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In the human genome, miR‐451a, miR‐144‐5p (passenger strand), and miR‐144‐3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs is significantly associated with poor prognosis of patients with renal cell carcinoma (RCC) (miR‐451a: P = .00305; miR‐144‐5p: P = .00128; miR‐144‐3p: P = 9.45 × 10−5). We previously reported that miR‐451a acted as an antitumor miRNA in RCC cells. Involvement of the passenger strand of the miR‐144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR‐144‐5p and miR‐144‐3p significantly reduced cancer cell migration and invasive abilities, suggesting these miRNAs acted as antitumor miRNAs in RCC cells. Analyses of miR‐144‐5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes (FAM64A, F2, TRIP13, ANKRD36, CENPF, NCAPG, CLEC2D, SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR‐144‐5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP, SDC3, SH2D1A, GZMH, KIF21B, TMC8, GAB3, HLA‐DPB2, PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR‐144‐5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR‐451a, miR‐144‐5p, and miR‐144‐3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis. Our study showed that expression of miR‐144‐5p and miR‐144‐3p was downregulated, and these microRNAs (miRNAs) acted as antitumor miRNAs in renal cell carcinoma. SDC3 was directly controlled by miR‐144‐5p, and its expression enhanced cancer cell aggressiveness. Clustered miRNAs (miR‐451a, miR‐144‐5p, and miR‐144‐3p) acted as antitumor miRNAs, and their targets were intimately involved in renal cell carcinoma pathogenesis.

The dorsal premotor cortex (PMd) plays an essential role in visually guided goal-directed motor behavior. Although there are several planning processes for achieving goal-directed behavior, the separate neural processes are largely unknown. Here, we created a new visuo-goal task to investigate the step-by-step planning processes for visuomotor and visuo-goal behavior in humans. Using functional magnetic resonance imaging, we found activation in different portions of the bilateral PMd during each processing step. In particular, the activated area for rule-based visuomotor and visuo-goal mapping was located at the ventrorostral portion of the bilateral PMd, that for action plan specification was at the dorsocaudal portion of the left PMd, that for transformation was at the rostral portion of the left PMd, and that for action preparation was at the caudal portion of the bilateral PMd. Thus, the left PMd was involved throughout all of the processes, but the right PMd was involved only in rule-based visuomotor and visuo-goal mapping and action preparation. The locations related to each process were generally spatially separated from each other, but they overlapped partially. These findings revealed that there are functional subregions in the bilateral PMd in humans and these subregions form a functional gradient to achieve goal-directed behavior.

Motor skill memory is first encoded online in a fragile form during practice and then converted into a stable form by offline consolidation, which is the behavioral stage critical for successful learning. Praise, a social reward, is thought to boost motor skill learning by increasing motivation, which leads to increased practice. However, the effect of praise on consolidation is unknown. Here, we tested the hypothesis that praise following motor training directly facilitates skill consolidation. Forty-eight healthy participants were trained on a sequential finger-tapping task. Immediately after training, participants were divided into three groups according to whether they received praise for their own training performance, praise for another participant's performance, or no praise. Participants who received praise for their own performance showed a significantly higher rate of offline improvement relative to other participants when performing a surprise recall test of the learned sequence. On the other hand, the average performance of the novel sequence and randomly-ordered tapping did not differ between the three experimental groups. These results are the first to indicate that praise-related improvements in motor skill memory are not due to a feedback-incentive mechanism, but instead involve direct effects on the offline consolidation process.

Recent studies suggest that action video game players exhibit superior performance in visuospatial cognitive tasks compared with non-game players. However, the neural basis underlying this visuospatial cognitive performance advantage remains largely unknown. The present human behavioral and imaging study compared gray matter volume in action video game experts and non-experts using structural magnetic resonance imaging and voxel-based morphometry analysis. The results revealed significantly larger gray matter volume in the right posterior parietal cortex in experts compared with non-experts. Furthermore, the larger gray matter volume in the right posterior parietal cortex significantly correlated with individual performance in a visual working memory task in experts. These results suggest that differences in brain structure may be linked to extensive video game play, leading to superior visuospatial cognitive performance in action video game experts.

