We have developed an integrated strategy for targeted resequencing and analysis of gene subsets from the human exome for variants. Our capture technology is geared towards resequencing gene subsets substantially larger than can be done efficiently with simplex or multiplex PCR but smaller in scale than exome sequencing. We describe all the steps from the initial capture assay to single nucleotide variant (SNV) discovery. The capture methodology uses in-solution 80-mer oligonucleotides. To provide optimal flexibility in choosing human gene targets, we designed an in silico set of oligonucleotides, the Human OligoExome, that covers the gene exons annotated by the Consensus Coding Sequencing Project (CCDS). This resource is openly available as an Internet accessible database where one can download capture oligonucleotides sequences for any CCDS gene and design custom capture assays. Using this resource, we demonstrated the flexibility of this assay by custom designing capture assays ranging from 10 to over 100 gene targets with total capture sizes from over 100 Kilobases to nearly one Megabase. We established a method to reduce capture variability and incorporated indexing schemes to increase sample throughput. Our approach has multiple applications that include but are not limited to population targeted resequencing studies of specific gene subsets, validation of variants discovered in whole genome sequencing surveys and possible diagnostic analysis of disease gene subsets. We also present a cost analysis demonstrating its cost-effectiveness for large population studies.

The automatic extraction of chemical information from text requires the recognition of chemical entity mentions as one of its key steps. When developing supervised named entity recognition (NER) systems, the availability of a large, manually annotated text corpus is desirable. Furthermore, large corpora permit the robust evaluation and comparison of different approaches that detect chemicals in documents. We present the CHEMDNER corpus, a collection of 10,000 PubMed abstracts that contain a total of 84,355 chemical entity mentions labeled manually by expert chemistry literature curators, following annotation guidelines specifically defined for this task. The abstracts of the CHEMDNER corpus were selected to be representative for all major chemical disciplines. Each of the chemical entity mentions was manually labeled according to its structure-associated chemical entity mention (SACEM) class: abbreviation, family, formula, identifier, multiple, systematic and trivial. The difficulty and consistency of tagging chemicals in text was measured using an agreement study between annotators, obtaining a percentage agreement of 91. For a subset of the CHEMDNER corpus (the test set of 3,000 abstracts) we provide not only the Gold Standard manual annotations, but also mentions automatically detected by the 26 teams that participated in the BioCreative IV CHEMDNER chemical mention recognition task. In addition, we release the CHEMDNER silver standard corpus of automatically extracted mentions from 17,000 randomly selected PubMed abstracts. A version of the CHEMDNER corpus in the BioC format has been generated as well. We propose a standard for required minimum information about entity annotations for the construction of domain specific corpora on chemical and drug entities. The CHEMDNER corpus and annotation guidelines are available at: http://www.biocreative.org/resources/biocreative-iv/chemdner-corpus/.

Chemical compounds and drugs (together called chemical entities) embedded in scientific articles are crucial for many information extraction tasks in the biomedical domain. However, only a very limited number of chemical entity recognition systems are publically available, probably due to the lack of large manually annotated corpora. To accelerate the development of chemical entity recognition systems, the Spanish National Cancer Research Center (CNIO) and The University of Navarra organized a challenge on Chemical and Drug Named Entity Recognition (CHEMDNER). The CHEMDNER challenge contains two individual subtasks: 1) Chemical Entity Mention recognition (CEM); and 2) Chemical Document Indexing (CDI). Our study proposes machine learning-based systems for the CEM task.

Defective tumor suppressor genes (TSGs) and hyperactive oncogenes (OCGs) heavily contribute to cell proliferation and apoptosis during cancer development through genetic variations such as somatic mutations and deletions. Moreover, they usually do not perform their cellular functions individually but rather execute jointly. Therefore, a comprehensive comparison of their mutation patterns and network properties may provide a deeper understanding of their roles in the cancer development and provide some clues for identification of novel targets.

