Bmc Genomics
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Opioids are the cornerstone of treatment for moderate to severe pain, but chronic use leads to maladaptations that include: tolerance, dependence and opioid-induced hyperalgesia (OIH). These responses limit the utility of opioids, as well as our ability to control chronic pain. Despite decades of research, we have no therapies or proven strategies to overcome this problem. However, murine haplotype based computational genetic mapping and a SNP data base generated from analysis of whole-genome sequence data (whole-genome HBCGM), provides a hypothesis-free method for discovering novel genes affecting opioid maladaptive responses. ⋯ Whole-genome HBCGM is a powerful tool for identifying genes affecting biomedical traits such as opioid maladaptations. We demonstrate that Dcc affects tolerance, dependence and OIH after chronic opioid exposure, though not through simple differences in expression in the adult spinal cord.
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Acute kidney injury (AKI) is a common and serious complication of cardiac surgery using cardiopulmonary bypass (CPB). The pathogenesis is poorly understood and the study of AKI in rodent models has not led to improvements in clinical outcomes. We sought to determine the changes in renal medullary gene expression in a novel and clinically relevant porcine model of CPB-induced AKI. ⋯ Post CPB AKI, as defined by clinical criteria, is characterised by molecular changes in renal medulla that are associated with both injury and survival programmes. Our observations highlight the value of large animal models in AKI research and provide insights into the failure of findings in rodent models to translate into clinical progress.
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Traumatic brain injury (TBI) results in irreversible damage at the site of impact and initiates cellular and molecular processes that lead to secondary neural injury in the surrounding tissue. We used microarray analysis to determine which genes, pathways and networks were significantly altered using a rat model of TBI. Adult rats received a unilateral controlled cortical impact (CCI) and were sacrificed 24 h post-injury. The ipsilateral hemi-brain tissue at the site of the injury, the corresponding contralateral hemi-brain tissue, and naïve (control) brain tissue were used for microarray analysis. Ingenuity Pathway Analysis (IPA) software was used to identify molecular pathways and networks that were associated with the altered gene expression in brain tissues following TBI. ⋯ Bioinformatic analysis of microarray data following TBI identified key molecular pathways and networks associated with neural injury following TBI. The GIH created here provides a starting point for investigating therapeutic targets in a ranked order that is somewhat different than what has been presented previously. In addition to being a vehicle for identifying potential targets for post-TBI therapeutic strategies, our findings can also provide a context for evaluating the potential of therapeutic agents currently in development.
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Genome-wide association studies (GWAS) have identified many common polymorphisms associated with complex traits. However, these associated common variants explain only a small fraction of the phenotypic variances, leaving a substantial portion of genetic heritability unexplained. As a result, searches for "missing" heritability are drawing increasing attention, particularly for rare variant studies that often require a large sample size and, thus, extensive sequencing effort. Although the development of next generation sequencing (NGS) technologies has made it possible to sequence a large number of reads economically and efficiently, it is still often cost prohibitive to sequence thousands of individuals that are generally required for association studies. A more efficient and cost-effective design would involve pooling the genetic materials of multiple individuals together and then sequencing the pools, instead of the individuals. This pooled sequencing approach has improved the plausibility of association studies for rare variants, while, at the same time, posed a great challenge to the pooled sequencing data analysis, essentially because individual sample identity is lost, and NGS sequencing errors could be hard to distinguish from low frequency alleles. ⋯ The EM-based approach for the analysis of pooled sequencing data can accurately estimate minor allele frequencies, call SNPs, and find associations between variants and complex traits. This approach is especially useful for studies involving rare variants.
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Meta Analysis
An expression atlas of human primary cells: inference of gene function from coexpression networks.
The specialisation of mammalian cells in time and space requires genes associated with specific pathways and functions to be co-ordinately expressed. Here we have combined a large number of publically available microarray datasets derived from human primary cells and analysed large correlation graphs of these data. ⋯ We consider the regulation of genes in human primary cells and specifically in the human mononuclear phagocyte system. Of particular note is the fact that these data do not support the identity of putative markers of antigen-presenting dendritic cells, nor classification of M1 and M2 activation states, a current subject of debate within immunological field. We have provided this data resource on the BioGPS web site (http://biogps.org/dataset/2429/primary-cell-atlas/) and on macrophages.com (http://www.macrophages.com/hu-cell-atlas).