Biology subjects

Ito, H.

Publications and source records attributed to Ito, H..

47 records · Page 3Linked to original sources

bioRxiv2020

Schizophrenia and autism-associated mutations and disrupted m6A signal by YTHDF1 cause defects in microtubule function and neurodevelopment

Subcellular mRNA localization and local translation are crucial for spatially regulated gene expression in neurons. However, the precise mechanisms governing the selective transport and translation of mRNAs contributing to processes such as axonal growth and branching are only partially understood. Here, we present evidence of N6-methyladenosine (m6A)-mediated translational control of the RNA-binding protein, APC, influencing cytoskeletal dynamics at the growth cone. Our findings demonstrate that m6A modifications occur on Apc mRNA, facilitating its recognition by YTHDF1 to promote APC translation in neuronal somata. Additionally, we observe that disrupting the m6A pathway impairs the transport and local translation of {beta}-actin mRNA in the axon and growth cones, a deficiency that can be rescued by the exogenous expression of APC protein in cultured neurons. Furthermore, we establish the essential role of YTHDF1 in axon development, particularly in callosal projection neurons during cortical development. Our findings suggest a novel mechanism involving m6A-mediated regulation of APC protein translation, linking epitranscriptomics to axonal mRNA targeting, cytoskeletal dynamics, and axon development.

neuroscience↗

bioRxiv2020

Tracking tau fibrillogenesis and consequent primary phagocytosis of neurons mediated by microglia in a living tauopathy model

Fibrillary tau pathologies have been implicated in Alzheimers and allied neurodegenerative diseases, while mechanisms by which neurons bearing tau tangles die remain enigmatic. To address this issue, we pursued tau and related key pathologies macroscopically by PET and MRI and microscopically by intravital two-photon laser optics. Time-course macroscopic assays of tau transgenic mice demonstrated intimate associations of tau deposition and increase of an inflammatory microglial marker, translocator protein (TSPO), with regional brain atrophy. Longitudinal microscopy of these mice revealed a rapid turnover of tau lesions resulting from continuous generation of new tau aggregates followed by loss of neurons and their fibrillar contents. This technology also allowed the capturing of the disappearance of tangle-bearing neurons several days after being engulfed by activated microglia. Notably, a therapeutic TSPO ligand profoundly suppressed the mobility and phagocytotic activity of microglia and improved neuronal survival in this model, supporting the involvement of primary phagocytosis of viable neurons by microglia in tau-primed neuronal death. Finally, partial depletion of microglia revealed roles of immune factors, MFG-E8 and C1q, as eat-me signals for an immediate attraction of phagocytic microglia towards the elimination of tangle-loaded neurons.

neuroscience↗

bioRxiv2020

Redesigned Reporter Gene for Improved Proton Exchange-based Molecular MRI Contrast

Reporter gene imaging allows for non-invasive monitoring of molecular processes in living cells, providing insights on the mechanisms underlying pathology and therapy. A lysine-rich protein (LRP) chemical exchange saturation transfer (CEST) MRI reporter gene has previously been developed and used to image tumor cells, cardiac viral gene transfer, and oncolytic virotherapy. However, the highly repetitive nature of the LRP reporter gene sequence leads to DNA recombination events and the expression of a range of truncated LRP protein fragments, thereby greatly limiting the CEST sensitivity. Here we report the use of a redesigned LRP reporter (rdLRP), aimed to provide excellent stability and CEST sensitivity. The rdLRP contains no DNA repeats or GC rich regions and 30% less positively charged amino-acids. RT-PCR of cell lysates transfected with rdLRP demonstrated a stable reporter gene with a single distinct band corresponding to full-length DNA. A distinct increase in CEST-MRI contrast was obtained in cell lysates of rdLRP transfected cells and in in vivo LRP expressing mouse brain tumors (p=0.0275, n=10).

bioengineering↗

bioRxiv2020

AI boosted molecular MRI for apoptosis detection in oncolytic virotherapy

Oncolytic virotherapy is a promising treatment for high mortality cancers1. Non-invasive imaging of the underlying molecular processes is an essential tool for therapy optimization and assessment of viral spread, innate immunity, and therapeutic response2, 3. However, previous methods for imaging oncolytic viruses did not correlate with late viral activity4 or had poor sensitivity and specificity5. Similarly, methods developed to image treatment response, such as apoptosis, proved to be slow, nonspecific, or require the use of radioactive or metal-based contrast agents6-8. To date, no method has been widely adopted for clinical use. We describe here a new method for fast magnetic resonance molecular imaging with quantitative proton chemical-exchange specificity to monitor oncolytic virotherapy treatment response. A deep neural network enabled the computation of quantitative biomarker maps of protein and lipid/macromolecule concentrations as well as intracellular pH in a glioblastoma multiforme mouse brain tumor model. Early detection of apoptotic response to oncolytic virotherapy, characterized by decreased cytosolic pH and protein synthesis, was observed in agreement with histology. Clinical translation was demonstrated in a normal human subject, yielding molecular parameters in good agreement with literature values9. The developed method is directly applicable to a wide range of pathologies, including stroke10, cancer11-13, and neurological disorders14, 15.