Although progress has been made in the detection and characterization of neural plasticity in depression, it has not been fully understood in individual synaptic changes in the neural circuits under chronic stress and antidepressant treatment.

Saccharomyces boulardii (Sb) can protect against intestinal injury and tumor formation, but how this probiotic yeast controls protective mucosal host responses is unclear. Angiogenesis is an integral process of inflammatory responses in inflammatory bowel diseases (IBD) and required for mucosal remodeling during restitution. The aim of this study was to determine whether Sb alters VEGFR (vascular endothelial growth factor receptor) signaling, a central regulator of angiogenesis.

More recently laparoscopic radical cystectomy (LRC) has increasingly been an attractive alternative to open radical cystectomy (ORC) and many centers have reported their early experiences in the treatment of bladder cancer. Evaluate the safety and efficacy of LRC compared with ORC in the treatment of bladder cancer.

Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis.

Drug addiction is a chronic and complex brain disease, adding much burden on the community. Though numerous efforts have been made to identify the effective treatment, it is necessary to find more novel therapeutics for this complex disease. As network pharmacology has become a promising approach for drug repurposing, we proposed to apply the approach to drug addiction, which might provide new clues for the development of effective addiction treatment drugs. We first extracted 44 addictive drugs from the NIDA and their targets from DrugBank. Then, we constructed two networks: an addictive drug-target network and an expanded addictive drug-target network by adding other drugs that have at least one common target with these addictive drugs. By performing network analyses, we found that those addictive drugs with similar actions tended to cluster together. Additionally, we predicted 94 nonaddictive drugs with potential pharmacological functions to the addictive drugs. By examining the PubMed data, 51 drugs significantly cooccurred with addictive keywords than expected. Thus, the network analyses provide a list of candidate drugs for further investigation of their potential in addiction treatment or risk.

The recently identified phenomenon of double-stranded RNA (dsRNA)-mediated gene activation (RNAa) has been studied extensively, as it is present in humans, mice, and Caenorhabditis elegans, suggesting that dsRNA-mediated RNAa is an evolutionarily conserved mechanism. Previous studies have shown that dsP21-322 can induce tumor suppressor gene p21 expression in several human cancer cells. Nonetheless, the role of dsRNAs in the activation of gene expression, including their target molecules and associated key factors, remains poorly understood.

Lily tepals have a short lifespan. Once the tepals senesce, the ornamental value of the flower is lost. Some cultivars have attractive purple ovaries and fruits which greatly enhance the ornamental value of Asiatic hybrid lilies. However, little is known about the molecular mechanisms of anthocyanin biosynthesis in Asiatic hybrid lily ovaries. To investigate the transcriptional network that governs purple ovary coloration in Asiatic hybrid lilies, we obtained transcriptome data from green ovaries (S1) and purple ovaries (S2) of Asiatic "Tiny Padhye". Comparative transcriptome analysis revealed 4228 differentially expressed genes. Differential expression analysis revealed that ten unigenes including four CHS genes, one CHI gene, one F3H gene, one F3'H gene, one DFR gene, one UFGT gene, and one 3RT gene were significantly up-regulated in purple ovaries. One MYB gene, LhMYB12-Lat, was identified as a key transcription factor determining the distribution of anthocyanins in Asiatic hybrid lily ovaries. Further qPCR results showed unigenes related to anthocyanin biosynthesis were highly expressed in purple ovaries of three purple-ovaried Asiatic hybrid lilies at stages 2 and 3, while they showed an extremely low level of expression in ovaries of three green-ovaried Asiatic hybrid lilies during all developmental stages. In addition, shading treatment significantly decreased pigment accumulation by suppressing the expression of several unigenes related to anthocyanin biosynthesis in ovaries of Asiatic "Tiny Padhye". Lastly, a total of 15,048 Simple Sequence Repeats (SSRs) were identified in 13,710 sequences, and primer pairs for SSRs were designed. The results could further our understanding of the molecular mechanisms of anthocyanin biosynthesis in Asiatic hybrid lily ovaries.

