Embodied bidirectional simulation of a spiking cortico-basal ganglia-cerebellar-thalamic brain model and a mouse musculoskeletal body model distributed across computers including the supercomputer Fugaku.

Embodied simulation with a digital brain model and a realistic musculoskeletal body model provides a means to understand animal behavior and behavioral change. Such simulation can be too large and complex to conduct on a single computer, and so distributed simulation across multiple computers over the Internet is necessary. In this study, we report our joint effort on developing a spiking brain model and a mouse body model, connecting over the Internet, and conducting bidirectional simulation while synchronizing them. Specifically, the brain model consisted of multiple regions including secondary motor cortex, primary motor and somatosensory cortices, basal ganglia, cerebellum and thalamus, whereas the mouse body model, provided by the Neurorobotics Platform of the Human Brain Project, had a movable forelimb with three joints and six antagonistic muscles to act in a virtual environment. Those were simulated in a distributed manner across multiple computers including the supercomputer Fugaku, which is the flagship supercomputer in Japan, while communicating via Robot Operating System (ROS). To incorporate models written in C/C++ in the distributed simulation, we developed a C++ version of the rosbridge library from scratch, which has been released under an open source license. These results provide necessary tools for distributed embodied simulation, and demonstrate its possibility and usefulness toward understanding animal behavior and behavioral change.

Assessment of Sound Source Tracking Using Multiple Drones Equipped with Multiple Microphone Arrays.

Drone audition techniques are helpful for listening to target sound sources from the sky, which can be used for human searching tasks in disaster sites. Among many techniques required for drone audition, sound source tracking is an essential technique, and thus several tracking methods have been proposed. Authors have also proposed a sound source tracking method that utilizes multiple microphone arrays to obtain the likelihood distribution of the sound source locations. These methods have been demonstrated in benchmark experiments. However, the performance against various sound sources with different distances and signal-to-noise ratios (SNRs) has been less evaluated. Since drone audition often needs to listen to distant sound sources and the input acoustic signal generally has a low SNR due to drone noise, making a performance assessment against source distance and SNR is essential. Therefore, this paper presents a concrete evaluation of sound source tracking methods using numerical simulation, focusing on various source distances and SNRs. The simulated results captured how the tracking performance will change when the sound source distance and SNR change. The proposed approach based on location distribution estimation tended to be more robust against distance increase, while existing approaches based on directional estimation tended to be more robust against decreasing SNR.

Telomere shortening in head and neck cancer: association between DNA demethylation and survival.

A growing body of evidence indicates that telomere dysfunction is a biological marker of progression in several types of cancer. However, the association between head and neck squamous cell carcinoma (HNSCC) and telomere length (TL) remains unknown. We measured the absolute TL levels in a well-characterised dataset of 211 tumoral vs normal tissues obtained from the same patients by quantitative polymerase chain reaction assay. Normalised TL levels were significantly lower in tumour samples than in normal tissue (P < 0.001) and there was a positive correlation between tumour tissue and normal mucosal tissue (R2 = 0.176, P < 0.001). We were able to distinguish two classes, one with a tumour/normal TL ratio ≤ 0.3 (38.4%), which showed clear telomere erosion, and the other with a tumour/normal TL ratio > 0.3 (61.6%), in which the TL was slightly shorter or longer than that in normal tissue. Notably, the tumour/normal TL ratio was correlated with the likelihood of disease recurrence (P = 0.002), the 5-hydroxymethylcytosine level (P = 0.043), and expression of the ten-eleven translocation (TET) gene (P = 0.043). Our findings show that TL shortening and subsequent low levels of 5-hydroxymethylcytosine and TET expression may contribute to development of HNSCC.

G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer.

