Biology subjects

Takagi, A.

Publications and source records attributed to Takagi, A..

11 recordsLinked to original sources

bioRxiv2025

Intermittent movement control emerges from information-based planning

Mammalian motor control is inherently discrete, with movement corrections occurring at rates determined by task demands and the quality of sensory information. While several models have been proposed to explain this discreteness, it remains unclear when a new movement should be initiated and how long it should last. To address this gap, we introduce the Information Predictive Control (IPC) framework, which combines model predictive control with information theory. IPC triggers corrections only when unexpected deviations arise and when corrective actions are likely to succeed. By quantifying "surprise" relative to predicted internal and external states, IPC generates successful movements while robustly integrating sensorimotor noise, task constraints, and target variability. Simulations show that IPC reproduces human-like behavior in discrete reaching, continuous target tracking, and adaptive planning under uncertainty, while dynamically adjusting the planning horizon in complex, unpredictable environments.

neuroscience↗

bioRxiv2024

15 second assessment of hand and foot motor skill using a smartphone

Motor skills are essential for daily functioning and serve as key indicators of healthy development and aging. However, existing assessments of motor skill are inaccessible to the public and do not directly measure the quality of the movement. Here, we developed a convenient and robust measure of motor skill that uses a smartphone app to provide on-the-spot assessment in just 15 seconds. To validate our method, we asked 1675 participants between the ages of three to eighty-eight years old to trace circles at a fixed rhythm with a smartphone, which was either held in the hand or strapped to the ankle. Motor skill was quantified by the smartphone app using an algorithm that calculated the variability in the accelerations trajectory. Our assessment revealed significant changes in the skill of the hands and feet with age and practice. The variability of the hands and feet linearly decreased and matured in the mid-teens, but it regressed gradually thereafter. Laterality, or the difference in the motor skill between the left and right limbs, increased with age as the non-dominant hand and foot regressed faster in the elderly. Motor practice affected both skill and laterality as left-handers who were forced to write with their right-hand during childhood had a tell-tale sign of stronger right-handedness and, surprisingly, right-footedness. Our assessment aims to democratize motor skill assessment, making it accessible for professionals and users of all ages.

neuroscience↗

bioRxiv2024

Minimizing command timing volatility is a key factor in skilled actions

Variability between movements prevents the best athletes from making a perfect shot every time. While fluctuations in the amplitude of neural sensory inputs and motor outputs are thought to be primarily responsible, they only account for a fraction of the observed variability. Here, we propose that a significant portion of the variability is due to imprecisely timed motor commands. This command timing volatility theory best explained the three peaks observed in the force variabilitys time-series in discrete reaching movements and during periodic force control. Furthermore, we show how the timing volatility in the non-dominant arms muscles is larger than in the dominant arm, then develop a variability index that estimates the arms timing volatility via its variability during circle tracing. The difference in the variability index between the left and right hands accurately predicts the Edinburgh Quotient, suggesting a relationship between handedness and the command timing volatility of the left- and right-hands. Lastly, we constructed a simulation of reaching movements made by an arm controlled by muscles whose command timing was made incrementally more volatile. As timing volatility increased, aiming became less precise and movements jerkier. Such impairments during reaching are reported in patients with different neuronal diseases that damage any brain regions critical to motor timing, suggesting that essential aspects of these symptoms may be caused by excessive timing volatility. Our theory provides a unifying computational perspective of movement variability in healthy and diseased individuals that is essential to understanding the control of movements.

neuroscience↗

bioRxiv2022

A model predictive control strategy to regulate movements and interactions

Humans are adept at moving the arm to interact with objects and surfaces. The brain is thought to regulate motion and interactions using two different controllers, one specialized for movements and the other for force regulation. However, it remains unclear whether different control mechanisms are necessary. Here we show that the brain can employ a single high-level control strategy for both movement and interaction control. The Model Predictive Control (MPC) strategy introduced in this paper uses an internal model of the environment to plan the arms muscle activity whilst updating its predictions using periodic feedback. Computer simulations demonstrate MPCs ability to produce human-like movements and after-effects in free and force field environments. It can simultaneously regulate both force and stiffness during interactions, and can accomplish motor tasks demanding transitions between motion and interaction control. Model Predictive Control promises to be an important tool to test ideas of motor control as it can handle nonlinear dynamics with changing environments and goals without having to specify the movement duration.