biophysics↗

bioRxiv2020

Combined impact of pesticides and other environmental stressors on taxonomic richness of freshwater animals in irrigation ponds

Rice paddy irrigation ponds can sustain surprisingly high taxonomic richness and make significant contributions to regional biodiversity. We evaluated the impacts of pesticides and other environmental stressors on the taxonomic richness of freshwater animals in 21 irrigation ponds in Japan. We sampled a wide range of freshwater animals (reptiles, amphibians, fishes, mollusks, crustaceans, insects, annelids, bryozoans, and sponges) and surveyed environmental variables related to pesticide contamination, eutrophication, decreased macrophyte coverage, physical habitat destruction, and invasive alien species. Statistical analyses comprised contraction of highly correlated environmental variables, best-subset model selection, stepwise model selection, and permutation tests. Results showed that: (i) probenazole (fungicide) was the unique significant stressor on fish (i.e., contamination with this compound had a significantly negative correlation with fish taxonomic richness), (ii) the interaction of BPMC (insecticide; also known as fenobucarb) and bluegill (invasive alien fish) was a significant stressor on a "large insect" category (Coleoptera, Ephemeroptera, Hemiptera, Lepidoptera, Odonata, and Trichoptera), (iii) the interaction of BPMC and concrete bank was a significant stressor on an "invertebrate" category, (iv) the combined impacts of BPMC and the other stressors on the invertebrate and large insect categories resulted in an estimated mean loss of taxonomic richness by 15% and 77%, respectively, in comparison with a hypothetical pond with preferable conditions.

ecology↗

bioRxiv2019

Seasonal and annual fluctuations of deer populations estimated by a Bayesian state-space model

Deer overabundance is a contributing factor in the degradation of plant communities and ecosystems worldwide. The management and conservation of the deer-affected ecosystems requires us to urgently grasp deer population trends and to identify the factors that affect them. In this study, we developed a Bayesian state-space model to estimate the population dynamics of sika deer (Cervus nippon) in a cool-temperate forest in Japan, where wolves (Canis lupus hodophilax) are extinct. The model was based on field data collected from block count surveys, road count surveys by vehicles, mortality surveys during the winter, and nuisance control for 12 years (2007-2018). We clarified the seasonal and annual fluctuation of the deer population. We found two peaks of deer abundance (2007 and 2010) over 12 years. In 2011 the estimated deer abundance decreased drastically and has remained at a low level then. The deer population increased from spring to autumn and decreased from autumn to winter in most years. The seasonal fluctuation we detected could reflect the seasonal migration pattern of deer and the population recruitment through fawn births in early summer. In our model, snowfall accumulation, which can be a lethal factor for deer, may have slightly affected their mortality during the winter. Although we could not detect a direct effect of snow on population dynamics, snowfall decrease due to global warming may decelerate the winter migration of deer; subsequently, deer staying on-site may intensively forage evergreen perennial plants during the winter season. The nuisance control affected population dynamics. Even in wildlife protection areas and national parks where hunting is regulated, nuisance control could be effective in buffering the effect of deer browsing on forest ecosystems.

ecology↗

bioRxiv2019

Discovery of the prickle patterning on the stem of rose and the mathematical model of the pattern.

Reproducible pattern is a key characteristic of organisms. Many developmental patterns are known that it is orchestrated by diffusion of the factors. Herein, we reported a novel patterning that seems to be controlled by diffusion factors. Although it looks like the prickles randomly emerge on the stem of rose, we deciphered patterns for the position of prickles with statistical data and proposed a mathematical model to explain the process via which the pattern emerged. By changing the model parameters, we reproduce another pattern on other plant species. This finding indicates that the patterns between many species are organized by similar systems. Moreover, although the pattern of organisms is often linked to its function, we consider the spatial pattern of prickles may have a function to play the role of prickles effectively. Further studies will clarify the role of prickles and reveal the entity of diffusive factors.

developmental biology↗

bioRxiv2019

Large scale genome-wide association study in a Japanese population identified 45 novel susceptibility loci for 22 diseases

