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A-to-I RNA editing is a prevalent type of RNA modification in animals. The dysregulation of RNA editing has led to multiple human cancers. However, the role of RNA editing has never been studied in osteosarcoma, a complex bone cancer with unknown molecular basis. We retrieved the RNA-sequencing data from 24 primary osteosarcoma patients and 3 healthy controls. We systematically profiled the RNA editomes in these samples and quantitatively identified reliable differential editing sites (DES) between osteosarcoma and normal samples. RNA editing efficiency is dramatically increased in osteosarcoma, presumably due to the significant up-regulation of editing enzymes ADAR1 and ADAR2. Up-regulated DES in osteosarcoma are enriched in 3'UTRs. Strikingly, such 3'UTR sites are further enriched in microRNA binding regions of gene EMP2 and other oncogenes, abolishing the microRNA suppression on target genes. Accordingly, the expression of these tumor-promoting genes is elevated in osteosarcoma. There might be an RNA editing-dependent pathway leading to osteosarcoma. We expanded our knowledge on the potential roles of RNA editing in oncogenesis. Based on these molecular features, our work is valuable for future prognosis and diagnosis of osteosarcoma. [ABSTRACT FROM AUTHOR]

Neuron tracing, also known as neuron reconstruction, is an essential step in investigating the morphology of neuronal circuits and mechanisms of the brain. Since the ultra-high throughput of optical microscopy (OM) imaging leads to images of multiple gigabytes or even terabytes, it takes tens of hours for the state-of-the-art methods to generate a neuron reconstruction from a whole mouse brain OM image. We introduce InstantTrace, a novel framework that utilizes parallel neuron tracing on GPUs, achieving a significant speed boost of more than 20 × compared to state-of-the-art methods with comparable reconstruction quality on the BigNeuron dataset. Our framework utilizes two methods to achieve this performance advance. Firstly, it takes advantage of the sparse feature and tree structure of the neuron image, which serial tracing methods cannot fully exploit. Secondly, all stages of the neuron tracing pipeline, including the initial reconstruction stage that have not been parallelized in the past, are executed on GPU using carefully designed parallel algorithms. Furthermore, to investigate the applicability and robustness of the InstantTrace framework, a test on a whole mouse brain OM Image is conducted, and a preliminary neuron reconstruction of the whole brain is finished within 1 h on a single GPU, an order of magnitude faster than the existing methods. Our framework has the potential to significantly improve the efficiency of the neuron tracing process, allowing neuron image experts to obtain a preliminary reconstruction result instantly before engaging in manual verification and refinement. [ABSTRACT FROM AUTHOR]

Illustrating the molecular consequence of deleterious mutations is essential for bridging the gap between genotype and phenotype. In the cancer field, differential expression of the two alleles on heterozygous sites could directly reflect the effect of a mutation under certain trans environment. We retrieved transcriptomes of osteosarcoma and normal tissues in human and mouse. We defined tumor-specific heterozygous mutations with stringent criteria by considering sequencing depth and ancestral state. We calculated the relative expression of mutated alleles and normal alleles on the missense mutation sites in osteosarcoma. There is a conserved pattern that the mutated alleles have globally higher expression levels than the normal alleles in tumors. In the shared genes with missense mutations in both human and mouse, the relative expression of mutated alleles is highly correlated. Moreover, shared genes are functionally more important than unshared genes, and are enriched in oncogenes. The oncogenic role of mutations in oncogene KMT2A is experimentally verified. We systematically illustrate the deleterious effects of missense mutations by showing the over-expression of mutated alleles. We partially bridge the gap between genotype and phenotype by surmising that the over-expression of the mutated alleles might break the cellular equilibrium and lead to tumorigenesis. [ABSTRACT FROM AUTHOR]

Mutations that reduce the biosynthetic cost of ATP production or increase the gene translation efficiency (tAI) are favorable for rapid cell growth and proliferation and therefore likely to be observed in tumors. Whether the mutations in tumors optimize the trade-off between the ATP biosynthesis cost and gene translation efficiency by increasing the tAI/ATP ratio is currently unknown. We retrieved transcriptome data of normal and osteosarcoma tissue samples from humans and mice and identified tumor-specific mutations in each species by using stringent cutoffs and outgroup information. We compared the tAI/ATP values of genes before and after mutation. The tAI/ATP profile was found to be highly conserved in humans and mice, and also correlated with the essentiality of genes. Tumor-specific rather than shared mutations were found to lead to increased tAI/ATP values in both species. Thus, tumor-specific mutations were found to optimize the cost-efficiency trade-off by increasing the tAI/ATP ratio of genes in osteosarcoma. This may indicate an evolutionarily conserved mechanism that promotes tumorigenesis by facilitating rapid cell growth and proliferation. [ABSTRACT FROM AUTHOR]

