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Genomics
CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor
Feb 24, 2017   Nature Communications
Funnell T, Tasaki S, Oloumi A, Araki S, Kong E,   . . . . . .   , Morin GB, Nakanishi A, Shah S, Toyoshiba H, Aparicio S
CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor
Feb 24, 2017
Nature Communications
CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kinase-responsive alternative splicing events, the large majority of which monotonically increase or decrease with increasing CDC-like kinase inhibition. We show that distinct RNA-binding motifs are associated with T3 response in skipped exons. Unexpectedly, we observe dose-dependent conjoined gene transcription, which is associated with motif enrichment in the last and second exons of upstream and downstream partners, respectively. siRNA knockdown of CLK2-associated genes significantly increases conjoined gene formation. Collectively, our results reveal an unexpected role for CDC-like kinase in conjoined gene formation, via regulation of 3'-end processing and associated splicing factors.The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.
Molecular Cloning and Induced Expression of Six Small Heat Shock Proteins Mediating Cold-Hardiness in
Feb 24, 2017   Frontiers In Physiology
Wang HJ, Shi ZK, Shen QD, Xu CD, Wang B, Meng ZJ, Wang SG, Tang B, Wang S
Molecular Cloning and Induced Expression of Six Small Heat Shock Proteins Mediating Cold-Hardiness in
Feb 24, 2017
Frontiers In Physiology
The main function of small heat shock proteins (sHSPs) as molecular chaperones is to protect proteins from denaturation under adverse conditions. Molecular and physiological data were used to examine the sHSPs underlying cold-hardiness in
Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity
Feb 24, 2017   Nature Communications
Yu Y, Zuo X, He M, Gao J, Fu Y,   . . . . . .   , Ludwig KU, Beaty TH, Zhang X, Sun L, Bian Z
Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity
Feb 24, 2017
Nature Communications
Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.
Quantifying protein (dis)order
Feb 24, 2017   Science (New York, N.Y.)
Vogel C
Quantifying protein (dis)order
Feb 24, 2017
Science (New York, N.Y.)
ABySS 2.0: Resource-efficient assembly of large genomes using a Bloom filter
Feb 24, 2017   Genome Research
Jackman SD, Vandervalk BP, Mohamadi H, Chu J, Yeo S, Hammond SA, Jahesh G, Khan H, Coombe L, Warren RL, Birol I
ABySS 2.0: Resource-efficient assembly of large genomes using a Bloom filter
Feb 24, 2017
Genome Research
The assembly of DNA sequences de novo is fundamental to genomics research. It is the first of many steps towards elucidating and characterizing whole genomes. Downstream applications, including analysis of genomic variation between species, between or within individuals critically depend on robustly assembled sequences. In the span of a single decade, the sequence throughput of leading DNA sequencing instruments has increased drastically, and coupled with established and planned large-scale, personalized medicine initiatives to sequence genomes in the thousands and even millions, the development of efficient, scalable and accurate bioinformatics tools for producing high-quality reference draft genomes is timely. With ABySS 1.0, we originally showed that assembling the human genome using short 50 bp sequencing reads was possible by aggregating the half terabyte of compute memory needed over several computers using a standardized message-passing system (MPI). We present here its re-design, which departs from MPI and instead implements algorithms that employ a Bloom filter, a probabilistic data structure, to represent a de Bruijn graph and reduce memory requirements. We benchmarked ABySS 2.0 human genome assembly using a Genome in a Bottle dataset of 250 bp Illumina paired-end and 6 kbp mate-pair libraries from a single individual. Our assembly yielded a NG50 (NGA50) scaffold contiguity of 3.5 (3.0) Mbp using less than 35 GB of RAM. This is a modest memory requirement by today's standards, and is often available on a single computer. We also investigate the use of BioNano Genomics and 10x Genomics' Chromium data to further improve the scaffold NG50 (NGA50) of this assembly to 42 (15) Mbp.Published by Cold Spring Harbor Laboratory Press.