neuroscience↗

bioRxiv2022

An attenuated vaccinia vaccine encoding the SARS-CoV-2 spike protein elicits broad and durable immune responses, and protects cynomolgus macaques and human ACE2 transgenic mice from SARS-CoV-2 and its variants

As long as the coronavirus disease 2019 (COVID-19) pandemic continues, new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with altered antigenicity will emerge. The development of vaccines that elicit robust, broad, and durable protection against SARS-CoV-2 variants is urgently needed. We have developed a vaccine (rDIs-S) consisting of the attenuated vaccinia virus DIs strain platform carrying the SARS-CoV-2 S gene. rDIs-S induced neutralizing antibody and T-lymphocyte responses in cynomolgus macaques and human angiotensin converting enzyme 2 (hACE2) transgenic mice, and showed broad protection against SARS-CoV-2 isolates ranging from the early-pandemic strain (WK-521) to the recent Omicron BA. 1 variant (TY38-839). Using a tandem mass tag (TMT) -based quantitative proteomic analysis of lung homogenates from hACE2 transgenic mice, we found that, among mice subjected to challenge infection with WK-521, vaccination with rDIs-S prevented protein expression related to the severe pathogenic effects of SARS-CoV-2 infection (tissue destruction, inflammation, coagulation, fibrosis, and angiogenesis) and restored protein expression related to immune responses (antigen presentation and cellular response to stress). Furthermore, long-term studies in mice showed that rDIs-S maintains S protein-specific antibody titers for at least 6 months after a 1st vaccination. Thus, rDIs-S appears to provide broad and durable protective immunity against SARS-CoV-2, including current and possibly future variants.

microbiology↗

bioRxiv2021

Identification of HLA-A*24:02-restricted CTL candidate epitopes derived from the non-structural polyprotein 1a of SARS-CoV-2 and analysis of their conservation using the mutation database of SARS-CoV-2 variants

COVID-19 vaccines are currently being administrated worldwide and playing a critical role in controlling the pandemic. They have been designed to elicit neutralizing antibodies against Spike protein of the original SARS-CoV-2, and hence they are less effective against SARS-CoV-2 variants with mutated Spike than the original virus. It is possible that novel variants with abilities of enhanced transmissibility and/or immunoevasion will appear in the near future and perfectly escape from vaccine-elicited immunity. Therefore, the current vaccines may need to be improved to compensate for the viral evolution. For this purpose, it may be beneficial to take advantage of CD8+ cytotoxic T lymphocytes (CTLs). Several lines of evidence suggest the contribution of CTLs on the viral control in COVID-19, and CTLs target a wide range of proteins involving comparatively conserved non-structural proteins. Here, we identified twenty-two HLA-A*24:02-restricted CTL candidate epitopes derived from the non-structural polyprotein 1a (pp1a) of SARS-CoV-2 using computational algorithms, HLA-A*24:02 transgenic mice and the peptide-encapsulated liposomes. We focused on pp1a and HLA-A*24:02 because pp1a is relatively conserved and HLA-A*24:02 is predominant in East Asians such as Japanese. The conservation analysis revealed that the amino acid sequences of 7 out of the 22 epitopes were hardly affected by a number of mutations in the Sequence Read Archive database of SARS-CoV-2 variants. The information of such conserved epitopes might be useful for designing the next-generation COVID-19 vaccine that is universally effective against any SARS-CoV-2 variants by the induction of both anti-Spike neutralizing antibodies and CTLs specific for conserved epitopes. ImportanceCOVID-19 vaccines have been designed to elicit neutralizing antibodies against the Spike protein of the original SARS-CoV-2, and hence they are less effective against variants. It is possible that novel variants will appear and escape from vaccine-elicited immunity. Therefore, the current vaccines may need to be improved to compensate for the viral evolution. For this purpose, it may be beneficial to take advantage of CD8+ cytotoxic T lymphocytes (CTLs). Here, we identified twenty-two HLA-A*24:02-restricted CTL candidate epitopes derived from the non-structural polyprotein 1a (pp1a) of SARS-CoV-2. We focused on pp1a and HLA-A*24:02 because pp1a is conserved and HLA-A*24:02 is predominant in East Asians. The conservation analysis revealed that the amino acid sequences of 7 out of the 22 epitopes were hardly affected by mutations in the database of SARS-CoV-2 variants. The information might be useful for designing the next-generation COVID-19 vaccine that is universally effective against any variants.

