How complete are current yeast and human protein-interaction networks?

We estimate the full yeast protein-protein interaction network to contain 37,800-75,500 interactions and the human network 154,000-369,000, but owing to a high false-positive rate, current maps are roughly only 50% and 10% complete, respectively. Paradoxically, releasing raw, unfiltered assay data might help separate true from false interactions

Analysis of North Korea’s February 2016 Successful Space Launch (ISSSP Report No.2 /2016)

The Democratic Peoples' Republic of Korea (DPRK) or North Korea succeeded in placing a 100 kg Earth Observation (EO) satellite Kwangmyongsong-4 into a Sun Synchronous Orbit (SSO) on February 7, 2016. As it had done in earlier launches, the DPRK used its Unha-3 launch vehicle for the latest mission. The launch was conducted from the Sohae Space Center in Ch’o’lsan County, North Pyongyang Province

Consolidating the set of known human protein-protein interactions in preparation for large-scale mapping of the human interactome

BACKGROUND: Extensive protein interaction maps are being constructed for yeast, worm, and fly to ask how the proteins organize into pathways and systems, but no such genome-wide interaction map yet exists for the set of human proteins. To prepare for studies in humans, we wished to establish tests for the accuracy of future interaction assays and to consolidate the known interactions among human proteins. RESULTS: We established two tests of the accuracy of human protein interaction datasets and measured the relative accuracy of the available data. We then developed and applied natural language processing and literature-mining algorithms to recover from Medline abstracts 6,580 interactions among 3,737 human proteins. A three-part algorithm was used: first, human protein names were identified in Medline abstracts using a discriminator based on conditional random fields, then interactions were identified by the co-occurrence of protein names across the set of Medline abstracts, filtering the interactions with a Bayesian classifier to enrich for legitimate physical interactions. These mined interactions were combined with existing interaction data to obtain a network of 31,609 interactions among 7,748 human proteins, accurate to the same degree as the existing datasets. CONCLUSION: These interactions and the accuracy benchmarks will aid interpretation of current functional genomics data and provide a basis for determining the quality of future large-scale human protein interaction assays. Projecting from the approximately 15 interactions per protein in the best-sampled interaction set to the estimated 25,000 human genes implies more than 375,000 interactions in the complete human protein interaction network. This set therefore represents no more than 10% of the complete network

High resolution transcriptome maps for wild-type and nonsense-mediated decay-defective Caenorhabditis elegans

The high-resolution transcriptome of wild-type and nonsense-mediated decay (NMD) defective C. elegans during development reveals insights into the NMD pathway and it’s role in development

A map of human protein interactions derived from co-expression of human mRNAs and their orthologs

The human protein interaction network will offer global insights into the molecular organization of cells and provide a framework for modeling human disease, but the network's large scale demands new approaches. We report a set of 7000 physical associations among human proteins inferred from indirect evidence: the comparison of human mRNA co-expression patterns with those of orthologous genes in five other eukaryotes, which we demonstrate identifies proteins in the same physical complexes. To evaluate the accuracy of the predicted physical associations, we apply quantitative mass spectrometry shotgun proteomics to measure elution profiles of 3013 human proteins during native biochemical fractionation, demonstrating systematically that putative interaction partners tend to co-sediment. We further validate uncharacterized proteins implicated by the associations in ribosome biogenesis, including WBSCR20C, associated with Williams–Beuren syndrome. This meta-analysis therefore exploits non-protein-based data, but successfully predicts associations, including 5589 novel human physical protein associations, with measured accuracies of 54±10%, comparable to direct large-scale interaction assays. The new associations' derivation from conserved in vivo phenomena argues strongly for their biological relevance

Splicing is an alternate oncogenic pathway activation mechanism in glioma

High-grade diffuse glioma (HGG) is the leading cause of brain tumour death. While the genetic drivers of HGG have been well described, targeting these has thus far had little impact on survival suggesting other mechanisms are at play. Here we interrogate the alternative splicing landscape of pediatric and adult HGG through multi-omic analyses, uncovering an increased splicing burden compared with normal brain. The rate of recurrent alternative splicing in cancer drivers exceeds their mutation rate, a pattern that is recapitulated in pan-cancer analyses, and is associated with worse prognosis in HGG. We investigate potential oncogenicity by interrogating cancer pathways affected by alternative splicing in HGG; spliced cancer drivers include members of the RAS/MAPK pathway. RAS suppressor neurofibromin 1 is differentially spliced to a less active isoform in >80% of HGG downstream from REST upregulation, activating the RAS/MAPK pathway and reducing glioblastoma patient survival. Overall, our results identify non-mutagenic mechanisms by which cancers activate oncogenic pathways which need to accounted for in personalized medicine approaches

