Biology subjects

Miyakoshi, M.

Publications and source records attributed to Miyakoshi, M..

10 recordsLinked to original sources

bioRxiv2026

Loss of NKX2-1 predisposes thyroid to neoplasm development through regulation of oxidative stress

Many factors including ionizing radiation and iodine deficiency are known to increase thyroid carcinogenesis risk. Our dataset analysis of The Cancer Genome Atlas (TCGA) showed that lower mRNA expression of NK2 homeobox 1 (NKX2-1) transcription factor, a master regulator of genesis, homeostasis, and function of thyroid, is linked to poor prognosis of papillary thyroid cancer patients. Here we provide the findings that thyroid-specific Nkx2-1 conditional knockout (Nkx2-1{Delta}T) mice develop thyroid adenoma and carcinoma in higher frequency with combined exposure to radiation and iodine deficiency than control Nkx2-1fl/fl mice. Iodine deficiency caused oxidative stress, which subsequently resulted in DNA damage, leading to transformation of thyroid follicular cells. RNA-seq gene set enrichment analysis indicated higher production of reactive oxygen species (ROS) in the thyroids of Nkx2-1{Delta}T as compared to Nkx2-1fl/fl mice with combined exposure to radiation and iodine deficiency. This was accompanied by a feedback induction of SOD3 (superoxide dismutase 3) and GPX2 (glutathione peroxidase 2). These antioxidants were naturally expressed at higher levels in the thyroids of Nkx2-1{Delta}T than Nkx2-1fl/fl mice without iodine deficiency or radiation. Nkx2-1{Delta}T thyroids exhibited abnormal follicle architecture and up-regulation of Acox2 (encoding acyl-CoA oxidase 2), which produces hydrogen peroxide. These results suggest that loss of NKX2-1 may contribute to excess ROS production, which elevates basal oxidative stress resulting in the promotion of ROS-induced carcinogenesis. We propose a role for NKX2-1 as a regulator of ROS production homeostasis in the thyroid. Its disturbance would dispose thyroid follicular cells more vulnerable to the ROS-producing carcinogens.

cancer biology↗

bioRxiv2025

Prediction of treatment response in infantile epileptic spasms syndrome using EEG phase-amplitude coupling

ObjectiveTreatment selection for infantile epileptic spasms syndrome (IESS) is complex and multifaceted, and currently no EEG biomarkers can guide this decision by predicting treatment response. We tested the predictive value of phase-amplitude coupling (PAC), as IESS patients are known to have elevated PAC. MethodsWe analyzed retrospective EEG recordings from 40 IESS patients, before and after treatment, and 20 healthy controls. Patients were classified as responders (n=25) or non-responders (n=15) based on short-term treatment outcomes. We measured PAC in each EEG using modulation index (MI) and mean vector length (MVL) and analyzed the relationship between pre- and post-treatment values and the ability of pre-treatment values to predict response. ResultsMI and MVL values decreased with treatment in almost all subjects. However, non-responders had significantly higher pre-treatment MI than responders (P<0.05), suggesting utility for predicting treatment response. Logistic regression modeling suggested that a 0.5 unit decrease in log(MI), which is approximately one IQR of the pre-treatment log(MI) values, results in a 6-fold increase in odds of positive treatment response. SignificanceMI reflects short-term treatment response and is a candidate predictive EEG biomarker for IESS. MI may offer individualized insights for treatment selection and management strategies for IESS. Key Points BoxO_LIInfantile epileptic spasms syndrome (IESS) is associated with high phase-amplitude coupling (PAC) that decreases with treatment C_LIO_LILow pre-treatment values of EEG PAC are predictive of positive short-term treatment response for IESS C_LIO_LIThe results were strongest when PAC was measured using the modulation index, as this method is known to be robust to noise C_LI

neuroscience↗

bioRxiv2025

3'UTR-derived small RNA couples acid resistance to metabolic reprogramming of Salmonella within macrophages

