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

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

Evaluation of Trace Alignment Quality and its Application in Medical Process Mining

Trace alignment algorithms have been used in process mining for discovering the consensus treatment procedures and process deviations. Different alignment algorithms, however, may produce very different results. No widely-adopted method exists for evaluating the results of trace alignment. Existing reference-free evaluation methods cannot adequately and comprehensively assess the alignment quality. We analyzed and compared the existing evaluation methods, identifying their limitations, and introduced improvements in two reference-free evaluation methods. Our approach assesses the alignment result globally instead of locally, and therefore helps the algorithm to optimize overall alignment quality. We also introduced a novel metric to measure the alignment complexity, which can be used as a constraint on alignment algorithm optimization. We tested our evaluation methods on a trauma resuscitation dataset and provided the medical explanation of the activities and patterns identified as deviations using our proposed evaluation methods.Comment: 10 pages, 6 figures and 5 table

Abnormal surface morphology of the central sulcus in children with attention-deficit/hyperactivity disorder

The central sulcus (CS) divides the primary motor and somatosensory areas, and its three-dimensional (3D) anatomy reveals the structural changes of the sensorimotor regions. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is associated with sensorimotor and executive function deficits. However, it is largely unknown whether the morphology of the CS alters due to inappropriate development in the ADHD brain. Here, we employed the sulcus-based morphometry approach to investigate the 3D morphology of the CS in 42 children whose ages spanned from 8.8 to 13.5 years (21 with ADHD and 21 controls). After automatic labeling of each CS, we computed 7 regional shape metrics for each CS, including the global average length, average depth, maximum depth, average span, surface area, average cortical thickness and local sulcal profile. We found that the average depth and maximum depth of the left CS as well as the average cortical thickness of bilateral CS in the ADHD group were significantly larger than those in the healthy children. Moreover, significant between-group differences in the sulcal profile had been found in middle sections of the CSs bilaterally, and these changes were positively correlated with the hyperactivity-impulsivity scores in the children with ADHD. Altogether, our results provide evidence for the abnormity of the CS anatomical morphology in children with ADHD due to the structural changes in the motor cortex, which significantly contribute to the clinical symptomatology of the disorder

Type I interferon signaling facilitates the development of IL-10-producing effector CD8+ T cells during influenza virus infection

Recent evidence has suggested that IL-10-producing effector CD8+ T cells play an important role in regulating excessive inflammation during acute viral infections. However, the cellular and molecular cues regulating the development of IL-10-producing effector CD8+ T cells are not completely defined. Here, we show that type I interferons (IFNs) are required for the development of IL-10-producing effector CD8+ T cells during influenza virus infection in mice. We find that type I IFNs can enhance IL-27 production by lung APCs, thereby facilitating IL-10-producing CD8+ T-cell development through a CD8+ T-cell-nonautonomous way. Surprisingly, we also demonstrate that direct type I IFN signaling in CD8+ T cells is required for the maximal generation of IL-10-producing CD8+ T cells. Type I IFN signaling in CD8+ T cells, in cooperation with IL-27 and IL-2 signaling, promotes and sustains the expression of IFN regulatory factor 4 (IRF4) and B-lymphocyte-induced maturation protein-1 (Blimp-1), two transcription factors required for the production of IL-10 by effector CD8+ T cells. Our data reveal a critical role of the innate antiviral effector cytokines in regulating the production of a regulatory cytokine by effector CD8+ T cells during respiratory virus infection

Effect of ecological restoration programs on dust concentrations in the North China Plain: a case study

In recent decades, the Chinese government has made a great effort in initiating large-scale ecological restoration programs (ERPs) to reduce the dust concentrations in China, especially for dust storm episodes. Using the Moderate Resolution Imaging Spectroradiometer (MODIS) land cover product, the ERP-induced land cover changes are quantitatively evaluated in this study. Two obvious vegetation protective barriers arise throughout China from the southwest to the northeast, which are well known as the "Green Great Wall" (GGW). Both the grass GGW and forest GGW are located between the dust source region (DSR) and the densely populated North China Plain (NCP). To assess the effect of ERPs on dust concentrations, a regional transport/dust model (WRF-DUST, Weather Research and Forecast model with dust) is applied to investigate the evolution of dust plumes during a strong dust storm episode from 2 to 8 March 2016. The WRF-DUST model generally performs reasonably well in reproducing the temporal variations and spatial distributions of near-surface [PMC] (mass concentration of particulate matter with aerodynamic diameter between 2.5 and 10 mu m) during the dust storm event. Sensitivity experiments have indicated that the ERP-induced GGWs help to reduce the dust concentration in the NCP, especially in BTH (Beijing, Tianjin, and Hebei). When the dust storm is transported from the upwind DSR to the downwind NCP, the [PMC] reduction ranges from -5 to -15% in the NCP, with a maximum reduction of -12.4% (-19.2 mu gm(3)) in BTH and -7.6% (-10.1 mu g m(3)) in the NCP. We find the dust plumes move up to the upper atmosphere and are transported from the upwind DSR to the downwind NCP, accompanied by dust decrease. During the episode, the forest GGW is nonsignificant in dust concentration control because it is of benefit for dry deposition and not for emission. Conversely, the grass GGW is beneficial in controlling dust erosion and is the dominant reason for [PMC] decrease in the NCP. Because the air pollution is severe in eastern China, especially in the NCP, and the contribution of dust episodes is significant, the reduction of dust concentrations will have important effects on severe air pollution. This study illustrates the considerable contribution of ERPs to the control of air pollution in China, especially in springtime