High resolution transcriptome maps for wild-type and nonsense-mediated decay-defective Caenorhabditis elegans.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: While many genome sequences are complete, transcriptomes are less well characterized. We used both genome-scale tiling arrays and massively parallel sequencing to map the Caenorhabditis elegans transcriptome across development. We utilized this framework to identify transcriptome changes in animals lacking the nonsense-mediated decay (NMD) pathway. RESULTS: We find that while the majority of detectable transcripts map to known gene structures, >5% of transcribed regions fall outside current gene annotations. We show that >40% of these are novel exons. Using both technologies to assess isoform complexity, we estimate that >17% of genes change isoform across development. Next we examined how the transcriptome is perturbed in animals lacking NMD. NMD prevents expression of truncated proteins by degrading transcripts containing premature termination codons. We find that approximately 20% of genes produce transcripts that appear to be NMD targets. While most of these arise from splicing errors, NMD targets are enriched for transcripts containing open reading frames upstream of the predicted translational start (uORFs). We identify a relationship between the Kozak consensus surrounding the true start codon and the degree to which uORF-containing transcripts are targeted by NMD and speculate that translational efficiency may be coupled to transcript turnover via the NMD pathway for some transcripts. CONCLUSIONS: We generated a high-resolution transcriptome map for C. elegans and used it to identify endogenous targets of NMD. We find that these transcripts arise principally through splicing errors, strengthening the prevailing view that splicing and NMD are highly interlinked processes

Whole genome analysis for 163 gRNAs in Cas9-edited mice reveals minimal off-target activity.

Genome editing with CRISPR-associated (Cas) proteins holds exceptional promise for correcting variants causing genetic disease. To realize this promise, off-target genomic changes cannot occur during the editing process. Here, we use whole genome sequencing to compare the genomes of 50 Cas9-edited founder mice to 28 untreated control mice to assess the occurrence of S. pyogenes Cas9-induced off-target mutagenesis. Computational analysis of whole-genome sequencing data detects 26 unique sequence variants at 23 predicted off-target sites for 18/163 guides used. While computationally detected variants are identified in 30% (15/50) of Cas9 gene-edited founder animals, only 38% (10/26) of the variants in 8/15 founders validate by Sanger sequencing. In vitro assays for Cas9 off-target activity identify only two unpredicted off-target sites present in genome sequencing data. In total, only 4.9% (8/163) of guides tested have detectable off-target activity, a rate of 0.2 Cas9 off-target mutations per founder analyzed. In comparison, we observe ~1,100 unique variants in each mouse regardless of genome exposure to Cas9 indicating off-target variants comprise a small fraction of genetic heterogeneity in Cas9-edited mice. These findings will inform future design and use of Cas9-edited animal models as well as provide context for evaluating off-target potential in genetically diverse patient populations

The Perioperative Quality Improvement Programme (PQIP patient study): protocol for a UK multicentre, prospective cohort study to measure quality of care and outcomes after major surgery

INTRODUCTION: Major surgery accounts for a substantial proportion of health service activity, due not only to the primary procedure, but the longer-term health implications of poor short-term outcome. Data from small studies or from outside the UK indicate that rates of complications and failure to rescue vary between hospitals, as does compliance with best practice processes. Within the UK, there is currently no system for monitoring postoperative complications (other than short-term mortality) in major non-cardiac surgery. Further, there is variation between national audit programmes, in the emphasis placed on quality assurance versus quality improvement, and therefore the principles of measurement and reporting which are used to design such programmes. METHODS AND ANALYSIS: The PQIP patient study is a multi-centre prospective cohort study which recruits patients undergoing major surgery. Patient provide informed consent and contribute baseline and outcome data from their perspective using a suite of patient-reported outcome tools. Research and clinical staff complete data on patient risk factors and outcomes in-hospital, including two measures of complications. Longer-term outcome data are collected through patient feedback and linkage to national administrative datasets (mortality and readmissions). As well as providing a uniquely granular dataset for research, PQIP provides feedback to participating sites on their compliance with evidence-based processes and their patients' outcomes, with the aim of supporting local quality improvement. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Health Research Authority in the UK. Dissemination of interim findings (non-inferential) will form a part of the improvement methodology and will be provided to participating centres at regular intervals, including near-real time feedback of key process measures. Inferential analyses will be published in the peer-reviewed literature, supported by a comprehensive multi-modal communications strategy including to patients, policy makers and academic audiences as well as clinicians

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas

© The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.info:eu-repo/semantics/publishedVersio