collected from the two inlet tributaries of Lake Chinishibetsu. White-spotted charr Salvelinus leucomaenis and Siberian stone loach Barbatula oreas, neither of which is native to the Shiretoko Peninsula, were also collected and had presumably invaded the area at the same time as the rainbow trout. The sampled rainbow trout included immature and mature males and females. The distribution of fork lengths of mature females was bimodal, and the sex ratio of mature rainbow trout was male-biased. Our results indicate that the rainbow trout population in the inlet tributaries of Lake Chinishibetsu is reproducing continuously and exhibits a dimorphic life history with river residents and lake migrants of both sexes. Additionally, rainbow trout continue to be collected downstream of the Chinishibetsu River, which is the primary habitat for this species in the Shiretoko Peninsula. Therefore, unless rainbow trout are eliminated from Lake Chinishibetsu, which serves as a source of non-native species upstream of the Chinishibetsu River, it will be difficult to control rainbow trout distributions and minimize population sizes on the Shiretoko Peninsula.

ecology↗

bioRxiv2023

Structure and its transformation of elliptical nege-like virus Tanay virus

Negeviruses that infect insects are recently identified virus species that are phylogenetically related to several plant viruses. They exhibit a unique virion structure, an elliptical core with a short projection. Negeviruses encode two structural proteins, a glycoprotein that forms a short projection, and an envelope protein that forms an elliptical core. The glycoprotein has been reported only in the negeviruses genes, and not in phylogenetically related plant viruses genes. In this report, we first describe the three-dimensional electron cryo-microscopy (cryo-EM) structure of Tanay virus (TANAV), one of the nege-like viruses. TANAV particle demonstrates a periodical envelope structure consisting of three layers surrounding the centered viral RNA. The elliptical core dynamically changes its shape under acidic and even low detergent conditions to form bullet-like or tubular shapes. The further cryo-EM studies on these transformed TANAV particles reveal their overall structural rearrangement. These findings suggest putative geometries of TANAV and its transformation in the life cycle, and the potential importance of the short projection for enabling cell entry to the insect hosts. Impact statementNegeviridae has recently been declared as a virus family that includes virus species exhibiting a unique particle structure that differs from other known viruses. They are known to be common mosquito viruses isolated around the world, but also phylogenetically related to several plant viruses that impair crop production. Therefore, the negeviruses may also play a role in plant ecosystems that threaten agriculture. However, the mechanism of infection and assembly of the negeviruses as well as their structure were unknown. In this study, intact and dissociated structures of the TANAV were first examined using cryo-EM single particle analysis (SPA) and electron cryo-tomography (cryo-ET). These results reveal new structural geometries of the TANAV particle and its dynamic transformation under acidic and even low-detergent conditions, providing new insights into the infection and assembly mechanism in negeviruses.

biophysics↗

bioRxiv2022

Expected Costs of Mental Efforts are Updated When People Exert Effort, not by Prospective Information

To understand why people avoid mental effort, it is crucial to reveal the mechanisms by which we learn and decide about mental effort costs. This study investigated whether mental effort cost learning aligns with temporal-difference (TD) learning or alternative mechanisms. Model-based fMRI analyses showed no correlation between cost prediction errors (CPEs) and activity in the dorsomedial frontal cortex/dorsal anterior cingulate cortex (dmFC/dACC) or striatum at the time of a fully informative effort cue about upcoming effort demands, contradicting the TD hypothesis. Instead, CPEs correlate with dmFC/dACC (positively) and caudate (negatively) activity at effort completion. Furthermore, only activity patterns at effort completion predict subsequent choices. These results show that decision policies are updated retrospectively at effort completion, updating expected costs with prediction error between experienced effort and prior expectations, demonstrating mental effort cost learning is retrospective, and imply that adaptive learning of mental effort cost does not follow canonical TD learning. Significance StatementUnderstanding how people learn about mental effort costs is essential for advancing theories of motivation and cognitive control. However, the algorithms supporting such learning remain unclear. This study addressed this gap and found that temporal-difference learning, commonly used to explain reward learning, could not account for how people learn about effort. Instead, decision policies were updated retrospectively at effort completion, based on a prediction error between experienced effort and prior expectations. These findings reveal that mental effort cost learning is fundamentally retrospective and imply that it relies on mechanisms distinct from canonical temporal-difference learning.