Epigenetic alterations, such as aberrant DNA methylation of promoter and enhancer regions, which lead to atypical gene expression, have been associated with carcinogenesis. In hepatocellular carcinoma (HCC), genome-wide analysis of methylation has only recently been used. For a better understanding of hepatocarcinogenesis, we applied an even higher resolution analysis of the promoter methylome to identify previously unknown regions and genes differentially methylated in HCC.

Metastatic renal cell carcinoma (mRCC) is nearly incurable and accounts for most of the mortality associated with RCC. Von Hippel Lindau (VHL) is a tumour suppressor that is lost in the majority of clear cell RCC (ccRCC) cases. Its role in regulating hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α) is well-studied. Recent work has demonstrated that VHL knock down induces an epithelial-mesenchymal transition (EMT) phenotype. In this study we showed that a CRISPR/Cas9-mediated knock out of VHL in the RENCA model leads to morphologic and molecular changes indicative of EMT, which in turn drives increased metastasis to the lungs. RENCA cells deficient in HIF-1α failed to undergo EMT changes upon VHL knockout. RNA-seq revealed several HIF-1α-regulated genes that are upregulated in our VHL knockout cells and whose overexpression signifies an aggressive form of ccRCC in the cancer genome atlas (TCGA) database. Independent validation in a new clinical dataset confirms the upregulation of these genes in ccRCC samples compared to adjacent normal tissue. Our findings indicate that loss of VHL could be driving tumour cell dissemination through stabilization of HIF-1α in RCC. A better understanding of the mechanisms involved in this phenomenon can guide the search for more effective treatments to combat mRCC.

The inner mucus layer in mouse colon normally separates bacteria from the epithelium. Do humans have a similar inner mucus layer and are defects in this mucus layer a common denominator for spontaneous colitis in mice models and ulcerative colitis (UC)?

MCM-41 was prepared through the sol-gel method and encapsulated by polydopamine (PDA) before being coordinated with metal ions to form a highly efficient sustained release system (M-PDA-MCM-41) for triazolone delivery. The characterization results confirmed the existence of the coordination bond between the PDA layer and triazolone through the bridge effect from metal ions, which enhanced the interaction between PDA-MCM-41 and triazolone. The adsorption capacity of Fe-PDA-MCM-41 increased up to 173 mg g-1, which was 160% more than that of MCM-41. The sustained release performance of M-PDA-MCM-41 in different pH values was investigated. Under the conditions of pH ≤7, the release speed of triazolone increased with pH decreasing, whereas its release speed in the weak base condition was slower than in the neutral condition. Therefore, the as-synthesized system showed significant pH-sensitivity in the sustained release process, indicating that the sustained release system can be well stored in the neutral or basic environment and activated in the acid environment. Their sustained release curves described by the Korsmeyer-Peppas equation at pH 7 showed the same behaviour, indicating that PDA decoration or metal ion coordination only increases the steric hindrance and the interaction between carrier and triazolone instead of changing the original structure of the pure MCM material in accordance with X-ray diffraction and Brunauer-Emmett-Teller analysis results.