Comparative Genomics Integrated with Association Analysis Identifies Candidate Effector Genes Corresponding to
Feb 24, 2017   Frontiers In Plant Science
Wu JQ, Sakthikumar S, Dong C, Zhang P, Cuomo CA, Park RF
Comparative Genomics Integrated with Association Analysis Identifies Candidate Effector Genes Corresponding to
Feb 24, 2017
Frontiers In Plant Science
Leaf rust is one of the most common and damaging diseases of wheat, and is caused by an obligate biotrophic basidiomycete,
Integration of EGA secure data access into Galaxy
Feb 24, 2017   F1000Research
Hoogstrate Y, Zhang C, Senf A, Bijlard J, Hiltemann S,   . . . . . .   , A Meijer G, Stubbs A, Rambla J, Spalding D, Abeln S
Integration of EGA secure data access into Galaxy
Feb 24, 2017
F1000Research
High-throughput molecular profiling techniques are routinely generating vast amounts of data for translational medicine studies. Secure access controlled systems are needed to manage, store, transfer and distribute these data due to its personally identifiable nature. The European Genome-phenome Archive (EGA) was created to facilitate access and management to long-term archival of bio-molecular data. Each data provider is responsible for ensuring a Data Access Committee is in place to grant access to data stored in the EGA. Moreover, the transfer of data during upload and download is encrypted. ELIXIR, a European research infrastructure for life-science data, initiated a project (2016 Human Data Implementation Study) to understand and document the ELIXIR requirements for secure management of controlled-access data. As part of this project, a full ecosystem was designed to connect archived raw experimental molecular profiling data with interpreted data and the computational workflows, using the CTMM Translational Research IT (CTMM-TraIT) infrastructure http://www.ctmm-trait.nl as an example. Here we present the first outcomes of this project, a framework to enable the download of EGA data to a Galaxy server in a secure way. Galaxy provides an intuitive user interface for molecular biologists and bioinformaticians to run and design data analysis workflows. More specifically, we developed a tool -- ega_download_streamer - that can download data securely from EGA into a Galaxy server, which can subsequently be further processed. This tool will allow a user within the browser to run an entire analysis containing sensitive data from EGA, and to make this analysis available for other researchers in a reproducible manner, as shown with a proof of concept study.  The tool ega_download_streamer is available in the Galaxy tool shed: https://toolshed.g2.bx.psu.edu/view/yhoogstrate/ega_download_streamer.
Responses of the microalga Chlorophyta sp. to bacterial quorum sensing molecules (N-acylhomoserine lactones): aromatic protein-induced self-aggregation
Feb 24, 2017   Environmental Science & Technology
Zhou D, Zhang C, Fu L, Xu L, Cui X, Li Q, Crittenden JC
Responses of the microalga Chlorophyta sp. to bacterial quorum sensing molecules (N-acylhomoserine lactones): aromatic protein-induced self-aggregation
Feb 24, 2017
Environmental Science & Technology
Bacteria and microalgae often coexist during the recycling of microalgal bioresources in wastewater treatment processes. Although the bacteria may compete with the microalgae for nutrients, they could also facilitate microalgal harvesting by forming algal-bacterial aggregates. However, very little is known about inter-species interactions between bacteria and microalgae. In this study, we investigated the responses of a model microalga, Chlorophyta sp., to the typical quorum sensing (QS) molecules N-acylhomoserine lactones (AHLs) extracted from activated sludge bacteria. Chlorophyta sp. self-aggregated in 200 μm bio-flocs by secreting 460-1000 kDa aromatic proteins upon interacting with AHLs, and the settling efficiency of Chlorophyta sp. reached as high as 41%. However, Chlorophyta sp. cells were essentially in a free suspension in the absence of AHLs. Fluorescence intensity of the aromatic proteins had significant (P
Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy
Feb 24, 2017   Scientific Reports
Wobst HJ, Denk F, Oliver PL, Livieratos A, Taylor TN, Knudsen MH, Bengoa-Vergniory N, Bannerman D, Wade-Martins R
Increased 4R tau expression and behavioural changes in a novel MAPT-N296H genomic mouse model of tauopathy
Feb 24, 2017
Scientific Reports
The microtubule-associated protein tau is implicated in various neurodegenerative diseases including Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, which are characterized by intracellular accumulation of hyperphosphorylated tau. Mutations in the tau gene MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). In the human central nervous system, six tau isoforms are expressed, and imbalances in tau isoform ratios are associated with pathology. To date, few animal models of tauopathy allow for the potential influence of these protein isoforms, relying instead on cDNA-based transgene expression. Using the P1-derived artificial chromosome (PAC) technology, we created mouse lines expressing all six tau isoforms from the human MAPT locus, harbouring either the wild-type sequence or the disease-associated N296H mutation on an endogenous Mapt-/- background. Animals expressing N296H mutant tau recapitulated early key features of tauopathic disease, including a tau isoform imbalance and tau hyperphosphorylation in the absence of somatodendritic tau inclusions. Furthermore, N296H animals displayed behavioural anomalies such as hyperactivity, increased time in the open arms of the elevated plus maze and increased immobility during the tail suspension test. The mouse models described provide an excellent model to study the function of wild-type or mutant tau in a highly physiological setting.
