Biology subjects

Tsumura, K.

Publications and source records attributed to Tsumura, K..

5 recordsLinked to original sources

bioRxiv2023

A novel in silico scaffold-hopping method for drug repositioning in rare and intractable diseases

In the field of rare and intractable diseases, new drug development is difficult and drug repositioning (DR) is a key method to improve this situation. In this study, we present a new method for finding DR candidates utilizing virtual screening, which integrates amino acid interaction mapping into scaffold-hopping (AI-AAM). At first, we used a spleen associated tyrosine kinase (SYK) inhibitor as a reference to evaluate the technique, and succeeded in scaffold-hopping maintaining the pharmacological activity. Then we applied this method to five drugs and obtained 144 compounds with diverse structures. Among these, 31 compounds were known to target the same proteins as their reference compounds and 113 compounds were known to target different proteins. We found that AI-AAM dominantly selected functionally similar compounds; thus, these selected compounds may represent improved alternatives to their reference compounds. Moreover, the latter compounds were presumed to bind to the targets of their references as well. This new "compound-target" information provided DR candidates that could be utilized for future drug development.

pharmacology and toxicology↗

bioRxiv2022

An excitatory-inhibitory fronto-cerebellar loop resolves the Stroop effect

The Stroop effect is a well-known behavioral phenomenon in humans that refers to robust interference between language and color information. Although this effect has long been studied, it remains unclear when the interference occurs and how it is resolved in the brain. By manipulating the verbality of stimulus perception and response generation, here we show that the Stroop effect occurs during perception of color-word stimuli and is resolved by a cross-hemispheric, excitatory-inhibitory functional loop involving the lateral prefrontal cortex and cerebellum. Humans performed a Stroop task and a control task in which the stimulus did not contain verbal information, and made a response either vocally or manually. The resolution of Stroop interference involved the lateral prefrontal cortex in the left hemisphere and the cerebellum in the right hemisphere, independently of whether the response was made vocally or manually. In contrast, such cross-hemispheric lateralization was absent during the non-verbal control task. Moreover, the prefrontal cortex amplified cerebellar activity, whereas the cerebellum suppressed prefrontal activity, and these effects were enhanced during interference resolution. These results suggest that this fronto-cerebellar loop involving language and cognitive systems regulates goal-relevant information to resolve the interference occurring during simultaneous perception of a word and color.

neuroscience↗

bioRxiv2021

Perceptual uncertainty alternates top-down and bottom-up fronto-temporal network signaling during response inhibition

Response inhibition is a primary executive control function that allows the withholding of inappropriate responses, and requires appropriate perception of the external environment to achieve a behavioral goal. It remains unclear, however, how response inhibition is achieved when goal-relevant information involves perceptual uncertainty. Twenty-six human participants of both sexes performed a go/no-go task where visually presented random-dot motion stimuli involved perceptual uncertainties. The right inferior frontal cortex (rIFC) was involved in response inhibition, and the middle temporal (MT) region showed greater activity when dot motions involved less uncertainty. A neocortical temporal region in the superior temporal sulcus (STS) specifically showed greater activity during response inhibition in more perceptually certain trials. In this STS region, activity was greater when response inhibition was successful than when it failed. Directional effective connectivity analysis revealed that in more coherent trials, the MT and STS regions showed enhanced connectivity to the rIFC, whereas in less coherent trials, the signal direction was reversed. These results suggest that a reversible fronto-temporal functional network guides response inhibition under perceptual uncertainty, and in this network, perceptual information in the MT is converted to control information in the rIFC via STS, enabling achievement of response inhibition. Significance statementResponse inhibition refers to withholding inappropriate behavior and is an important for achieving goals. Often, however, decision must be made based on limited environmental evidence. We showed that successful response inhibition is guided by a neocortical temporal region that plays a hub role in converting perceived information coded in a posterior temporal region to control information coded in the prefrontal cortex. Interestingly, when a perceived stimulus becomes more uncertain, the prefrontal cortex supplements stimulus encoding in the temporal regions. Our results highlight fronto-temporal mechanisms of response inhibition in which conversion of stimulus-control information is regulated based on the uncertainty of environmental evidence.

neuroscience↗

bioRxiv2021

Executive control by fronto-parietal activity explains counterintuitive decision behavior in complex value-based decision-making

In real life, humans make decisions by taking into account multiple independent factors, such as delay and probability. Cognitive psychology suggests that cognitive control mechanisms play a key role when facing such complex task conditions. However, in value-based decision-making, it still remains unclear to what extent cognitive control mechanisms become essential when the task condition is complex. In this study, we investigated decision-making behaviors and underlying neural mechanisms using a multifactor gambling task where participants simultaneously considered probability and delay. Decision-making behavior in the multifactor task was modulated by both probability and delay. The behavioral effect of probability was stronger than delay, consistent with previous studies. Furthermore, in a subset of conditions that recruited fronto-parietal activations, reaction times were paradoxically elongated despite lower probabilistic uncertainty. Notably, such a reaction time elongation did not occur in control tasks involving single factors. Meta-analysis of brain activations suggested an association between the paradoxical increase of reaction time and strategy switching. Together, these results suggest a novel aspect of complex value-based decision-makings that is strongly influenced by fronto-parietal cognitive control. Highlights* A value-based decision task with concurrent delay and probabilistic uncertainty * Stronger behavioral effect of probability than delay * Paradoxically long reaction time despite low probabilistic uncertainty * The task activated fronto-parietal cognitive control network * Reaction time elongation coincided with activation similar to strategy switching

neuroscience↗

bioRxiv2020

Flexible decision under ambiguous cues reverses neural signaling from occipitotemporal to prefrontal cortex

Adaptation to changing environments involves the appropriate extraction of environmental information to achieve a behavioral goal. It remains unclear how behavioral flexibility is guided under situations where the relevant behavior is ambiguous. Using functional brain mapping of machine-learning decoders and directional functional connectivity, we show that brain-wide reversible neural signaling underpins task encoding and behavioral flexibility in ambiguously changing environments. When relevant behavior is cued ambiguously during behavioral shifting, neural coding is attenuated in distributed cortical regions, but top-down signals from the prefrontal cortex complement the coding. When behavioral shifting is cued more explicitly, modality-specialized occipitotemporal regions implement distinct neural coding about relevant behavior, and bottom-up signals from the occipitotemporal region to the prefrontal cortex supplement the behavioral shift. These results suggest that our adaptation to an ever-changing world is orchestrated by the alternation of top-down and bottom-up signaling in the fronto-occipitotemporal circuit depending on the availability of environmental information.

neuroscience↗