Biology subjects

Kawai, A.

Publications and source records attributed to Kawai, A..

4 recordsLinked to original sources

bioRxiv2025

Genome-edited retinal organoids restore host bipolar connectivity in the primate macula

Retinal organoids (ROs) represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but whether host cone bipolar cells (BCs) in the primate macula can rewire with transplanted photoreceptors remains unresolved. Here, we transplanted genome-edited human retinal organoids lacking ON-BCs (Islet-1-/- ROs) into a non-human primate macular degeneration model. Remarkably, host rod and cone BCs extended dendrites toward grafted photoreceptors, forming functional synapses confirmed by immunohistochemistry, ultrastructural imaging, and focal macular electroretinography. Both ON- and OFF-pathway connectivity was rebuilt, providing the first demonstration of host-graft synaptic integration in the primate macula. These results establish that primate cone circuits retain a surprising capacity for rewiring and highlight genome-edited ROs as a powerful platform for vision restoration. Our findings represent a critical translational step toward stem cell-based therapies capable of repairing central vision in patients with advanced macular degeneration.

neuroscience↗

bioRxiv2025

Trends Assessment of the Genetic Mutation Induced Protein-Protein Interaction Variation via Protein Large Language Driven Method

Protein-protein interaction (PPI) variations are widely observed in many principal biological processes related to various diseases, while genetic mutation is one of the most common factors resulting in those variations. Unraveling these underlying biomolecular interactions is a key challenge that hinders a profound understanding of disease mechanisms. Although current models can accurately predict quantitative binding affinity, their application in pathogenic research is limited by difficulties in defining trend types, particularly extreme "disrupting" cases, along with poor generalizability beyond single-point mutations (SNP) and insufficient biological interpretability. Here, we present TAPPI, an interpretable large language model-driven deep learning framework, to perform Trends Assessment of Protein-Protein Interaction. It categorizes PPI variations trends into four types: disrupting, decreasing, no effect, and increasing, enabling fine-grained functional assessments and bridging genetic mutation and disease mechanisms. The framework generalizes effectively across both single-point and multi-point mutations and captures complex trend outcomes relevant to diverse disease landscapes. In benchmark evaluations, TAPPI achieved the state-of-the-art prediction performance and demonstrated biological relevance through interpretable results. In external datasets from Autism Spectrum Disorder, Lennox-Gastaut syndrome, and Epileptic Encephalopathies, given the premise that TAPPIs predicted results align with pathogenic patterns, these results reveal how genetic mutations indirectly perturb disease-associated pathways and supporting our perspective of "crucial disrupting" and "bridging mutations-disease". In summary, accurate, interpretable, and pathogenically relevant prediction of PPI variations trend predicted by TAPPI provides a novel approach for mechanistic discovery.

bioinformatics↗

bioRxiv2023

High-level ceftazidime-avibactam resistance in Escherichia coli conferred by the novel plasmid-mediated beta-lactamase CMY-185 variant

ObjectivesTo characterize a blaCMY variant associated with ceftazidime-avibactam (CZA) resistance from a serially collected Escherichia coli isolate. MethodsA patient with an intra-abdominal infection due to recurrent E. coli was treated with CZA. On day 48 of CZA therapy, E. coli with a CZA MIC of >256 mg/L was identified from abdominal drainage. Illumina WGS was performed on all isolates to identify potential resistance mechanisms. Site-directed mutants of CMY {beta}-lactamase were constructed to identify amino acid residues responsible for CZA resistance. ResultsWGS revealed that all three isolates were E. coli ST410. The CZA-resistant strain uniquely acquired a novel CMY {beta}-lactamase gene, herein called blaCMY-185, harbored on an IncI{gamma}-type conjugative plasmid. The CMY-185 enzyme possessed four amino acid substitutions relative to CMY-2 including A114E, Q120K, V211S, and N346Y and conferred high-level CZA resistance with an MIC of 32 mg/L. Single CMY-2 mutants did not confer reduced CZA susceptibility. However, double and triple mutants containing N346Y previously associated with CZA resistance in other AmpC enzymes, conferred CZA MICs ranging between 4 and 32 mg/L as well as reduced susceptibility to the newly developed cephalosporin, cefiderocol. Molecular modelling suggested that the N346Y substitution confers the reduction of avibactam inhibition due to the steric hindrance between the side chain of Y346 and the sulfate group of avibactam. ConclusionWe identified CZA resistance in E. coli associated with a novel CMY variant. Unlike other AmpC enzymes, CMY-185 appears to require an additional substitution on top of N346Y to confer CZA resistance.

microbiology↗

bioRxiv2021

Astrocyte GluN2C NMDA receptors control basal synaptic strengths of hippocampal CA1 pyramidal neurons in the stratum radiatum

Experience-dependent plasticity is a key feature of brain synapses for which neuronal N-Methyl-D-Aspartate receptors (NMDARs) play a major role, from developmental circuit refinement to learning and memory. Astrocytes also express NMDARs although their exact function has remained controversial. Here we identify a circuit function for GluN2C NMDAR, a subtype highly expressed in astrocytes, in layer-specific tuning of synaptic strengths in mouse hippocampal CA1 pyramidal neurons. Interfering with astrocyte NMDAR or GluN2C NMDAR activity reduces the range of presynaptic strength distribution specifically in the stratum radiatum inputs without an appreciable change in the mean presynaptic strength. Mathematical modeling shows that narrowing of the width of presynaptic release probability distribution compromises the expression of long-term synaptic plasticity. Our findings suggest a novel feedback signaling system that uses astrocyte GluN2C NMDARs to adjust basal synaptic weight distribution of Schaffer collateral inputs, which in turn impacts computations performed by the CA1 pyramidal neuron.

neuroscience↗