Biology subjects

Akashi, T.

Publications and source records attributed to Akashi, T..

5 recordsLinked to original sources

bioRxiv2024

Dysregulated expanded endocannabinoid system as therapeutic targets of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of upper and lower motor neurons. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance. Herein, to elucidate the systemic metabolic changes related to ALS progression, we performed metabolomics analysis on the serum of ALS patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NAT) were correlated with the longitudinal change in the revised ALS functional rating scale (ALSFRS-R) rating. In vitro experiments with ALS cell models and in vivo studies with SOD1G93A transgenic mice revealed that PF-04457845, a fatty amide acid hydrolase (FAAH) inhibitor, up-regulated the expanded ECS, particularly the levels of NATs and N-acyl ethanolamine and ameliorates motor neuron degeneration through the regulation of microglial polarization, synapse plasticity, and neuronal development. Our study indicates that dysregulation of the expanded ECS is associated with ALS progression and a target for novel disease-modifying therapies.

neuroscience↗

bioRxiv2024

Dysregulated synaptic gene expression in oligodendrocytes of spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. To elucidate the cell type-specific temporal gene expression in SBMA, we performed single-nucleus RNA sequencing on the spinal cords of AR-97Q mice. Among all cell types, oligodendrocytes (OLs) had the highest number of differentially expressed genes before disease onset. Analysis of OL clusters suggested that pathways associated with cation channels and synaptic function were activated before disease onset, with increased output from OLs to neurons in AR-97Q mice compared to wild-type mice. These changes in the early stages were abrogated in the advanced stages. An OL cell model of SBMA showed phenotypes similar to those of AR-97Q mice at early stages, such as increased transcriptional changes in synapse organization. Our results indicate that the dysregulation of cell-to-cell communication has a major impact on the early pathology of SBMA and is a potential therapeutic target for SBMA.

neuroscience↗

bioRxiv2023

Survivability and Life Support in Sealed Mini-Ecosystems with Simulated Planetary Soils

Establishing a sustainable life-support system for space exploration is challenging due to the vast distances, costs, and differing environments from Earth. Using insights from the Biosphere 2 experiment, we introduced the "Ecosphere" and "Biosealed" systems in custom containers to replicate Earths ecosystems, suggesting feasible space migration through transplanting Earth-like biomes. Over four years, we gained deeper insights into these enclosed ecosystems. Moisture deficiency was a major obstacle to plant growth, which we addressed by incorporating a groundwater layer in the containers. We underscored the critical role of microorganisms in building and sustaining these ecosystems. However, temperature spikes from sunlight threatened stability. Our experiments confirmed fruit flies survival on plant-produced oxygen and photosynthetic bacteria. Interactions between plants, microbes, and simulated space soils were examined. Detailed analysis unveiled diverse microbes shaping both confined and simulated space environments. Major findings include the symbiotic relationship of plants with cyanobacteria, the potential of LED lighting in sun-limited missions, and challenges with ethylene gas and moisture. Microbial integration in rough soils holds promise for seed germination, but understanding their role in space soils is crucial. Our research offers a comprehensive foundation for future space life-support systems and underlines potential concerns about microbes affecting human health.

ecology↗

bioRxiv2023

Structural insights into the mechanism of the human SGLT2-MAP17 glucose transporter

Selective sodium-glucose cotransporter 2 (SGLT2) plays an important role in glucose reabsorption. SGLT2 inhibitors suppress glucose reabsorption from the kidneys, thus reducing blood glucose levels in type 2 diabetes patients. We and other groups have developed several SGLT2 inhibitors starting from a natural product, phlorizin, but their action mechanisms remain unknown. Here, we elucidated the physiological hSGLT2-MAP17 complex structures bound to five SGLT2 inhibitors using single-particle cryo-electron microscopy. Canagliflozin, dapagliflozin, TA-1887, and sotagliflozin were bound in the outward-facing structure, whereas phlorizin was bound in the inward-open structure. The phlorizin-hSGLT2 interaction biochemically exhibited biphasic binding. Phlorizin weakly binds, via the phloretin motif, from its intracellular side near the Na+-binding site, while strongly interacts from its extracellular side. Unexpectedly, bound Na+ stabilizes the outward-open conformation, while its release allows the transporter to adopt inward-open state. Our results first visualized the Na+-binding and inward-open conformation of hSGLT2-MAP17, clarifying the unprecedented Na+-dependent sugar transport mechanism with MAP17 acting as a scaffold, and may pave the way for development of next-generation SGLT inhibitors.

molecular biology↗

bioRxiv2022

Preservation of Conditioned Behavior Based on UV Light Sensitivity in Dissected Tail Halves of Planarians- a Proof by DNN

Planarians are aquatic worms with powerful regenerative and memory retention abilities. This paper examines whether a dissected tail half of a Planarian (Dugesia Dorotocephala) can retain and exhibit a previously-conditioned response, possibly before the regeneration of the head and the ganglia. We conditioned intact Planarians in a Pavlovian procedure with an electric shock (ES) as the unconditioned stimulus and weak ultraviolet (UV) light as the conditioned stimulus. Then, we dissected their bodies into halves, keeping the dissected tail halves. Starting from the 2nd day after dissection, we presented the same UV light 3 times daily while video-recording the responses. The recorded responses were then classified by a DNN: a VGG16 model was pre-trained by ImageNet for extracting features from images and additionally trained with 211 responses to ES and 118 to UV light before conditioning/dissection to categorize planarians reactions into "UV-induced" or "ES-induced" reactions. The cross-validated accuracy in categorization was 83.6%. We then let the DNN analyze 99 recorded responses to UV from 20 individual conditioned tail halves. 96.8 % of their reactions were classified as "ES-induced" (against 22.0% wrongly classified as "ES-induced" for unconditioned samples under UV), indicating they have shown the "Conditioned Response" (p<3.06E-30). This provides evidence that planarians can conserve and reveal a learned response even without the head/ganglia, as it takes approximately 7 days for the head/ganglia to regenerate versus the given 2-3 days. Although similar findings have been reported repeatedly in the literature, this is the first positive evidence with automated procedures and DNN classification. The result implies the presence of a decentralized nervous structure outside of its head/ganglia that allows a tail half to retain memory and execute motion accordingly, despite their cephalization.

animal behavior and cognition↗