1,162 research outputs found

    PseudoFuN: Deriving functional potentials of pseudogenes from integrative relationships with genes and microRNAs across 32 cancers

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    BACKGROUND: Long thought "relics" of evolution, not until recently have pseudogenes been of medical interest regarding regulation in cancer. Often, these regulatory roles are a direct by-product of their close sequence homology to protein-coding genes. Novel pseudogene-gene (PGG) functional associations can be identified through the integration of biomedical data, such as sequence homology, functional pathways, gene expression, pseudogene expression, and microRNA expression. However, not all of the information has been integrated, and almost all previous pseudogene studies relied on 1:1 pseudogene-parent gene relationships without leveraging other homologous genes/pseudogenes. RESULTS: We produce PGG families that expand beyond the current 1:1 paradigm. First, we construct expansive PGG databases by (i) CUDAlign graphics processing unit (GPU) accelerated local alignment of all pseudogenes to gene families (totaling 1.6 billion individual local alignments and >40,000 GPU hours) and (ii) BLAST-based assignment of pseudogenes to gene families. Second, we create an open-source web application (PseudoFuN [Pseudogene Functional Networks]) to search for integrative functional relationships of sequence homology, microRNA expression, gene expression, pseudogene expression, and gene ontology. We produce four "flavors" of CUDAlign-based databases (>462,000,000 PGG pairwise alignments and 133,770 PGG families) that can be queried and downloaded using PseudoFuN. These databases are consistent with previous 1:1 PGG annotation and also are much more powerful including millions of de novo PGG associations. For example, we find multiple known (e.g., miR-20a-PTEN-PTENP1) and novel (e.g., miR-375-SOX15-PPP4R1L) microRNA-gene-pseudogene associations in prostate cancer. PseudoFuN provides a "one stop shop" for identifying and visualizing thousands of potential regulatory relationships related to pseudogenes in The Cancer Genome Atlas cancers. CONCLUSIONS: Thousands of new PGG associations can be explored in the context of microRNA-gene-pseudogene co-expression and differential expression with a simple-to-use online tool by bioinformaticians and oncologists alike

    Suppression of microglial Ccl2 reduces neuropathic pain associated with chronic spinal compression

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    IntroductionChronic spinal compression is a common complication of spinal cord injury (SCI), which can lead to spinal stenosis or herniated discs. The ensuing neuropathic pain is often associated with the activation of microglia. In this investigation, our objective was to explore whether modifying the levels of chemokine (C-C motif) ligand 2 (Ccl2) in microglia could alleviate neuropathic pain resulting from chronic spinal compression.MethodsWe used a public database to look for major altered gene associated in a SCI model established in rats. We then employed adeno-associated virus (AAV) vectors, expressing siRNA for the identified significantly altered gene under a microglia-specific TMEM119 promoter. We also tested the impact of this treatment in microglia in vivo on the severity of chronic spinal compression and associated pain using a ttw mouse model for progressive spinal compression.ResultsWe identified chemokine (C-C motif) ligand 2 (Ccl2) as the primary gene altered in microglia within a rat SCI model, utilizing a public database. Microglial Ccl2 levels were then found to be significantly elevated in disc specimens from SCI patients diagnosed with chronic spinal compression and strongly correlated with the Thompson classification of the degeneration level and pain score. Depletion of Ccl2 in microglia-specific TMEM119 promoter were developed to transfect mouse microglia in vitro, resulting in a proinflammatory to anti-inflammatory phenotypic adaption. In vivo depletion of Ccl2 in microglia mitigated the severity of chronic spinal compression and related pain in ttw mice, likely due to significant changes in pain-associated cytokines and factors.ConclusionDisc microglia expressing high levels of Ccl2 may contribute to chronic spinal compression and SCI-associated pain. Therapeutically targeting Ccl2 in microglia could offer a potential avenue for treating chronic spinal compression and SCI-associated pain

    The topological differences between visitation and pollen transport networks: a comparison in species rich communities of the Himalaya–Hengduan Mountains

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    Pollination networks are usually constructed and assessed by direct field observations which commonly assume that all flower visitors are true pollinators. However, this assumption is often invalid and the use of data based on mere visitors to flowers may lead to a misunderstanding of intrinsic pollination networks. Here, using a large dataset by both sampling floral visitors and analyzing their pollen loads, we constructed 32 networks pairs (visitation versus pollen transport) across one flowering season at four elevation sites in the Himalaya–Hengduan Mountains region. Pollen analysis was conducted to determine which flower visitors acted as potential pollinators (pollen vectors) or as cheaters (those not carrying pollen of the visited plants). We tested whether there were topological differences between visitation and pollen transport networks and whether different taxonomic groups of insect visitors differed in their ability to carry pollen of the visited plants. Our results indicated that there was a significantly higher degree of specialization at both the network and species levels in the pollen transport networks in contrast to the visitation networks. Modularity was lower but nestedness was higher in the visitation networks compared to the pollen transport networks. All the cheaters were identified as peripheral species and most of them contributed positively to the nested structure. This may explain in part the differences in modularity and nestedness between the two network types. Bees carried the highest proportion of pollen of the visited plants. This was followed by Coleoptera, other Hymenoptera and Diptera. Lepidoptera carried the lowest proportion of pollen of the visited plants. Our study shows that the construction of pollen transport networks could provide a more in-depth understanding of plant–pollinator interactions. Moreover, it suggests that detecting and removing cheater interactions when studying the topology of other mutualistic networks might be also important.This study was supported by Strategic Priority Research Program of the Chinese Academy of Sciences (XDB31020000), National Key Basic Research Program of China (2014CB954100), Joint Fund of the National Natural Science Foundation of China-Yunnan Province (U1502261), Major International Joint Research Project of NSF China (31320103919), Applied Fundamental Research Foundation of Yunnan Province (2014GA003), National Natural Science Foundation of China (31700361), Yunlin Scholarship of Yunnan Province to H. Wang (YLXL20170001) and CAS ‘Light of West China’ Program to Y.H. Zhao. A. Lázaro was supported by a Ramóny Cajal contract financed by the Spanish Ministry of Economy and Competitiveness
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