Acid resistance is crucial for enterobacteria to withstand host acidic environments during infection, including the gastrointestinal tract and macrophage phagosomes. A key acid resistance mechanism of the facultative intracellular pathogen Salmonella is expression of the arginine decarboxylase AdiA. While AdiA confers acid resistance via an H+-consuming reaction, we discover that the 3'-untranslated region (UTR) of adiA mRNA is processed by RNase E into a regulatory small RNA, AdiZ. Through RNA-RNA interactome profiling and transcriptomic analysis, followed by in vitro structural probing and in vivo validations, we demonstrate that AdiZ directly base-pairs with and negatively regulates ptsG, pykF, and dmsA mRNAs involved in glucose uptake, glycolysis, and anaerobic respiration, respectively. Intriguingly, AdiZ is induced and facilitates Salmonella survival within macrophages, where acidic and hypoxic stresses prevail. Thus, simultaneous expression of AdiA and AdiZ from a single mRNA ties arginine-dependent acid resistance to metabolic reprogramming of Salmonella in the host intracellular niches. HIGHLIGHTSO_LISalmonella adiA transcript expresses both acid resistance enzyme and sRNA AdiZ C_LIO_LIAdiZ derived from the adiA 3'UTR is induced under an acidic and anaerobic condition C_LIO_LIAdiZ base-pairs with mRNAs to modulate glucose metabolism and anaerobic respiration C_LIO_LIAdiZ promotes Salmonella survival in acidic and hypoxic macrophage vacuoles C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/658255v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@10aec22org.highwire.dtl.DTLVardef@14b5f2org.highwire.dtl.DTLVardef@1b53c8dorg.highwire.dtl.DTLVardef@19a8540_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Event-Related Spatio-Spectral Perturbation (ERSSP): A Scalp-Wide EEG Analysis Framework for Capturing Extralemniscal Thalamocortical Activity, Validated Using a Fragile X Syndrome Model

The extralemniscal thalamocortical pathway regulates large-scale modulation of cortical states but remains inaccessible to traditional EEG analysis due to its diffuse, variable, and asynchronous nature. To address this, we introduce the Event-Related Spatio-Spectral Perturbation (ERSSP) framework, which quantifies spatially distributed time-frequency responses. ERSSP summarizes the number of channels exhibiting significant spectral perturbations, capturing diffuse cortical dynamics from sensor-space EEG. We validated this approach using a passive auditory habituation task in individuals with Fragile X Syndrome (FXS), a condition marked by disrupted thalamocortical modulation. ERSSP revealed enhanced spatial extent of power increases (but not phase-locking) in FXS compared to controls. Results also showed expected gender differences, further supporting biological sensitivity of ERSSP. ERSSP provides a conceptually simple and computationally efficient method for quantifying broadly distributed sensory modulation and may enable new insights into thalamocortical function in both basic and clinical neuroscience.

neuroscience↗

bioRxiv2024

m6A-mediated epi-transcriptomic dysregulation underlies synaptic dysfunction in fragile X syndrome

Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and loss of the FMRP protein. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP is known to bind to and regulate the stability of m6A-containing transcripts. However, how loss of FMRP impacts on transcriptome-wide m6A modifications in FXS patients remains unknown. To answer this question, we generated cortical neurons differentiated from induced pluripotent stem cells (iPSC) derived from healthy subjects and FXS patients. In electrophysiology recordings, we validated that synaptic and neuronal network defects in iPSC-derived FXS neurons corresponded to the clinical EEG data of the patients from which the corresponding iPSC line was derived. In analysis of transcriptome-wide methylation, we show that FMRP deficiency led to increased translation of m6A writers, resulting in hypermethylation that primarily affecting synapse-associated transcripts and increased mRNA decay. Conversely, in the presence of an m6A writer inhibitor, synaptic defects in FXS neurons were rescued. Taken together, our findings uncover that an FMRP-dependent epi-transcriptomic mechanism contributes to FXS pathogenesis by disrupting m6A modifications in FXS, suggesting a promising avenue for m6A- targeted therapies.

neuroscience↗

bioRxiv2024

Frontal Cortex Hyperactivation and Gamma Desynchrony in Fragile X Syndrome: Correlates of Auditory Hypersensitivity

Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in top-down modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.

neuroscience↗

bioRxiv2023

Click-train evoked steady-state harmonic response as a novel pharmacodynamic biomarker of cortical oscillatory synchrony

Sensory networks naturally entrain to rhythmic stimuli like a click train delivered at a particular frequency. Such synchronization is integral to information processing, can be measured by electroencephalography (EEG) and is an accessible index of neural network function. Click trains evoke neural entrainment not only at the driving frequency (F), referred to as the auditory steady state response (ASSR), but also at its higher multiples called the steady state harmonic response (SSHR). Since harmonics play an important and non-redundant role in acoustic information processing, we hypothesized that SSHR may differ from ASSR in presentation and pharmacological sensitivity. In female SD rats, a 2 s-long train stimulus was used to evoke ASSR at 20 Hz and its SSHR at 40, 60 and 80 Hz. Narrow band evoked responses were evident at all frequencies; signal power was strongest at 20 Hz while phase synchrony was strongest at 80 Hz. SSHR at 40 Hz took the longest time ([~]180 ms from stimulus onset) to establish synchrony. The NMDA antagonist MK801 (0.025-0.1 mg/kg) did not consistently affect 20 Hz ASSR phase synchrony but robustly and dose-dependently attenuated synchrony of all SSHR. Evoked power was attenuated by MK801 at 20 Hz ASSR and 40 Hz SSHR only. Thus, presentation as well as pharmacological sensitivity distinguished SSHR from ASSR, making them non-redundant markers of cortical network function. SSHR is a novel and promising translational biomarker of cortical oscillatory dynamics that may have important applications in CNS drug development and personalized medicine.