immunology↗

bioRxiv2021

Network-based pathogenicity prediction for variants of uncertain significance

While the number of genome sequences continues to increase, the functions of many detected gene variants remain to be identified. These variants of uncertain significance constitute a major barrier to precision medicine 1-3. Although many computational methods have been developed to predict the function of these variants, they all rely on individual gene features and do not consider complex molecular relationships. Here we develop PathoGN, a molecular network-based approach for predicting variant pathogenicity. PathoGN significantly outperforms existing methods using benchmark datasets. Moreover, PathoGN successfully predicts the pathogenicity of 3,994 variants of uncertain significance in the real-world database ClinVar and designates potential pathogenicity. This is the first computational method for the clinical interpretation of variants using biomolecular networks, and we anticipate our method to be broadly useful for the clinical interpretation of variants and for assigning biological function to unknown variants at the genomic scale.

genomics↗

bioRxiv2021

Periosteum-derived podoplanin-expressing stromal cells regulate nascent vascularization during epiphyseal marrow development

Bone marrow development and endochondral bone formation occur simultaneously. During endochondral ossification, periosteal vasculatures and stromal progenitors invade the primary avascular cartilaginous anlage; this induces primitive marrow development. We previously determined that bone marrow podoplanin (PDPN)-expressing stromal cells exist in a perivascular microenvironment, and promote megakaryopoiesis and erythropoiesis. In this study, we aimed to examine the involvement of PDPN-expressing stromal cells in the postnatal bone marrow generation. We found that periosteum-derived PDPN-expressing stromal cells regulate vascularization during postnatal epiphyseal marrow development. Our findings suggest that these cells act as pericytes on the primitive vasculature of the nascent marrow. They invade the cartilaginous epiphysis and regulate marrow development and homeostasis by maintaining vascular integrity. To the best of our knowledge, this is the first study to comprehensively examine how PDPN-expressing stromal cells contribute to marrow development and homeostasis.

developmental biology↗

bioRxiv2020

The alopecia areata phenotype is induced by the water avoidance stress test in cchcr1-deficient mice.

BackgroundWe recently discovered a nonsynonymous variant in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene within the alopecia areata (AA) risk haplotype; mice engineered to carry the risk allele displayed a hair loss phenotype. ObjectiveTo further investigate the involvement of the CCHCR1 gene in AA pathogenesis. MethodsWe developed an AA model using C57BL/6N cchcr1 gene knockout mice. Mice (6-8 weeks) were divided into two groups: cchcr1 -/- mice and wild-type (WT) mice. Both groups were subjected to a water avoidance stress (WAS) test. ResultsEight weeks after the WAS test, 25% of cchcr1 mice exhibited noninflammatory foci of alopecia on the dorsal skin. The foci resembled human AA in terms of gross morphology, trichoscopic findings and histological findings. ConclusionsOur results strongly suggest that CCHCR1 is associated with AA pathogenesis and that cchcr1-/- mice are a good model for investigating AA. Author summaryAlopecia areata is thought to affect 1-2% of the population. In severe alopecia areata, changes in appearance significantly reduce the patients quality of life, but there is no established treatment. Its pathogenic mechanism is thought to cause an autoimmune disease of the hair bulb of growing hair. Many genes and factors associated with AA onset form a background that easily causes such an immune reaction, and the causative genes related to alopecia areata are being elucidated worldwide. We were able to identify the CCHCR1 gene as one of the causative genes by genome analysis. In this study, we created CCHCR1-deficient mice using Cre/loxP technology and confirmed that 25% of CCHCR1-deficient mice that underwent the WAS test for psychological stimulation developed hair loss similar to that observed in human alopecia areata. This suggests that the CCHCR1 gene is a disease susceptibility gene for alopecia areata.

genetics↗

bioRxiv2020

An immunodominance hierarchy exists in CD8+ T cell responses to HLA-A*02:01-restricted epitopes identified from the non-structural polyprotein 1a of SARS-CoV-2.

