Tubulin has been recently reported to form a large family consisting of various gene isoforms; however, the differences in the molecular features of tubulin dimers composed of a combination of these ...isoforms remain unknown. Therefore, we attempted to elucidate the physical differences in the molecular motility of these tubulin dimers using the method of measurable pico-meter-scale molecular motility, diffracted X-ray tracking (DXT) analysis, regarding characteristic tubulin dimers, including neuronal TUBB3 and ubiquitous TUBB5. We first conducted a DXT analysis of neuronal (TUBB3-TUBA1A) and ubiquitous (TUBB5-TUBA1B) tubulin dimers and found that the molecular motility around the vertical axis of the neuronal tubulin dimer was lower than that of the ubiquitous tubulin dimer. The results of molecular dynamics (MD) simulation suggest that the difference in motility between the neuronal and ubiquitous tubulin dimers was probably caused by a change in the major contact of Gln245 in the T7 loop of TUBB from Glu11 in TUBA to Val353 in TUBB. The present study is the first report of a novel phenomenon in which the pico-meter-scale molecular motility between neuronal and ubiquitous tubulin dimers is different.
The HPC-1/syntaxin 1A (
) gene, which is involved in synaptic transmission and neurodevelopmental disorders, is a TATA-less gene with several transcription start sites. It is activated by the binding ...of Sp1 and acetylated histone H3 to the -204 to +2 core promoter region (CPR) in neuronal cell/tissue. Furthermore, it is depressed by the association of class 1 histone deacetylases (HDACs) to
-CPR in non-neuronal cell/tissue. To further clarify the factors characterizing
gene silencing in non-neuronal cell/tissue not expressing
, we attempted to identify the promoter region forming DNA-protein complex only in non-neuronal cells. Electrophoresis mobility shift assays (EMSA) demonstrated that the -183 to -137 OL2 promoter region forms DNA-protein complex only in non-neuronal fetal rat skin keratinocyte (FRSK) cells which do not express
. Furthermore, the Yin-Yang 1 (YY1) transcription factor binds to the -183 to -137 promoter region of
in FRSK cells, as shown by competitive EMSA and supershift assay. Chromatin immunoprecipitation assay revealed that YY1 in vivo associates to
-CPR in cell/tissue not expressing
and that trichostatin A treatment in FRSK cells decreases the high-level association of YY1 to
-CPR in default. Reporter assay indicated that YY1 negatively regulates
transcription. Finally, mass spectrometry analysis showed that gene silencing factors, including HDAC1, associate onto the -183 to -137 promoter region together with YY1. The current study is the first to report that
transcription is negatively regulated in a cell/tissue-specific manner by YY1 transcription factor, which binds to the -183 to -137 promoter region together with gene silencing factors, including HDAC.
Reduced cortical plasticity has been previously reported in older adult as compared with young adults. However, the effects of dopamine on this plasticity reduction remain unknown. Here, we assessed ...the effects of high-dose (200 mg) and medium-dose (100 mg) L-3,4-dihydroxyphenylalanine (L-DOPA) intake on the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS) in older adults (aged ∼65 years). The subjects were 32 (200 mg) and 20 (100 mg) healthy older adult volunteers. This study was designed as a double-blind, crossover and placebo-controlled trial on one dose of L-dopa. Two hours after taking L-DOPA or placebo-drug, QPS was applied over the motor cortex. Motor evoked potentials were recorded to evaluate the motor cortical excitability changes. We found that both doses of L-DOPA enhanced LTP after QPS in older adults as one group. We classified subjects into QPS responders and QPS nonresponders. Both L-DOPA doses produced significant LTP enhancement in QPS nonresponders, whereas either of doses did not produce significant LTP enhancement in QPS responders. Collectively, our findings suggest that the neural plasticity reductions observed in older adults could be partly improved by dopamine.
•L-3,4-dihydroxyphenylalanine enhanced quadripulse magnetic stimulation–induced long-term potentiation in a subset of older adults.•High- (200 mg) and medium-dose (100 mg) L-3,4-dihydroxyphenylalanine produced similar long-term potentiation enhancement.•The reduction in QPS-induced LTP observed in older adults could be partly explained by reduced Dopamine synthesis.
The aim of this study was to investigate where neurologists look when they view brain computed tomography (CT) images and to evaluate how they deploy their visual attention by comparing their gaze ...distribution with saliency maps. Brain CT images showing cerebrovascular accidents were presented to 12 neurologists and 12 control subjects. The subjects' ocular fixation positions were recorded using an eye-tracking device (Eyelink 1000). Heat maps were created based on the eye-fixation patterns of each group and compared between the two groups. The heat maps revealed that the areas on which control subjects frequently fixated often coincided with areas identified as outstanding in saliency maps, while the areas on which neurologists frequently fixated often did not. Dwell time in regions of interest (ROI) was likewise compared between the two groups, revealing that, although dwell time on large lesions was not different between the two groups, dwell time in clinically important areas with low salience was longer in neurologists than in controls. Therefore it appears that neurologists intentionally scan clinically important areas when reading brain CT images showing cerebrovascular accidents. Both neurologists and control subjects used the "bottom-up salience" form of visual attention, although the neurologists more effectively used the "top-down instruction" form.
Both pre-supplementary motor area (pre-SMA) and SMA-proper (SMA) must play important roles in visuomotor sequence learning. However, functional differences between the pre-SMA and SMA have not been ...well studied in humans.