INTRODUCTORY PARAGRAPHThe overwhelming majority of participants in current genetic studies are of European ancestry1-3, limiting our genetic understanding of complex disease in non-European populations. To address this, we aimed to elucidate polygenic disease biology in the East Asian population by conducting a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 383 independent signals in 331 loci for 30 diseases, among which 45 loci were novel (P < 5 x 10-8). Compared with known variants, novel variants have lower frequency in European populations but comparable frequency in East Asian populations, suggesting the advantage of this study in discovering these novel variants. Three novel signals were in linkage disequilibrium (r2 > 0.6) with missense variants which are monomorphic in European populations (1000 Genomes Project) including rs11235604(p.R220W of ATG16L2, a autophagy-related gene) associated with coronary artery disease. We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, andidentified 378 significant enrichments across nine diseases (FDR < 0.05) (e.g. NF-{kappa}B for immune-related diseases). This large-scale GWAS in a Japanese population provides insights into the etiology of common complex diseases and highlights the importance of performing GWAS in non-European populations.

genetics↗

bioRxiv2019

Corticotrophin-Releasing Hormone neurons of Barrington’s nucleus: Probabilistic, spinally-gated control of bladder pressure and micturition

Micturition, the co-ordinated process of expulsion of urine from the bladder, requires precise control of bladder and urethral sphincter via parasympathetic, sympathetic and somatic motoneurons. In adult mammals this involves a spinobulbospinal control circuit incorporating Barringtons nucleus in the pons (Barr). The largest Barr cell population is comprised of pontospinal glutamatergic neurons that express corticotrophin-releasing hormone. There is evidence that BarrCRH neurons can generate bladder contractions but it is unknown whether they act as a simple switch or a high-fidelity pre-parasympathetic motor drive and whether their activation can actually trigger voids. Combined opto- and chemo-genetic manipulations along with recordings in mice shows that BarrCRH neurons provide a probabilistic drive that generates co-ordinated voids or non-voiding contractions depending on the phase of the micturition cycle. These findings inform a new inferential model of micturition and emphasise the importance of the state of the spinal gating circuit in the generation of voiding.

neuroscience↗

bioRxiv2019

The Prevalence and Patterns of Combined Psychotropic Polypharmacy among Acute Care Hospitals in Japan

PurposeTo evaluate the prescribing patterns of psychotropic polypharmacy for inpatients of acute care hospitals in Japan.\n\nMethodsAdministrative data on 2,639,885 patients admitted to acute care hospitals in Japan between July and December of 2008 were analyzed retrospectively. We defined psychotropic medications as antipsychotics, antidepressants, benzodiazepines, and other sedatives/hypnotics and studied their prescription patterns during the hospitalization of patients with stroke, acute cardiac infarction, cancer, and diabetes mellitus.\n\nResultsAt least one psychotropic drug was prescribed in 35.9% of all cases. Two-drug combinations of antipsychotic drugs were prescribed for stroke patients in 14,615 cases (1.4%), more than 2 in 3,132 cases (0.3%), and 22.4% of cases were prescribed 2 or more psychotropic drugs in addition to antipsychotic drugs. Amongst upper gastrointestinal cancer patients, 7.7% were prescribed a combination of 2 or more drugs, including benzodiazepines. Of the upper gastrointestinal cancer patients who were prescribed benzodiazepines, 20.3% were also prescribed 2 or more psychotropic drugs. Amongst stroke and upper gastrointestinal cancer patients, 36.6% and 35.6%, respectively, were treated with combination therapy using drugs of this class and others.\n\nConclusionThere is a pattern of polypharmacy that combines benzodiazepines and other sedatives/hypnotics with antidepressants or antipsychotic drugs, and this study provides a detailed analysis of this within acute care hospitals. Our results indicate the need for additional research into the efficacy of polypharmacy for inpatients in non-psychiatric settings.

epidemiology↗

bioRxiv2018

Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population

The etiology of pancreatic cancer remains largely unknown. Here, we report the results of a meta-analysis of three genome-wide association studies (GWASs) comprising 2,039 pancreatic cancer cases and 32,592 controls, the largest sample size in the Japanese population. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P<5.0x10-8) and 4 suggestive loci (P<1.0x10-6) for pancreatic cancer. Of these risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (odds ratio (OR)=1.46, 95% CI=1.29-1.66, P=4.28x10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant predicted to be highly deleterious. Additionally, the gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified GP2 gene variants were pleiotropic for multiple traits, including type 2 diabetes, hemoglobin A1c (HbA1c) levels, and pancreatic cancer. Mendelian randomization analyses corroborated causality between HbA1c and pancreatic cancer. These findings suggest that GP2 gene variants are associated with pancreatic cancer susceptibility in the Japanese population, prompting further functional characterization of this locus.

genetics↗