neuroscience↗

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↗

bioRxiv2022

In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and genetically obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

systems biology↗

bioRxiv2021

Combination of successor representation-based appetitive learning and individual representation-based aversive learning is a good strategy and can be implemented in the cortico-basal ganglia circuits

The direct and indirect pathways of the basal ganglia (BG) have been suggested to learn mainly from positive and negative feedbacks, respectively. Since these pathways unevenly receive inputs from different cortical neuron types and/or regions, they may preferentially use different state/action representations. We explored whether such combined use of different representations coupled with appetitive or aversive learning has computational benefits. We simulated reward learning tasks in dynamic environments, and examined the performance of animal modeled as an agent equipped with two learning systems, each of which used individual representation (IR) or successor representation (SR) of states. With varying the combination of IR or SR and also the learning rates from positive and negative reward prediction errors (RPEs) in each system, we found that combination of an SR-based system learning mainly from positive RPEs and an IR-based system learning mainly from negative RPEs could achieve good performance, as compared to other combinations, in many situations. The architecture of such a combination provides a novel coherent explanation for the functional significance and underlying mechanism of diverse findings about the cortico-BG circuits. These results suggest that combining different representations with appetitive and aversive learning is an effective learning strategy adopted by the brain.

neuroscience↗

bioRxiv2021

A statistical test for clonal exclusivity in tumour evolution

Tumour progression is an evolutionary process in which different clones evolve over time, leading to intra-tumour heterogeneity. Interactions between clones can affect tumour evolution and hence disease progression and treatment outcome. Pairs of mutations that are overrepresented in a clonally exclusive fashion over a cohort of patient samples may be suggestive of a synergistic effect between the different clones carrying these mutations. We therefore developed a novel statistical test, called GeneAccord, to identify such gene pairs that are altered in distinct subclones of the same tumour. We analysed our test for calibration and power. By comparing its performance to baseline methods, we demonstrate that to control type I errors, it is essential to account for the evolutionary dependencies among clones. In applying GeneAccord to the single-cell sequencing of a cohort of 123 acute myeloid leukaemia patients, we find 6 clonally exclusive and 2 clonally co-occurring gene pairs. The clonally exclusive pairs mostly involve genes of the key signalling pathways.

cancer biology↗

bioRxiv2021

How does the magnitude of genetic variation affect eco-evolutionary dynamics in character displacement?

AO_SCPLOWBSTRACTC_SCPLOWWhile previous studies on character displacement tended to focus on trait divergence and convergence as a result of long-term evolution, recent studies suggest that character displacement can be a special case of evolutionary rescue, where rapid evolution prevents population extinction by weakening negative interspecific interactions. When the magnitude of genetic variation is small, however, the speed of trait divergence can be slow and populations may go extinct before the completion of character displacement. Here we analyzed a simple model to examine how the magnitude of genetic variation affects evolutionary rescue via ecological and reproductive character displacement that weakens resource competition and reproductive interference, respectively. We found that the large additive genetic variance is more important for preventing extinction in reproductive character displacement than in ecological character displacement. This is because reproductive interference produces a locally stable coexistence equilibrium with positive frequency-dependence (i.e., minority disadvantage) whereas ecological character displacement results in a globally stable coexistence equilibrium. Furthermore, population extinction becomes less likely when ecological and reproductive character displacement occur simultaneously due to positive covariance between ecological and reproductive traits. Our results suggest that while reproductive character displacement may be rarer than ecological character displacement, it is more likely to occur when there exists positive trait covariance, such as the case of a magic trait in reinforcement of speciation processes.