To elucidate the functional differences between the pre-SMA and SMA in sequence learning in humans.
To induce LTP/LTD, we administered quadripulse transcranial magnetic stimulation (QPS) with an inter-stimulus interval of 5 or 50 ms (QPS-5/50) over the pre-SMA or SMA in healthy volunteers. The sham stimulation was also done as a control. We studied the effects of LTP/LTD in the pre-SMA/SMA on a new sequence learning and the performance of well-learned sequence by using sequence learning task called the “2 × 10 task”. Effects on the simple choice reaction time task were also studied for comparison.
QPS-5 over the pre-SMA increased the error rate without any changes in movement speed. When administered over the SMA, QPS-5 decreased, and QPS-50 increased the rate of reaction time reduction across trials without changes in the error rate. QPS over neither the pre-SMA nor SMA affected the performances of a well-learned sequence or a simple choice reaction time task.
Our findings that QPS over the pre-SMA correlated with sequence learning performance and that over the SMA with execution speed are consistent with the previous results in animals and humans. Our results lend further support to the utility of QPS for modulating motor learning in humans.
•LTP-like effects of the pre-SMA worsened sequence learning.•LTP-like effects of the SMA inhibited, LTD-like effects enhanced the reaction time reduction across trials.•The performance of well-learned sequences was unaffected by QPS over the pre-SMA/SMA.•The performance in a 4-choice reaction task was unchanged by QPS.•The pre-SMA and SMA may be involved in different aspects of sequence learning.
•A case of anti-GABAA Receptor Antibody-Associated (anti-GABAAR) Encephalitis.•For a year, the patient could continue daily life despite drop out from treatment.•However, seizures relapsed with a ...gradual decline in cognitive function.•Brain MRI showed multifocal asynchronous lesions later showing brain atrophy.•Even with isolated seizure at onset, anti-GABAAR encephalitis should be considered.
The masked-priming paradigm is used to test unconscious inhibitory processes of the brain. A tendency towards responses that are incompatible with the prime, designated as negative compatibility ...effect (NCE), emerges when the perception of a priming visual stimulus is “masked” afterwards. This effect presumably stems from a subliminal inhibitory process against the masked-prime. Prior lesions as well as activation studies suggest a key role of SMA in this effect.
This study was conducted to elucidate a causal role of SMA in the subliminal response inhibition represented by the NCE.
Using a repeated-measures pre–post design with a group of healthy people, physiological measures (resting and active motor thresholds and motor evoked potential (MEP) amplitude) and behavioral ones (choice reaction time (CRT), positive compatibility effect (PCE) and NCE) were obtained before and after three quadripulse stimulation (QPS), namely sham, M1-QPS, and SMA-QPS, on different days. CRT and PCE served as indices for different aspects of motor execution.
Motor thresholds were not altered after any QPS, although the M1-QPS increased MEP amplitude. Neither CRT nor PCE was altered significantly after QPS protocols. NCE was abolished after the SMA-QPS.
Abolished NCE after the SMA-QPS in the absence of MEP changes suggests that (1) SMA plays a cardinal role in the NCE, and (2) the network involved in NCE is different from that of MEP generation.
•QPS over SMA disturbed subliminal response inhibition as indexed by masked-priming.•MEP amplitude was increased by M1-QPS, but not by SMA-QPS.•Response inhibition and MEP generation are accomplished with distinct networks.
Patients with Alzheimer's disease (AD) are known to exhibit visuospatial processing impairment, as reflected in eye movements from the early stages of the disease. We investigated whether the pattern ...of gaze exploration during visual tasks could be useful for detecting cognitive decline at the earliest stage.
Sixteen AD patients (age: 79.1 ± 7.9 years, Mini Mental State Examination MMSE score: 17.7 ± 5.3, mean ± standard deviation) and 16 control subjects (age: 79.4 ± 4.6, MMSE score: 26.9 ± 2.4) participated. In the visual memory task, subjects memorized presented line drawings for later recall. In the visual search tasks, they searched for a target Landolt ring of specific orientation (serial search task) or color (pop-out task) embedded among arrays of distractors. Using video-oculography, saccade parameters, patterns of gaze exploration, and pupil size change during task performance were recorded and compared between AD and control subjects.
In the visual memory task, the number of informative regions of interest (ROIs) fixated was significantly reduced in AD patients compared to control subjects. In the visual search task, AD patients took a significantly longer time and more saccades to detect the target in the serial but not in pop-out search. In both tasks, there was no significant difference in the saccade frequency and amplitude between groups. On-task pupil modulation during the serial search task was decreased in AD. The number of ROIs fixated in the visual memory task and search time and saccade numbers in the serial search task differentiated both groups of subjects with high sensitivity, whereas saccade parameters of pupil size modulation were effective in confirming normal cognition from cognitive decline with high specificity.
Reduced fixation on informative ROIs reflected impaired attentional allocation. Increased search time and saccade numbers in the visual search task indicated inefficient visual processing. Decreased on-task pupil size during visual search suggested decreased pupil modulation with cognitive load in AD patients, reflecting impaired function of the locus coeruleus. When patients perform the combination of these tasks to visualize multiple aspects of visuospatial processing, cognitive decline can be detected at an early stage with high sensitivity and specificity and its progression be evaluated.
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