De novo DNA methylation during monkey pre-implantation embryogenesis
Feb 24, 2017   Cell Research
Gao F, Niu Y, Sun YE, Lu H, Chen Y,   . . . . . .   , Sun N, Si W, Wang H, Ji W, Tan T
De novo DNA methylation during monkey pre-implantation embryogenesis
Feb 24, 2017
Cell Research
Critical epigenetic regulation of primate embryogenesis entails DNA methylome changes. Here we report genome-wide composition, patterning, and stage-specific dynamics of DNA methylation in pre-implantation rhesus monkey embryos as well as male and female gametes studied using an optimized tagmentation-based whole-genome bisulfite sequencing method. We show that upon fertilization, both paternal and maternal genomes undergo active DNA demethylation, and genome-wide de novo DNA methylation is also initiated in the same period. By the 8-cell stage, remethylation becomes more pronounced than demethylation, resulting in an increase in global DNA methylation. Promoters of genes associated with oxidative phosphorylation are preferentially remethylated at the 8-cell stage, suggesting that this mode of energy metabolism may not be favored. Unlike in rodents, X chromosome inactivation is not observed during monkey pre-implantation development. Our study provides the first comprehensive illustration of the 'wax and wane' phases of DNA methylation dynamics. Most importantly, our DNA methyltransferase loss-of-function analysis indicates that DNA methylation influences early monkey embryogenesis.Cell Research advance online publication 24 February 2017; doi:10.1038/cr.2017.25.
Scaffolding bacterial genomes and probing host-virus interactions in gut microbiome by proximity ligation (chromosome capture) assay
Feb 24, 2017   Science Advances
Marbouty M, Baudry L, Cournac A, Koszul R
Scaffolding bacterial genomes and probing host-virus interactions in gut microbiome by proximity ligation (chromosome capture) assay
Feb 24, 2017
Science Advances
The biochemical activities of microbial communities, or microbiomes, are essential parts of environmental and animal ecosystems. The dynamics, balance, and effects of these communities are strongly influenced by phages present in the population. Being able to characterize bacterium-phage relationships is therefore essential to investigate these ecosystems to the full extent of their complexity. However, this task is currently limited by (i) the ability to characterize complete bacterial and viral genomes from a complex mix of species and (ii) the difficulty to assign phage sequences to their bacterial hosts. We show that both limitations can be circumvented using meta3C, an experimental and computational approach that exploits the physical contacts between DNA molecules to infer their proximity. In a single experiment, dozens of bacterial and phage genomes present in a complex mouse gut microbiota were assembled and scaffolded de novo. The phage genomes were then assigned to their putative bacterial hosts according to the physical contacts between the different DNA molecules, opening new perspectives for a comprehensive picture of the genomic structure of the gut flora. Therefore, this work holds far-reaching implications for human health studies aiming to bridge the virome to the microbiome.
Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis
Feb 24, 2017   Antimicrobial Agents And Chemotherapy
Nigo M, Diaz L, Carvajal LP, Tran TT, Rios R, Panesso D, Garavito JD, Miller WR, Wanger A, Weinstock G, Munita JM, Arias CA, Chambers HF
Ceftaroline-Resistant, Daptomycin-Tolerant, and Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus Causing Infective Endocarditis
Feb 24, 2017
Antimicrobial Agents And Chemotherapy
We report a case of infective endocarditis (IE) caused by ceftaroline-resistant, daptomycin-tolerant, and heterogeneous vancomycin-intermediate methicillin-resistant Copyright © 2017 American Society for Microbiology.
Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy
Feb 24, 2017   Free Radical Biology & Medicine
Kudin AP, Baron G, Zsurka G, Hampel KG, Elger CE,   . . . . . .   , Schomburg L, Seeher S, Fradejas-Villar N, Schweizer U, Kunz WS
Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy
Feb 24, 2017
Free Radical Biology & Medicine
Increased oxidative stress has been widely implicated in the pathogenesis in various forms of human epilepsy. Here, we report a homozygous mutation in TXNRD1 (thioredoxin reductase 1) in a family with genetic generalized epilepsy. TXNRD1 is an essential selenium-containing enzyme involved in detoxification of reactive oxygen species (ROS) and redox signaling. The TXNRD1 mutation p.Pro190Leu affecting a highly conserved amino acid residue was identified by whole-exome sequencing of blood DNA from the index patient. The detected mutation and its segregation within the family - all siblings of the index patient were homozygous and the parents heterozygous - were confirmed by Sanger sequencing. TXNRD1 activity was determined in subcellular fractions from a skeletal muscle biopsy and skin fibroblasts of the index patient and the expression levels of the mutated protein were assessed by Copyright © 2017. Published by Elsevier Inc.
Using hiCLIP to identify RNA duplexes that interact with a specific RNA-binding protein
Feb 23, 2017   Nature Protocols Add nature.com free-link Cancel
Sugimoto Y, Chakrabarti AM, Luscombe NM, Ule J
Using hiCLIP to identify RNA duplexes that interact with a specific RNA-binding protein
Feb 23, 2017
Nature Protocols
The structure of RNA molecules has a critical role in regulating gene expression, largely through influencing their interactions with RNA-binding proteins (RBPs). RNA hybrid and individual-nucleotide resolution UV cross-linking and immunoprecipitation (hiCLIP) is a transcriptome-wide method of monitoring these interactions by identifying RNA duplexes bound by a specific RBP. The hiCLIP protocol consists of the following steps: in vivo cross-linking of RBPs to their bound RNAs; partial RNA digestion and purification of RNA duplexes interacting with the specific RBP using immunoprecipitation; ligation of the two arms of RNA duplexes via a linker; reverse transcription; cDNA library amplification; and finally high-throughput DNA sequencing. Mapping of the sequenced arms to a reference transcriptome identifies the exact locations of duplexes. hiCLIP data can directly identify all types of RNA duplexes bound by RBPs, including those that are challenging to predict computationally, such as intermolecular and long-range intramolecular duplexes. Moreover, the use of an adaptor that links the two arms of the RNA duplex permits hiCLIP to unambiguously identify the duplexes. Here we describe in detail the procedure for a hiCLIP experiment and the subsequent streamlined data analysis with an R package, 'hiclipr' (https://github.com/luslab/hiclipr/). Preparation of the library for high-throughput DNA sequencing takes ∼7 d and the basic bioinformatic pipeline takes 1 d.
