We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EM low PM low gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EM low PM low gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EM low PM low gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtypespecific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.

BackgroundBiomedical event extraction is a crucial task in biomedical text mining. As the primary forum for international evaluation of different biomedical event extraction technologies, BioNLP Shared Task represents a trend in biomedical text mining toward fine-grained information extraction (IE). The fourth series of BioNLP Shared Task in 2016 (BioNLP-ST’16) proposed three tasks, in which the Bacteria Biotope event extraction (BB) task has been put forward in the earlier BioNLP-ST. Deep learning methods provide an effective way to automatically extract more complex features and achieve notable results in various natural language processing tasks.ResultsThe experimental results show that the presented approach can achieve an F-score of 57.42% in the test set, which outperforms previous state-of-the-art official submissions to BioNLP-ST 2016.ConclusionsIn this paper, we propose a novel Gated Recurrent Unit Networks framework integrating attention mechanism for extracting biomedical events between biotope and bacteria from biomedical literature, utilizing the corpus from the BioNLP’16 Shared Task on Bacteria Biotope task. The experimental results demonstrate the potential and effectiveness of the proposed framework.

Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. However, the cellular stage at which BCP-ALL are arrested and whether this relates to expression of the pre-BCR components (IGHM, IGLL1 and VPREB1) is still unclear. Here, we show differential protein expression and copy number variation (CNV) patterns of the pre-BCR components in pediatric BCP-ALL. Moreover, analyzing six BCP-ALL data sets (n = 733), we demonstrate that TCF3-PBX1 ALL express high levels of IGHM, IGLL1 and VPREB1, and are arrested at the pre-B stage. By contrast, ETV6-RUNX1 ALL express low levels of IGHM or VPREB1, and are arrested at the pro-B stage. Irrespective of subtype, ALL with high levels of IGHM, IGLL1 and VPREB1 are arrested at the pre-B stage and correlate with good prognosis in high-risk pediatric BCP-ALL (n = 207). Our findings suggest that BCP-ALL are arrested at different cellular stages, which relates to the expression pattern of the pre-BCR components that could serve as prognostic markers for high-risk pediatric BCP-ALL patients.

In order to characterize environmental vanadium distribution, mobility, and bioaccumulation, a total of 55 soil samples and 36 plant samples were collected in four typical land-use districts in Panzhihua region, Southwestern China. Soil samples were analyzed with the modified Community Bureau of Reference (BCR) sequential extraction procedure, and the content of vanadium in soil and plant was determined by ICP-AES. The total content of vanadium was 208.1-938.4 mg kg(-1) in smelting area, 111.6-591.2 mg kg(-1) in mining area, 94.0-183.6 mg kg(-1) in urban park, and 71.7-227.2 mg kg(-1) in agricultural area, respectively, while the bio-available content of vanadium was characterized that the polluted areas (mining area 18.8-83.6 mg kg(-1), smelting area 41.7-132.1 mg kg(-1)) and the unpolluted area (agricultural area 9.8-26.4 mg kg(-1), urban park 9.9-25.2 mg kg(-1)). In addition, the contamination degree of vanadium in soil was smelting area > mining area > agricultural area ≈ urban park. Moreover, the fraction of vanadium in each sequential extraction characterized that residual fraction > oxidizable fraction > reducible fraction > acid soluble fraction. The bioaccumulation of vanadium from soil to plant was weak to intermediate absorption. Therefore, some countermeasures such as soil monitoring and remediation should be to take in the sooner future, especially in mining and smelting area.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.