We conducted an fMRI study to investigate the neural basis of bimanual coordination, which is fundamental to upper extremity control. Considering bimanual movement as a combination of bimanual chord formation and sequence control, we hypothesized that the areas with the learning effect of both chord formation and sequence learning are critical in bimanual coordination. We adopted the serial reaction time task (SRTT) to test this hypothesis. Thirty-five healthy right-handed volunteers practiced visually cued bimanual SRTT, including the “mirror” and more complex “parallel” modes of random movements or repeating fixed sequences to separately depict the neural substrates of bimanual posture control for chord formation and those of sequence. Random movements’ reaction time (RT) continuously declined, indicating learning of bimanual chord formation. The RT in the sequential condition declined more rapidly than in the random condition, confirming sequence learning. The parallel random conditions evoked a more prominent learning-related decrease of task-related activation in the left M1 and cerebellar vermis than the less difficult mirror random conditions. The left M1 showed learning-related enhancement of functional connectivity with the anterior cingulate cortex during the parallel random conditions compared with the mirror random conditions. Thus, the left M1, anterior cingulate cortex, and cerebellar vermis are related to learning bimanual chord formation. The left M1 and cerebellar vermis also showed sequence-specific learning-related activity increments more prominent in the parallel mode than in the mirror mode. Thus, the left M1 and cerebellar vermis are critical in the bimanual motor learning network.

During joint action, two or more persons depend on each other to accomplish a goal. This mutual recursion, or circular dependency, is one of the characteristics of cooperation. To evaluate the neural substrates of cooperation, we conducted a hyperscanning functional MRI study in which 19 dyads performed a joint force-production task. The goal of the task was to match their average grip forces to the target value (20% of their maximum grip forces) through visual feedback over a 30-s period; the task required taking into account other-produced force to regulate the self-generated one in real time, which represented cooperation. Time-series data of the dyad's exerted grip forces were recorded, and the noise contribution ratio (NCR), a measure of influence from the partner, was computed using a multivariate autoregressive model to identify the degree to which each participant's grip force was explained by that of their partner's, i.e., the degree of cooperation. Compared with the single force-production task, the joint task enhanced the NCR and activated the mentalizing system, including the medial prefrontal cortex, precuneus, and bilateral posterior subdivision of the temporoparietal junction (TPJ). In addition, specific activation of the anterior subdivision of the right TPJ significantly and positively correlated with the NCR across participants during the joint task. The effective connectivity of the anterior to posterior TPJ was upregulated when participants coordinated their grip forces. Finally, the joint task enhanced cross-brain functional connectivity of the right anterior TPJ, indicating shared attention toward the temporal patterns of the motor output of the partner. Since the posterior TPJ is part of the mentalizing system for tracking the intention of perceived agents, our findings indicate that cooperation, i.e., the degree of adjustment of individual motor output depending on that of the partner, is mediated by the interconnected subdivisions of the right TPJ. [Display omitted]

During a dyadic social interaction, two individuals can share visual attention through gaze, directed to each other (mutual gaze) or to a third person or an object (joint attention). Shared attention is fundamental to dyadic face-to-face interaction, but how attention is shared, retained, and neutrally represented in a pair-specific manner has not been well studied. Here, we conducted a two-day hyperscanning functional magnetic resonance imaging study in which pairs of participants performed a real-time mutual gaze task followed by a joint attention task on the first day, and mutual gaze tasks several days later. The joint attention task enhanced eye-blink synchronization, which is believed to be a behavioral index of shared attention. When the same participant pairs underwent mutual gaze without joint attention on the second day, enhanced eye-blink synchronization persisted, and this was positively correlated with inter-individual neural synchronization within the right inferior frontal gyrus. Neural synchronization was also positively correlated with enhanced eye-blink synchronization during the previous joint attention task session. Consistent with the Hebbian association hypothesis, the right inferior frontal gyrus had been activated both by initiating and responding to joint attention. These results indicate that shared attention is represented and retained by pair-specific neural synchronization that cannot be reduced to the individual level. •Attention is shared for establishing communicative link between humans.•Inter-brain neural synchronization during eye contact emerged after joint work.•The synchronization was localized to the right inferior frontal gyrus.•The neural synchronization correlated with behavioral measure of shared attention.•This is the pair-specific effect emerged from mutual interaction irreducible to the individual.