neuroscience↗

bioRxiv2022

Glutamine synthetase mRNA releases sRNA from its 3'UTR to regulate carbon/nitrogen metabolic balance

Glutamine synthetase is the key enzyme of nitrogen assimilation, which is encoded in the first cistron of glnALG operon and is induced under nitrogen limiting conditions through transcriptional activation by NtrBC in Salmonella and E. coli. 2-oxoglutarate serves as the carbon skeleton of glutamate and glutamine, but how 2-oxoglutarate fluctuation is controlled in response to nitrogen availability remained unknown. We show that the glnA mRNA produces an Hfq-dependent GlnZ sRNA from its 3 sUTR through RNase E-mediated cleavage. Through a base-pairing mechanism, GlnZ primarily regulates sucA, encoding the E1o component of 2-oxoglutarate dehydrogenase. In the cells grown on glutamine as the nitrogen source, the endogenous GlnZ represses the expression of SucA to redirect the carbon flow from the TCA cycle to the nitrogen assimilation pathway. This study also clarifies that the release of GlnZ sRNA from the glnA mRNA by RNase E is essential for the post-transcriptional regulation of sucA, and thus the mRNA coordinates the two independent functions to balance the supply and demand of the fundamental metabolites.

microbiology↗

bioRxiv2020

Neural network dynamics underlying gamma synchronization deficits in schizophrenia

Gamma band (40-Hz) activity is associated with many sensory and cognitive functions, and is critical for cortico-cortical transmission and the integration of information across neural networks. The capacity to support gamma band activity can be indexed by the auditory steady-state response (ASSR); schizophrenia patients have selectively reduced synchrony to 40-Hz stimulation. While 40-Hz ASSR is a translatable electroencephalographic biomarker with emerging utility for therapeutic development for neuropsychiatric disorders, the spatiotemporal dynamics underlying the ASSR have not yet been characterized. In this study, a novel Granger causality analysis was applied to assess the propagation of gamma oscillations in response to 40-Hz steady-state stimulation across cortical sources in schizophrenia patients (n=426) and healthy comparison subjects (n=293). Results revealed distinct, hierarchically sequenced temporal and spatial response dynamics underlying gamma synchronization deficits in patients. During the response onset interval, patients exhibited abnormal connectivity of superior temporal and frontal gyri, followed by decreased information flow from superior temporal to middle cingulate gyrus. In the later (300-500 ms) interval of the ASSR response, patients showed significantly increased connectivity from superior temporal to middle frontal gyrus followed by broad failures to engage multiple prefrontal brain regions. In conclusion, these findings reveal the rapid disorganization of neural circuit functioning in response to simple gamma-frequency stimulation in schizophrenia patients. Deficits in the generation and maintenance of gamma-band oscillations in schizophrenia reflect a fundamental connectivity abnormality across a distributed network of temporo-frontal networks.

physiology↗

bioRxiv2020

Unique contributions of sensory discrimination and gamma synchronization deficits to cognitive, clinical, and psychosocial functional impairments in schizophrenia

BackgroundSchizophrenia patients show widespread deficits in neurocognitive, clinical and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are robust biomarkers for domains of neuropsychiatric disorders that are impaired in schizophrenia patients and are separately associated with cognitive dysfunction, negative symptom severity and psychosocial disability. Although these measures of early auditory information processing are conceptually linked, it is unclear, whether these measures are redundant or account for unique variance in important outcome measures. In this study, we aimed to determine whether MMN and gamma-band ASSR are associated with cognitive, clinical, and functional variables and, if so, whether they account for shared vs. non-shared variance in those important domains. MethodsMultiple regression analyses with MMN, gamma-band ASSR and clinical measures were performed in large cohorts of schizophrenia outpatients (N=428) and healthy comparison subjects (N=283). ResultsReduced MMN (d = 0.67), gamma-band ASSR (d = -0.40), and lower cognitive function were confirmed in schizophrenia patients compared to healthy comparison subjects. Regression analyses revealed that both MMN and gamma-band ASSR have significant unique associations with tasks measuring of working memory, and daily functioning in schizophrenia patients. ConclusionThese findings suggest that MMN and ASSR measures are non-redundant and complementary measures. Studies are needed to clarify the neural substrates of MMN and gamma-band ASSR in order to improve our understanding of pathophysiology of schizophrenia and accelerate their use in the development of novel therapeutic interventions.

physiology↗