Mutation is the basis of phenotypic changes and serves as the source of natural selection. The development of limbs has been the milestone in vertebrate evolution. Several limb and bone-related genes were verified experimentally, but other indirect and regulatory factors of limb development remained untested, especially very few cases were observed in natural environment. We report a naturally born serpentized pig without hindlimbs. Whole genome sequencing followed by comparative genomic analysis revealed multiple interesting patterns on the handicapped pig-specific mutations. Although the bone-related genes are not directly subjected to mutations, other regulatory factors such as the RNA deaminase genes Adar are damaged in the handicapped pig, leading to the abolished A-to-I deamination in many functional, conserved genes as well as the bone-related genes. This is a precious case that the limbless phenotype is observed in naturally born non-model organisms. Our study broadened the generality of the limbless phenotype across mammals and extended the regulation of hindlimb development to other non-bone-related genes. Our knowledge of limb and bone-related mutations and regulation would also contribute to human genetics. [ABSTRACT FROM AUTHOR]

Objectives: To segment the mandible from cone-beam computed tomography (CBCT) images efficiently and accurately for the 3D mandible model is essential for subsequent research and diagnosis. Methods: This paper proposes a local region-based variational region growing algorithm, which integrates local region and shape prior to segment the mandible accurately. Firstly, we select initial seeds in the CBCT image and then calculate candidate point sets and the local region energy function of each point. If a point reduces the energy, it is selected to be a pixel of the foreground region. By multiple iterations, the mandible segmentation of the slice can be obtained. Secondly, the segmented result of the previous slice is adopted as the shape prior to the next slice until all of the slices in CBCT are segmented. At last, the final mandible model is reconstructed by the Marching Cubes algorithm. Results: The experimental results on CBCT datasets illustrate the LRVRG algorithm can obtain satisfied 3D mandible models from CBCT images and it can solve the fuzzy problem effectively. Furthermore, quantitative comparisons with other methods demonstrate the proposed method achieves the state-of-the-art performance in mandible segmentation. Conclusions: Experiments demonstrate that our method is efficient and accurate for the mandible model segmentation. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a highly relevant public health problem. RA fibroblast-like synoviocytes (RAFLSs) play an important role in RA progression. Long non-coding RNA growth arrest-specific transcript 5 (GAS5) could improve RA by inducing RAFLSs apoptosis. However, the mechanism of GAS5 in RA remains unclear. RT-qPCR detected the expressions of GAS5, microRNA-128-3p (miR-128-3p), and histone deacetylase 4 (HDAC4) in RA synovial tissues and RAFLSs. Proliferation, apoptosis, migration, and invasion were measured by Cell Counting Kit-8 assay (CCK-8), flow cytometry, and transwell assays, severally. The protein levels of B-cell lymphoma-2 (Bcl-2), C-caspase 3, Bcl-2 related X protein (Bax), Tumor Necrosis factor-α (TNF-α), Interleukin 6 (IL-6), Interleukin 17 (IL-17), HDAC4, phosphorylation-protein kinase B (p-AKT), AKT, a phosphorylation-mechanistic target of rapamycin (p-mTOR), and mTOR were assessed by western blot assay. The interaction between miR-128-3p and GAS5 or HDAC4 was predicted by ENCORI or TargetScan Human and verified by the dual-luciferase reporter, RNA Immunoprecipitation (RIP), and RNA pull-down assays. GAS5 and HDAC4 were downregulated, and miR-128-3p was upregulated in RA synovial tissues and RAFLSs. Function analysis indicated that GAS5 curbed proliferation, migration, invasion, inflammation, and facilitated apoptosis of RAFLSs. Rescue assay confirmed that miR-128-3p overexpression or HDAC4 knockdown weakened the inhibitory effect of GAS5 or anti-miR-128-3p on RA development. GAS5 acted as a miR-128-3p sponge to upregulate HDAC4 expression. Besides, GAS5/miR-128-3p/HDAC4 axis regulated RA progression partially through the AKT/mTOR pathway. Our studies disclosed that GAS5 restrained inflammation in synovial tissue partly through regulating HDAC4 via miR-128-3p, suggesting a potential lncRNA-targeted therapy for RA treatment. [ABSTRACT FROM AUTHOR]

To quantitatively assess the distribution pattern of hippocampal tau pathology in Alzheimer's disease (AD) and primary age-related tauopathy (PART), we investigated the distribution of phosphorylated tau protein (AT8) in 6 anatomically defined subregions of the hippocampal formation and developed a mathematical algorithm to compare the patterns of tau deposition in PART and AD. We demonstrated regional patterns of selective vulnerability as distinguishing features of PART and AD in functionally relevant structures of the hippocampus. In AD cases, tau pathology was high in both CA1 and subiculum, followed by CA2/3, entorhinal cortex (EC), CA4, and dentate gyrus (DG). In PART, the severity of tau pathology in CA1 and subiculum was high, followed by EC, CA2/3, CA4, and DG. There are significant differences between sector DG and CA1, DG and subiculum in both AD and PART. [ABSTRACT FROM AUTHOR]