Biology subjects

Ito, T.

Publications and source records attributed to Ito, T..

7 recordsLinked to original sources

bioRxiv2018

Orthogonal linear separation analysis: an approach to decompose the complex effect of a perturbagen

Drugs have multiple, not single, effects. Decomposition of drug effects into basic components helps us to understand the pharmacological properties of a drug and contributes to drug discovery. We have extended factor analysis and developed a novel profile data analysis method, orthogonal linear separation analysis (OLSA). OLSA contracted 11,911 genes to 118 factors from transcriptome data of MCF7 cells treated with 318 compounds in Connectivity Map. Ontology of the main genes constituting the factors detected significant enrichment of the ontology in 65 of 118 factors and similar results were obtained in two other data sets. One factor discriminated two Hsp90 inhibitors, geldanamycin and radicicol, while clustering analysis could not. Doxorubicin was estimated to inhibit Na+/K+ ATPase, one of the suggested mechanisms of doxorubicin-induced cardiotoxicity. Based on the factor including PI3K/AKT/mTORC1 inhibition activity, 5 compounds were predicted to be novel autophagy inducers, and other analysis including western blotting revealed that 4 of the 5 actually induced autophagy. These findings indicate the potential of OLSA to decompose the effects of a drug and identify its basic components. (<175 words)

bioinformatics↗

bioRxiv2018

In vitro characterization of multidrug-resistant influenza A(H1N1)pdm09 viruses carrying a dual amino acid substitution associated with reduced susceptibility to neuraminidase inhibitors

We detected influenza A(H1N1)pdm09 viruses carrying dual H275Y/I223R, H275Y/I223K, or H275Y/G147R substitutions in their neuraminidase protein, respectively. These viruses showed cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir. The H275Y/G147R virus retained its replication capability at least in vitro, but the H275Y/I223R and H275Y/I223K viruses did not.

microbiology↗

bioRxiv2018

Task activations produce spurious but systematic inflation of task functional connectivity estimates

Most neuroscientific studies have focused on task-evoked activations (activity amplitudes at specific brain locations), providing limited insight into the functional relationships between separate brain locations. Task-state functional connectivity (FC) - statistical association between brain activity time series during task performance moves beyond task-evoked activations by quantifying functional interactions during tasks. However, many task-state FC studies do not remove the first-order effect of taskevoked activations prior to estimating task-state FC. It has been argued that this results in the ambiguous inference \"likely active or interacting during the task\", rather than the intended inference \"likely interacting during the task\". Utilizing a neural mass computational model, we verified that task-evoked activations substantially and inappropriately inflate task-state FC estimates, especially in functional MRI (fMRI) data. Various methods attempting to address this problem have been developed, yet the efficacies of these approaches have not been systematically assessed. We found that most standard approaches for fitting and removing mean task-evoked activations were unable to correct these inflated correlations. In contrast, methods that flexibly fit mean task-evoked response shapes effectively corrected the inflated correlations without reducing effects of interest. Results with empirical fMRI data confirmed the models predictions, revealing activation-induced task-state FC inflation for both Pearson correlation and psychophysiological interaction (PPI) approaches. These results demonstrate that removal of mean task-evoked activations using an approach that flexibly models task-evoked response shape is an important preprocessing step for valid estimation of task-state FC.\n\nHighlightsO_LIComputational model shows task inflation of functional connectivity estimates\nC_LIO_LIHemodynamic responses cause task activations to further inflate estimates\nC_LIO_LIStandard approaches to remove task activations leave many false positives\nC_LIO_LIMethods that flexibly fit hemodynamic response shape effectively correct inflation\nC_LIO_LICorrection of functional connectivity inflation verified with empirical fMRI data\nC_LI

neuroscience↗

bioRxiv2018

Network dimensionality underlies flexible representation of cognitive information

Many studies have identified the role of localized and distributed cognitive functionality by mapping either local task-related activity or distributed functional connectivity (FC). However, few studies have directly explored the relationship between a brain regions localized task activity and its distributed task FC. Here we systematically evaluated the differential contributions of task-related activity and FC changes to identify a relationship between localized and distributed processes across the cortical hierarchy. We found that across multiple tasks, the magnitude of regional task-evoked activity was high in unimodal areas, but low in transmodal areas. In contrast, we found that task-state FC was significantly reduced in unimodal areas relative to transmodal areas. This revealed a strong negative relationship between localized task activity and distributed FC across cortical regions that was associated with the previously reported principal gradient of macroscale organization. Moreover, this dissociation corresponded to hierarchical cortical differences in the intrinsic timescale estimated from resting-state fMRI and region myelin content estimated from structural MRI. Together, our results contribute to a growing literature illustrating the differential contributions of a hierarchical cortical gradient representing localized and distributed cognitive processes. HighlightsO_LITask activations and functional connectivity changes are negatively correlated across cortex C_LIO_LITask activation and connectivity dissociations reflect differences in localized and distributed processes in cortex C_LIO_LIDifferences in localized and distributed processes are associated with differences in intrinsic timescale organization C_LIO_LIDifferences in localized and distributed processes are associated with differences in cortical myelin content C_LIO_LICortical heterogeneity in localized and distributed processes revealed by activity flow mapping prediction error C_LI

neuroscience↗

bioRxiv2017

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Interestingly, although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed. In addition, a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and independent manner.

molecular biology↗

bioRxiv2017

Global connectivity of the frontoparietal cognitive control network is related to depression symptoms in undiagnosed individuals

We all vary in our mental health, even among healthy (undiagnosed) individuals. Understanding this variability may reveal factors driving the onset of mental illness, as well as factors driving sub-clinical mental health problems that can still influence quality of life. To better understand the large-scale brain network mechanisms underlying this variability in mental health we examined the relationship between mental health symptoms and resting-state functional connectivity patterns in cognitive control systems. The frontoparietal cognitive control network (FPN) consists of flexible hubs that can regulate distributed systems depending on current goals, and dysfunction in the FPN has been identified in a variety of psychiatric disorders. Alterations in FPN connectivity may influence mental health by disrupting the ability to regulate symptoms in a goal-directed manner. This suggests that the FPN may play an important role in the promotion and maintenance of mental health generally. Here we test the hypothesis that disruptions in FPN connectivity are related to mental health (depression) symptoms even among healthy individuals. This hypothesis is consistent with a general role of FPN in the regulation of mental health symptoms. We found that depression symptoms were negatively correlated with between-network global connectivity (BGC) of the FPN as well as the default mode network (DMN). This suggests that decreased connectivity between the FPN (and, separately, DMN) and the rest of the brain is related to increased depression symptoms among undiagnosed individuals. These findings complement previous clinical studies to support the hypothesis that global FPN connectivity contributes to the regulation of mental health symptoms across both mentally healthy and unhealthy individuals.

neuroscience↗

bioRxiv2017

Cognitive task information is transferred between brain regions via resting-state network topology

Resting-state network connectivity has been associated with a variety of cognitive abilities, yet it remains unclear how these connectivity properties might contribute to the neurocognitive computations underlying these abilities. We developed a new approach - information transfer mapping - to test the hypothesis that resting-state functional network topology describes the computational mappings between brain regions that carry cognitive task information. Here we report that the transfer of diverse, task-rule information in distributed brain regions can be predicted based on estimated activity flow through resting-state network connections. Further, we find that these task-rule information transfers are coordinated by global hub regions within cognitive control networks. Activity flow over resting-state connections thus provides a large-scale network mechanism for cognitive task information transfer and global information coordination in the human brain, demonstrating the cognitive relevance of resting-state network topology.

neuroscience↗