Time-Specific Effects of Spindle Positioning on Embryonic Progenitor Pool Composition and Adult Neural Stem Cell Seeding
Feb 23, 2017   Neuron
Falk S, Bugeon S, Ninkovic J, Pilz GA, Postiglione MP, Cremer H, Knoblich JA, Götz M
Time-Specific Effects of Spindle Positioning on Embryonic Progenitor Pool Composition and Adult Neural Stem Cell Seeding
Feb 23, 2017
Neuron
The developmental mechanisms regulating the number of adult neural stem cells (aNSCs) are largely unknown. Here we show that the cleavage plane orientation in murine embryonic radial glia cells (RGCs) regulates the number of aNSCs in the lateral ganglionic eminence (LGE). Randomizing spindle orientation in RGCs by overexpression of Insc or a dominant-negative form of Lgn (dnLgn) reduces the frequency of self-renewing asymmetric divisions while favoring symmetric divisions generating two SNPs. Importantly, these changes during embryonic development result in reduced seeding of aNSCs. Interestingly, no effects on aNSC numbers were observed when Insc was overexpressed in postnatal RGCs or aNSCs. These data suggest a new mechanism for controlling aNSC numbers and show that the role of spindle orientation during brain development is highly time and region dependent.Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
Comparative Transcriptome Analysis of Penicillium citrinum Cultured with Different Carbon Sources Identifies Genes Involved in Citrinin Biosynthesis
Feb 23, 2017   Toxins
Li T, Jiang G, Qu H, Wang Y, Xiong Y, Jian Q, Wu Y, Duan X, Zhu X, Hu W, Wang J, Gong L, Jiang Y
A novel physiological role for cardiac myoglobin in lipid metabolism
Feb 23, 2017   Scientific Reports
Hendgen-Cotta UB, Esfeld S, Coman C, Ahrends R, Klein-Hitpass L, Flögel U, Rassaf T, Totzeck M
A novel physiological role for cardiac myoglobin in lipid metabolism
Feb 23, 2017
Scientific Reports
Continuous contractile activity of the heart is essential and the required energy is mostly provided by fatty acid (FA) oxidation. Myocardial lipid accumulation can lead to pathological responses, however the underlying mechanisms remain elusive. The role of myoglobin in dioxygen binding in cardiomyocytes and oxidative skeletal muscle has widely been appreciated. Our recent work established myoglobin as a protector of cardiac function in hypoxia and disease states. We here unravel a novel role of cardiac myoglobin in governing FA metabolism to ensure the physiological energy production through β-oxidation, preventing myocardial lipid accumulation and preserving cardiac functions. In vivo
Pentose sugars inhibit metabolism and increase expression of an AgrD-type cyclic pentapeptide in Clostridium thermocellum
Feb 23, 2017   Scientific Reports
Verbeke TJ, Giannone RJ, Klingeman DM, Engle NL, Rydzak T, Guss AM, Tschaplinski TJ, Brown SD, Hettich RL, Elkins JG
Pentose sugars inhibit metabolism and increase expression of an AgrD-type cyclic pentapeptide in Clostridium thermocellum
Feb 23, 2017
Scientific Reports
Clostridium thermocellum could potentially be used as a microbial biocatalyst to produce renewable fuels directly from lignocellulosic biomass due to its ability to rapidly solubilize plant cell walls. While the organism readily ferments sugars derived from cellulose, pentose sugars from xylan are not metabolized. Here, we show that non-fermentable pentoses inhibit growth and end-product formation during fermentation of cellulose-derived sugars. Metabolomic experiments confirmed that xylose is transported intracellularly and reduced to the dead-end metabolite xylitol. Comparative RNA-seq analysis of xylose-inhibited cultures revealed several up-regulated genes potentially involved in pentose transport and metabolism, which were targeted for disruption. Deletion of the ATP-dependent transporter, CbpD partially alleviated xylose inhibition. A putative xylitol dehydrogenase, encoded by Clo1313_0076, was also deleted resulting in decreased total xylitol production and yield by 41% and 46%, respectively. Finally, xylose-induced inhibition corresponds with the up-regulation and biogenesis of a cyclical AgrD-type, pentapeptide. Medium supplementation with the mature cyclical pentapeptide also inhibits bacterial growth. Together, these findings provide new foundational insights needed for engineering improved pentose utilizing strains of C. thermocellum and reveal the first functional Agr-type cyclic peptide to be produced by a thermophilic member of the Firmicutes.
