Biology subjects

Ito, N.

Publications and source records attributed to Ito, N..

22 records · Page 2Linked to original sources

bioRxiv2020

An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren's Disease

Dupuytrens Disease (DD) is a common fibroproliferative disease of the palmar fascia. We previously identified a strong association with a non-synonymous variant (rs1042704, pD273N) in MMP14 (encoding MT1-MMP). We investigated the functional consequences of this variant, and demonstrated that the variant MT1-MMP (MT1-N273) exhibits only 17% of cell surface collagenolytic activity compared to the ancestral enzyme (MT1-D273). Cells expressing both MT1-D273 and MT1-N273 in a 1:1 ratio, mimicking the heterozygous state, possess 38% of the collagenolytic activity compared to the cells expressing MT1-D273, suggesting that MT1-N273 acts in a dominant negative manner. Consistent with this hypothesis, patient-derived DD myofibroblasts expressing MT1-N273 demonstrated around 30% of full collagenolytic activity regardless of the heterozygous or homozygous state. 3D-molecular envelope modelling using small angle X-ray scattering demonstrated altered positioning of the catalytic domain within dimeric molecules. Taken together, our data suggest that rs1042704 directly contributes to the fibrotic phenotype of DD.

biochemistry↗

bioRxiv2019

Multi-domain cognitive assessment of male mice reveals whole body exposure to space radiation is not detrimental to high-level cognition and actually improves pattern separation.

Astronauts on interplanetary space missions - such as to Mars - will be exposed to space radiation, a spectrum of highly-charged, fast-moving particles that includes 56Fe and 28Si. Earth-based preclinical studies with mature, \"astronaut-aged\" rodents show space radiation decreases performance in low- and some high-level cognitive tasks. Given the prevalence of touchscreens in astronaut training and in-mission assessment, and the ability of rodent touchscreen tasks to assess the functional integrity of brain circuits and multiple cognitive domains in a non-aversive way, it is surprising the effect of space radiation on rodent touchscreen performance is unknown. To fill this knowledge gap, 6-month-old C57BL/6J male mice were exposed to whole-body space radiation and assessed on a touchscreen battery starting 1-month later. Relative to Sham, 56Fe irradiation did not overtly change performance on tasks of visual discrimination, reversal learning, rule-based, or object-spatial paired associates learning, suggesting preserved functional integrity of supporting brain circuits. Surprisingly, 56Fe irradiation led to better performance on a dentate gyrus-reliant task of pattern separation ability. Irradiated mice discriminated similar visual cues in [~]40% fewer days and [~]40% more accurately than control mice. Improved pattern separation was not touchscreen-, radiation-particle, or neurogenesis-dependent, as both 56Fe and 28Si irradiation led to faster context discrimination (e.g. Sham Block 5 vs. 56Fe Block 2) in a non-touchscreen task and 56Fe led to fewer new dentate gyrus neurons relative to Sham. These data urge revisitation of the broadly-held view that space radiation is detrimental to cognition.\n\nSIGNIFICANCE STATEMENTAstronauts on an interplanetary mission - such as to Mars - will be unavoidably exposed to galactic cosmic radiation, a spectrum of highly-charged, fast-moving particles. Rodent studies suggest space radiation is detrimental to cognition. However, here we show this is not universally true. Mature mice that received whole body exposure to Mars-relevant space radiation perform similarly to control mice on high-level cognitive tasks, reflecting the functional integrity of key neural circuits. Even more surprisingly, irradiated mice perform better than controls in both appetitive and aversive tests of pattern separation, a mission-critical task reliant on dentate gyrus integrity. Notably, improved pattern separation was not touchscreen-, radiation-particle-, or neurogenesis-dependent. Our work urges revisitation of the generally-accepted conclusion that space radiation is detrimental to cognition.

neuroscience↗

bioRxiv2019

Physiological determinants of the increase in oxygen consumption during exercise in individuals with stroke

BackgroundUnderstanding the physiological limitations of the increase in oxygen consumption ([V]O2) during exercise is essential to improve cardiorespiratory fitness in individuals with stroke. However, the physiological determinants of the increase in [V]O2 during exercise have not been examined using multivariate analysis in individuals with stroke. This study aimed to identify the physiological determinants of the increase in [V]O2 during a graded exercise in terms of the respiratory function, cardiac function, and ability of skeletal muscles to extract oxygen.\n\nMethodsEighteen individuals with stroke (60.1 {+/-} 9.4 years of age, 67.1 {+/-} 30.8 days poststroke) underwent a graded exercise test for the assessment of cardiorespiratory response to exercise. The increase in [V]O2 from rest to ventilatory threshold and that from rest to peak exercise were measured as a dependent variable. The increases in respiratory rate, tidal volume, heart rate, stroke volume, and arterial-venous oxygen difference from rest to ventilatory threshold and those from rest to peak exercise were measured as independent variables.\n\nResultsFrom rest to ventilatory threshold, the increases in heart rate ({beta} = 0.546) and arterial-venous oxygen difference ({beta} = 0.398) were significant determinants of the increase in [V]O2 (adjusted R2 = 0.703, p < 0.001). From rest to peak exercise, the increases in tidal volume ({beta} = 0.611) and heart rate ({beta} = 0.353) were significant determinants of the increase in [V]O2 (adjusted R2 = 0.702, p < 0.001).\n\nConclusion[V]O2 is well-known to increase nearly linearly with increasing heart rate; however, our results suggest that arterial-venous oxygen difference and tidal volume are also significant physiological determinants of the increase in [V]O2 from rest to ventilatory threshold and that from rest to peak exercise, respectively. Our findings could potentially contribute to the development of appropriate therapies to improve cardiorespiratory fitness in individuals with stroke.

physiology↗

bioRxiv2017

Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease endemic to the Philippines. We integrated genome and transcriptome assembly with induced pluripotent stem cell-based modeling to identify the XDP causal locus and potential pathogenic mechanism. Genome sequencing identified novel variation that was shared by all probands and three recombination events that narrowed the causal locus to a genomic segment including TAF1. Transcriptome assembly in neural derivative cells discovered novel TAF1 transcripts, including a truncated transcript exclusively observed in probands that involved aberrant splicing and intron retention (IR) associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion. This IR correlated with decreased expression of the predominant TAF1 transcript and altered expression of neurodevelopmental genes; both the IR and aberrant TAF1 expression patterns were rescued by CRISPR/Cas9 excision of the SVA. These data suggest a unique genomic cause of XDP and may provide a roadmap for integrative genomic studies in other unsolved Mendelian disorders.\n\nHighlights O_LIGenome assembly narrows the XDP causal locus to a segment including TAF1\nC_LIO_LIXDP-specific SVA insertion induces intron retention and down-regulation of TAF1\nC_LIO_LICRISPR/Cas9 excision of SVA rescues aberrant splicing and cTAF1 expression in XDP\nC_LIO_LIGene networks perturbed in proband cells associate to synapse and neurodevelopment\nC_LI

genomics↗