ecology↗

bioRxiv2020

5-amino levulinic acid inhibits SARS-CoV-2 infection in vitro

The current COVID-19 pandemic requires urgent development of effective therapeutics. 5-amino levulinic acid (5-ALA) is a naturally synthesized amino acid and has been used for multiple purposes including as an anticancer therapy and as a dietary supplement due to its high bioavailability. In this study, we demonstrated that 5-ALA treatment potently inhibited infection of SARS-CoV-2, a causative agent of COVID-19. The antiviral effects could be detected in both human and non-human cells, without significant cytotoxicity. Therefore, 5-ALA is a candidate as an oral antiviral drug for COVID-19.

microbiology↗

bioRxiv2020

Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we performed multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 68 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis revealed that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes was the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.

cancer biology↗

bioRxiv2020

Difficulty in Cessation of Undesired Habits: Goal-Based Reduced Successor Representation and Reward Prediction Errors

Difficulty in cessation of drinking, smoking, or gambling has been widely recognized. Conventional theories proposed relative dominance of habitual over goal-directed control, but human studies have not convincingly supported them. Referring to the recently suggested "successor representation" of states that enables partially goal-directed control, we propose a dopamine-related mechanism potentially underlying the difficulty in resisting habitual reward-seeking, common to substance and non-substance reward. Consider that a person has long been taking a series of actions leading to a certain reward without resisting temptation. Given the suggestions of the successor representation and the dimension reduction in the brain, we assumed that the person has acquired a dimension-reduced successor representation of states based on the goal state under the established non-resistant policy. Then, we show that if the person changes the policy to resist temptation, a large positive reward prediction error (RPE) becomes generated upon eventually reaching the goal, and it sustains given that the acquired state representation is so rigid that it does not change. Inspired by the anatomically suggested spiral striatum-midbrain circuit and the theoretically proposed spiraling accumulation of RPE bias in addiction, we further simulated the influence of RPEs generated in the goal-based representation system on another system representing individual actions. We then found that such an influence could potentially enhance the propensity of non-resistant choice. These results suggest that the inaccurate value estimation in the reduced successor representation system and its influence through the spiral striatum-midbrain circuit might contribute to the difficulty in cessation of habitual reward-seeking.

neuroscience↗

bioRxiv2020

Brain/MINDS Beyond Human Brain MRI Study: Multi-Site Harmonization for Brain Disorders Throughout the Lifespan

Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (FY2018 [~] FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. The Harmonization protocol (HARP) was established for five high-quality 3T scanners to obtain multimodal brain images including T1 and T2-weighted, resting state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, providing high reproducibility and sensitivity to subject-specific connectome. A total of 75 TS, as well as patients with various psychiatric and neurological disorders, are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a rigorous, prospective harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

neuroscience↗

bioRxiv2020

Patterns of functional and structural brain information are preserved over generations

There is clear evidence of intergenerational transmission of life values, cognitive traits, psychiatric disorders, and even aspects of daily decision making. To investigate biological substrates of this phenomenon, brain has received increasing attention as a measurable biomarker and potential target for intervention. However, no previous study has quantitatively and comprehensively investigated the effects of intergenerational transmission on functional and structural brain networks from parents to their children. Here, by employing an unusually large cohort dataset, we show that patterns of functional and structural brain networks are preserved over a generation. We also demonstrate that several demographic and behavioural phenotypes have effects on brain similarity. Collectively, our results provide a comprehensive picture of neurobiological substrates of parent-child similarity, and demonstrate the usability of our dataset for investigating the neurobiological substrates of intergenerational transmission.

neuroscience↗

bioRxiv2020

Clonal Evolution of Acute Myeloid Leukemia Revealed by High-Throughput Single-Cell Genomics