Differences in the biology of human papillomavirus (HPV)-associated oropharyngeal cancers (OPCs) and HPV-negative OPCs may have implications in patient management. Early detection is imperative to reduce HPV-associated OPC mortality. Circulating tumor DNA (ctDNA) can potentially serve as a biomarker for monitoring clinically relevant cancer-related genetic and epigenetic modifications. We analyzed the methylation status of 24 G protein-coupled receptor (GPCR) genes in verification (85 OPC primary samples) and validation (8 OPC ctDNA samples) studies using quantitative methylation-specific polymerase chain reaction (Q-MSP). The Q-MSP-based verification study with 85 OPC primary samples revealed the GPCR genes that were significantly associated with recurrence in high methylation groups (≥14 methylated genes) with OPC and HPV-associated OPC (p < 0.001). In the Kaplan-Meier estimate and multivariate Cox proportional hazard analyses, 13 GPCR genes were significantly related to increased recurrence in the methylation group. Furthermore, the validation study on ctDNA showed that three of these genes (Prostaglandin D2 receptor 1: PTGDR1, Prostaglandin D2 receptor 2: PTGDR2, and Prostaglandin I2 Receptor: PTGIR) had a prediction performance as emerging biomarkers. We characterized the relationship between the methylation status of GPCR genes and outcomes in HPV-associated OPC. Our results highlight the potential utility of ctDNA methylation-based detection for the clinical management of HPV-associated OPC.

Long interspersed nuclear element 1 hypomethylation has novel prognostic value and potential utility in liquid biopsy for oral cavity cancer.

BACKGROUND: New biomarkers are urgently needed to improve personalized treatment approaches for head and neck squamous cell carcinoma (HNSCC). Global DNA hypomethylation has wide-ranging functions in multistep carcinogenesis, and the hypomethylation of long interspersed nucleotide element-1 (LINE-1) is related to increased retrotransposon activity and induced genome instability. However, little information is available regarding LINE-1 hypomethylation and its prognostic implications in HNSCC. METHODS: In this study, we analyzed LINE-1 hypomethylation levels in a well-characterized dataset of 317 primary HNSCC tissues and 225 matched pairs of normal mucosa tissues, along with five oral cavity cancer (OCC) circulating tumor DNA (ctDNA) samples using quantitative real-time methylation and unmethylation PCR. The analysis was performed according to various clinical characteristics and prognostic implications. RESULTS: The results demonstrated that LINE-1 hypomethylation levels were significantly higher in the HNSCC tissues than in corresponding normal tissues from the same individuals (P < 0.001). Univariate analysis revealed that high levels of LINE-1 hypomethylation were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038), whereas multivariate analysis demonstrated that they were significant independent prognostic factor for DFS (hazard ratio: 2.10, 95% confidence interval: 1.02-4.36; P = 0.045). Moreover, samples with high LINE-1 hypomethylation levels exhibited the greatest decrease in 5-hydroxymethylcytosine (5-hmC) levels and increase in tumor-suppressor gene methylation index (P = 0.006 and P < 0.001, respectively). Further, ctDNA studies also showed that LINE-1 hypomethylation had high predictive ability in OCC. CONCLUSIONS: LINE-1 hypomethylation is associated with a higher risk of early OCC relapse, and is hence, a potential predictive biomarker for OCC. Furthermore, 5-hmC levels also exhibited predictive potential in OCC, based on their inverse correlation with LINE-1 hypomethylation levels. LINE-1 hypomethylation analysis, therefore, has applications in determining patient prognosis and real-time surveillance of disease recurrence, and could serve as an alternative method for OCC screening. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s40364-020-00235-y.

Increase of Anti-oxidative Capacity during Differentiation of 3T3-L1 Preadipocytes into Adipocytes.

Cells have developed ingenious defense mechanisms in response to oxidative stress. Here, we evaluated changes in anti-oxidative capacity during differentiation of 3T3-L1 preadipocytes into adipocytes. When 3T3-L1 preadipocytes were treated with H2O2 (0.10-2.0 mM) for 21 h, cell viability decreased in response to H2O2 concentration, with an LD50 of approximately 0.35 mM H2O2. In the cells undergoing differentiation at 2 and 6 d, LD50 increased to 1.0 and >2.0 mM H2O2, respectively. These results indicate that resistance to oxidative stress dramatically increased with progression of differentiation of preadipocytes into adipocytes. Catalase activity and GSH content increased in the differentiated cells at 6 d, whereas superoxide dismutase and glutathione peroxidase activities were slightly lower in adipocytes than in preadipocytes. Moreover, knockdown of catalase or depletion of intracellular GSH enhanced the sensitivity to H2O2. When GSH was added to the cells depleted of intracellular GSH, the antioxidant capacity recovered. Autophagy was increased in differentiated adipocytes but was not affected by H2O2 treatment. Therefore, these results suggest that the increase in intracellular catalase activity and GSH content played a role in the increased anti-oxidative capacity of differentiated 3T3-L1 adipocytes.