COVID-19 vaccines are being rapidly developed and human trials are underway. Almost all of these vaccines have been designed to induce antibodies targeting spike protein of SARS-CoV-2 in expectation of neutralizing activities. However, non-neutralizing antibodies are at risk of causing antibody-dependent enhancement. Further, the longevity of SARS-CoV-2-specific antibodies is very short. Therefore, in addition to antibody-induced vaccines, novel vaccines on the basis of SARS-CoV-2-specific cytotoxic T lymphocytes (CTLs) should be considered in the vaccine development. Here, we attempted to identify HLA-A*02:01-restricted CTL epitopes derived from the non-structural polyprotein 1a of SARS-CoV-2. Eighty-two peptides were firstly predicted as epitope candidates on bioinformatics. Fifty-four in 82 peptides showed high or medium binding affinities to HLA-A*02:01. HLA-A*02:01 transgenic mice were then immunized with each of the 54 peptides encapsulated into liposomes. The intracellular cytokine staining assay revealed that 18 out of 54 peptides were CTL epitopes because of the induction of IFN-{gamma}-producing CD8+ T cells. In the 18 peptides, 10 peptides were chosen for the following analyses because of their high responses. To identify dominant CTL epitopes, mice were immunized with liposomes containing the mixture of the 10 peptides. Some peptides were shown to be statistically predominant over the other peptides. Surprisingly, all mice immunized with the liposomal 10 peptide mixture did not show the same reaction pattern to the 10 peptides. There were three pattern types that varied sequentially, suggesting the existence of an immunodominance hierarchy, which may provide us more variations in the epitope selection for designing CTL-based COVID-19 vaccines. ImportanceFor the development of vaccines based on SARS-CoV-2-specific cytotoxic T lymphocytes (CTLs), we attempted to identify HLA-A*02:01-restricted CTL epitopes derived from the non-structural polyprotein 1a of SARS-CoV-2. Out of 82 peptides predicted on bioinformatics, 54 peptides showed good binding affinities to HLA-A*02:01. Using HLA-A*02:01 transgenic mice, 18 in 54 peptides were found to be CTL epitopes in the intracellular cytokine staining assay. Out of 18 peptides, 10 peptides were chosen for the following analyses because of their high responses. To identify dominant epitopes, mice were immunized with liposomes containing the mixture of the 10 peptides. Some peptides were shown to be statistically predominant. Surprisingly, all immunized mice did not show the same reaction pattern to the 10 peptides. There were three pattern types that varied sequentially, suggesting the existence of an immunodominance hierarchy, which may provide us more variations in the epitope selection for designing CTL-based COVID-19 vaccines.

immunology↗

bioRxiv2018

Alopecia areata susceptibility variant identified by MHC risk haplotype sequencing reproduces symptomatic patched hair loss in mice

BackgroundAlopecia areata (AA) is a highly heritable multifactorial and complex disease. However, no convincing susceptibility gene has yet been pinpointed in the major histocompatibility complex (MHC), a region in the human genome known to be associated with AA as compared to other regions.\n\nResultsBy sequencing MHC risk haplotypes, we identified a variant (rs142986308, p.Arg587Trp) in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene as the only non-synonymous variant in the AA risk haplotype. Using CRISPR/Cas9 for allele-specific genome editing, we then phenocopied AA symptomatic patched hair loss in mice engineered to carry the Cchcr1 risk allele. Skin biopsies of these alopecic mice showed strong up-regulation of hair-related genes, including hair keratin and keratin-associated proteins (KRTAPs). Using transcriptomics findings, we further identified CCHCR1 as a novel component of hair shafts and cuticles in areas where the engineered alopecic mice displayed fragile and impaired hair.\n\nConclusionsThese results suggest an alternative mechanism for the aetiology of AA based on aberrant keratinization, in addition to generally well-known autoimmune events.

genomics↗