The primary motor cortex (M1) is crucial for motor learning; however, its interaction with other brain areas during motor learning remains unclear. We hypothesized that the fronto-parietal execution network (FPN) provides learning-related information critical for the flexible cognitive control that is required for practice. We assessed network-level changes during sequential finger tapping learning under speed pressure by combining magnetic resonance spectroscopy and task and resting-state functional magnetic resonance imaging. There was a motor learning-related increase in preparatory activity in the fronto-parietal regions, including the right M1, overlapping the FPN and sensorimotor network (SMN). Learning-related increases in M1-seeded functional connectivity with the FPN, but not the SMN, were associated with decreased GABA/glutamate ratio in the M1, which were more prominent in the parietal than the frontal region. A decrease in the GABA/glutamate ratio in the right M1 was positively correlated with improvements in task performance ( p  = 0.042). Our findings indicate that motor learning driven by cognitive control is associated with local variations in the GABA/glutamate ratio in the M1 that reflects remote connectivity with the FPN, representing network-level motor sequence learning formations.

How coherent neural oscillations are involved in task execution is a fundamental question in neuroscience. Although several electrophysiological studies have tackled this issue, the brain-wide task modulation of neural coherence remains uncharacterized. Here, with a fast fMRI technique, we studied shifts of brain-wide neural coherence across different task states in the ultraslow frequency range (0.01–0.7 Hz). First, we examined whether the shifts of the brain-wide neural coherence occur in a frequency-dependent manner. We quantified the shift of a region's average neural coherence by the inter-state variance of the mean coherence between the region and the rest of the brain. A clustering analysis based on the variance's spatial correlation between frequency components revealed four frequency bands (0.01–0.15 Hz, 0.15–0.37 Hz, 0.37–0.53 Hz, and 0.53–0.7 Hz) showing band-specific shifts of the brain-wide neural coherence. Next, we investigated the similarity of the inter-state variance's spectra between all pairs of regions. We found that regions showing similar spectra correspond to those forming functional modules of the brain network. Then, we investigated the relationship between identified frequency bands and modules’ inter-state variances. We found that modules showing the highest variance are those made up of parieto-occipital regions at 0.01–0.15 Hz, while it is replaced with another consisting of frontal regions above 0.15 Hz. Furthermore, these modules showed specific shifting patterns of the mean coherence across states at 0.01–0.15 Hz and above 0.15 Hz, suggesting that identified frequency bands differentially contribute to neural interactions during task execution. Our results highlight that usage of the fast fMRI enables brain-wide investigation of neural coherence up to 0.7 Hz, which opens a promising track for assessment of the large-scale neural interactions in the ultraslow frequency range.

Recent analyses of our microRNA (miRNA) expression signatures obtained from several types of cancer have provided novel information on their molecular pathology. In renal cell carcinoma (RCC), expression of microRNA‐451a (miR‐451a) was significantly downregulated in patient specimens and low expression of miR‐451a was significantly associated with poor prognosis of RCC patients (P = .00305) based on data in The Cancer Genome Atlas. The aims of the present study were to investigate the antitumor roles of miR‐451a and to identify novel oncogenic networks it regulated in RCC cells. Ectopic expression of miR‐451a significantly inhibited cancer cell migration and invasion by RCC cell lines, suggesting that miR‐451a had antitumor roles. To identify oncogenes regulated by miR‐451a in RCC cells, we analyzed genome‐wide gene expression data and examined information in in silico databases. A total of 16 oncogenes and were found to be possible targets of miR‐451a regulation. Interestingly, high expression of 9 genes (PMM2, CRELD2, CLEC2D, SPC25, BST2, EVL, TBX15, DPYSL3, and NAMPT) was significantly associated with poor prognosis. In this study, we focused on phosphomannomutase 2 (PMM2), which was the most strongly associated with prognosis. Overexpression of PMM2 was detected in clinical specimens and Spearman's rank test indicated a negative correlation between the expression levels of miR‐451a and PMM2 (P = .0409). Knockdown of PMM2 in RCC cells inhibited cancer cell migration and invasion, indicating overexpression of PMM2 could promote malignancy. Analytic strategies based on antitumor miRNAs is an effective tool for identification of novel pathways of cancer. Our data demonstrated that expression of miR‐451a was significantly downregulated in clinical RCC cells and the miRNA acted as a tumor suppressor via targeting of PMM2. High expression of PMM2 was significantly associated with poor prognosis in RCC patients. Elucidation of the pathways mediated by the miR‐451a/PMM2 axis should improve our understanding of oncogenic mechanisms and lead to novel treatment strategies in RCC.