Sorghum (Sorghum bicolor) is an important bioenergy crop. Its biomass mainly consists of the cellulosic and non-cellulosic polysaccharides, both which can be converted to biofuels. The biosynthesis of non-cellulosic polysaccharides involves several glycosyltransferases (GT) families including GT47. However, there was no systemic study on GT47 family in sorghum to date. Here, we identified 39 sorghum GT47 family members and showed the functional divergences of MURUS3 (MUR3) homologs. Sorghum GT47 proteins were phylogenetically clustered into four distinct subfamilies. Within each subfamily, gene structure was relatively conserved between the members. Ten gene pairs were identified from the 39 GT47 genes, of which two pairs might be originated from tandem duplication. 25.6% (10/39) of sorghum GT47 genes were homologous to Arabidopsis MUR3, a xyloglucan biosynthesis gene in primary cell walls. SbGT47_2, SbGT47_7, and SbGT47_8, three most homologous genes of MUR3, exhibited different tissue expression patterns and were selected for complementation into Arabidopsis mur3-3. Physiological and cell wall analyses showed that SbGT47_2 and SbGT47_7 may be two functional xyloglucan galactosyltransferases in sorghum. Further studies found that MUR3-like genes are widely present in the seed plants but not in the chlorophytic alga Chlamydomonas reinhardtii. Our results provide novel information for evolutionary analysis and functional dissection of sorghum GT47 family members.

Histone lysine methyltransferases (HMTs), a category of enzymes, play essential roles in regulating transcription, cellular differentiation, and chromatin construction. The genomic landscape and clinical significance of HMTs in renal cell carcinoma (RCC) remain uncovered.

Histone lysine methylation plays an important role in the regulation of ventricular remodelling. NSD2 is involved in many types of tumours through enhancing H3K36me2 expression. However, the role of NSD2 in the regulation of histone lysine methylation during ventricular remodelling remains unclear. In this study, we established cardiac hypertrophy model in C57BL/6 mice by transverse aortic constriction and found that histone lysine methylation participated in ventricular remodelling regulation via the up-regulation of H3K27me2 and H3K36me2 expression. In addition, we constructed transgenic C57BL/6 mice with conditional knockout of NSD2 (NSD2-/- ) in the myocardium. NSD2-/- C57BL/6 mice had milder ventricular remodelling and significantly improved cardiac function compared with wild-type mice, and the expression of H3K36me2 but not H3K27me2 was down-regulated. In conclusion, NSD2 promotes ventricular remodelling mediated by the regulation of H3K36me2.

Finding relevant datasets is important for promoting data reuse in the biomedical domain, but it is challenging given the volume and complexity of biomedical data. Here we describe the development of an open source biomedical data discovery system called DataMed, with the goal of promoting the building of additional data indexes in the biomedical domain.

Monocyte activation and polarization play essential roles in many chronic inflammatory diseases. An imbalance of M1 and M2 macrophage activation (pro-inflammatory and alternatively activated, respectively) is believed to be a key aspect in the etiology of these diseases, thus a therapeutic approach that regulates macrophage activation could be of broad clinical relevance. Methylglyoxal-bis-guanylhydrazone (MGBG), a regulator of polyamine metabolism, has recently been shown to be concentrated in monocytes and macrophages, and interfere with HIV integration into the DNA of these cells in vitro. RNA expression analysis of monocytes from HIV+ and control donors with or without MGBG treatment revealed the only gene to be consistently down regulated by MGBG to be osteopontin (OPN). The elevated expression of this pro-inflammatory cytokine and monocyte chemoattractant is associated with various chronic inflammatory diseases. We demonstrate that MGBG is a potent inhibitor of secreted OPN (sOPN) in cultured monocytes with 50% inhibition achieved at 0.1 μM of the drug. Furthermore, inhibition of OPN RNA transcription in monocyte cultures occurs at similar concentrations of the drug. During differentiation of monocytes into macrophages in vitro, monocytes express cell surface CD16 and the cells undergo limited DNA synthesis as measured by uptake of BrdU. MGBG inhibited both activities at similar doses to those regulating OPN expression. In addition, monocyte treatment with MGBG inhibited differentiation into both M1 and M2 classes of macrophages at non-toxic doses. The inhibition of differentiation and anti-OPN effects of MGBG were specific for monocytes in that differentiated macrophages were nearly resistant to MGBG activities. Thus MGBG may have potential therapeutic utility in reducing or normalizing OPN levels and regulating monocyte activation in diseases that involve chronic inflammation.