One of the pervasive features of cancer is the diversity of mutations found in malignant cells within the same tumor; a phenomenon called clonal diversity or intratumor heterogeneity. Clonal diversity allows tumors to adapt to the selective pressure of treatment and likely contributes to the development of treatment resistance and cancer recurrence. Thus, the ability to precisely delineate the clonal substructure of a tumor, including the evolutionary history of its development and the co-occurrence of its mutations, is necessary to understand and overcome treatment resistance. However, DNA sequencing of bulk tumor samples cannot accurately resolve complex clonal architectures. Here, we performed high-throughput single-cell DNA sequencing to quantitatively assess the clonal architecture of acute myeloid leukemia (AML). We sequenced a total of 556,951 cells from 77 patients with AML for 19 genes known to be recurrently mutated in AML. The data revealed clonal relationship among AML driver mutations and identified mutations that often co-occurred (e.g., NPM1/FLT3-ITD, DNMT3A/NPM1, SRSF2/IDH2, and WT1/FLT3-ITD) and those that were mutually exclusive (e.g., NRAS/KRAS, FLT3-D835/ITD, and IDH1/IDH2) at single-cell resolution. Reconstruction of the tumor phylogeny uncovered history of tumor development that is characterized by linear and branching clonal evolution patterns with latter involving functional convergence of separately evolved clones. Analysis of longitudinal samples revealed remodeling of clonal architecture in response to therapeutic pressure that is driven by clonal selection. Furthermore, in this AML cohort, higher clonal diversity ([≥]4 subclones) was associated with significantly worse overall survival. These data portray clonal relationship, architecture, and evolution of AML driver genes with unprecedented resolution, and illuminate the role of clonal diversity in therapeutic resistance, relapse and clinical outcome in AML.

cancer biology↗

bioRxiv2019

Differential Striatal Axonal Arborizations of the Intratelencephalic and Pyramidal-Tract Neurons: Analysis of the Data in the MouseLight Database

There exist two major types of striatum-targeting neocortical neurons, specifically, intratelencephalic (IT) neurons and pyramidal-tract (PT) neurons. Regarding their striatal projections, it was once suggested that IT axons are extended whereas PT axons are primarily focal. However, subsequent study with an increased number of well-stained extended axons concluded that such an apparent distinction was spurious due to limited sample size. Recent work using genetically labeled neurons reintroduced the differential spatial extent of the striatal projections of IT and PT neurons through population-level analyses, complemented by observations of single axons. However, quantitative analysis of a large number of axons remained to be conducted. We analyzed the data of axonal end-points of 161 IT neurons and 33 PT neurons in the MouseLight database (http://ml-neuronbrowser.janelia.org/). The number of axonal end-points in the ipsilateral striatum exhibits roughly monotonically decreasing distributions in both neuron types. However, the proportion of neurons having >50 ipsilateral end-points is larger in IT neurons than in PT neurons. Moreover, distinguishing IT subpopulations in the secondary motor area (MOs), layer 5 neurons and bilateral striatum-targeting layer 2/3 neurons, but not contralateral striatum-non-targeting layer 2/3 neurons, have a larger number of ipsilateral end-points than MOs PT neurons. We also found that IT ipsilateral striatal axonal end-points are on average more widely distributed than PT end-points, especially in the medial-lateral direction. These results indicate that IT and PT striatal axons differ in the frequency of having numerous end-points and the spatial extent of end-points while there are wide varieties within each neuron type.

neuroscience↗

bioRxiv2019

Functional connectome linking child-parent relationships with psychological problems in adolescence

Paternal- and maternal-child relationships are associated with partly distinct psychobehavioral problems, which often manifest differently between boys and girls. In order to understand neural mechanisms underlying complicated mappings between child-parent relationship and adolescents problems, we used a dataset of early adolescents (N=93) and separately estimated the effects of paternal- and maternal-child relationships on resting-state functional connectivity and problems in boys and girls. General linear models identified the effects of paternal- and maternal-child relationships in different sets of functional connectivity, which we termed functional brain connectomes associated with paternal- and maternal-child relationship (FBCp and FBCm), respectively. Subsequent connectome-based models using these FBCs significantly predicted aggressive behaviors only for boys and internalizing problems selectively only girls. Lastly, a causal discovery method identified causal paths from daughter-mother relationship to FBCm, and then to daughters internalizing problems. These observations highlight sex-dependent mechanisms linking child-parent relationship, brain, and psychobehavioral problems in early adolescence.

neuroscience↗