Transposable Element Bm1645 is a Source of BmAGO2-associated Small RNAs that affect its expression in Bombyx mori
Feb 24, 2017   BMC Genomics
Si H, Cao Y, Zhu H, Li D, Lv Z, Sheng Q, Nie Z
Transposable Element Bm1645 is a Source of BmAGO2-associated Small RNAs that affect its expression in Bombyx mori
Feb 24, 2017
BMC Genomics
BACKGROUND: A transposable element (TE) is a DNA fragment that can change its position within a genome. Transposable elements play important roles in maintaining the stability and diversity of organisms by transposition. Recent studies have shown that approximately half of the genes in Bombyx mori are TEs. RESULTS: We systematically identified and analyzed the BmAGO2-associated TEs, which exceed 100 in the B. mori genome. Additionally, we also mapped the small RNAs associated with BmAGO2 in B.mori. The transposon Bm1645 is the most abundant TE associated with BmAGO2, and Bm1645-derived small RNAs represent a small RNA pool. We determined the expression patterns of several Bm1645-derived small RNAs by northern blotting, and the results showed there was differential expression of multiple small RNAs in normal and BmNPV-infected BmN cells and silkworms from various developmental stages. We confirmed that four TE-siRNAs could bind to BmAGO2 using EMSA and also validated the recognition sites of these four TE-siRNAs in Bm1645 by dual-luciferase reporter assays. Furthermore, qRT-PCR analysis revealed the overexpression of the four TE-siRNAs could downregulate the expression of Bm1645 in BmN cells, and the transcription of Bm1645 was upregulated by the downregulation of BmAGO2. CONCLUSIONS: Our results suggest Bm1645 functions as a source of small RNAs pool and this pool can produce many BmAGO2-associated small RNAs that regulate TE's expression.
KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome
Feb 24, 2017   Molecular Cancer
Ma G, Liu H, Hua Q, Wang M, Du M, Lin Y, Ge Y, Gong W, Zhao Q, Qiang F, Tao G, Zhang Z, Chu H
KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome
Feb 24, 2017
Molecular Cancer
BACKGROUND: Inactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. It is necessary to uncover the detailed pattern of whole genome-wide abnormal DNA methylation during the development of gastric cancer (GC). METHOD: We performed a genome-wide methylation detection using 12 paired of GC tissues and their corresponding normal tissues. Methylation-specific PCR (MSP) and bisulphite sequencing (BSP) were used to measure methylation status of specific CpG site. Based on the bioinformatic analysis, the cell phenotypes and mouse model experiments were constructed to detect effect of the target gene. Using the Kaplan-Meier survival curve, the clinical value of KCNMA1 was assessed in GC patients. RESULTS: The CpG site cg24113782 located at the promoter of KCNMA1 showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation of KCNMA1 was detected in 68.7% (77/112) of tumor tissues, compared with 16.2% (18/112) of normal tissues (P 
Improving data availability for brain image biobanking in healthy subjects: practice-based suggestions from an international multidisciplinary working group
Feb 24, 2017   NeuroImage
BRAINS (Brain Imaging in Normal Subjects) Expert Working Group, Shenkin SD, Pernet C, Nichols TE, Poline JB,   . . . . . .   , Anblagan D, Job DE, Alexander Dickie D, Rodriguez D, Wardlaw JM
Improving data availability for brain image biobanking in healthy subjects: practice-based suggestions from an international multidisciplinary working group
Feb 24, 2017
NeuroImage
Brain imaging is now ubiquitous in clinical practice and research. The case for bringing together large amounts of image data from well-characterised healthy subjects and those with a range of common brain diseases across the life course is now compelling. This report follows a meeting of international experts from multiple disciplines, all interested in brain image biobanking. The meeting included neuroimaging experts (clinical and non-clinical), computer scientists, epidemiologists, clinicians, ethicists, and lawyers involved in creating brain image banks. The meeting followed a structured format to discuss current and emerging brain image banks; applications such as atlases; conceptual and statistical problems (e.g. defining 'normality'); legal, ethical and technological issues (e.g. consents, potential for data linkage, data security, harmonisation, data storage and enabling of research data sharing). We summarise the lessons learned from the experiences of a wide range of individual image banks, and provide practical recommendations to enhance creation, use and reuse of neuroimaging data. Our aim is to maximise the benefit of the image data, provided voluntarily by research participants and funded by many organisations, for human health. Our ultimate vision is of a federated network of brain image biobanks accessible for large studies of brain structure and function.Copyright © 2017. Published by Elsevier Inc.
Rapid protein alignment in the cloud: HAMOND combines fast DIAMOND alignments with Hadoop parallelism
Feb 24, 2017   Journal Of Biotechnology
Yu J, Blom J, Sczyrba A, Goesmann A
Rapid protein alignment in the cloud: HAMOND combines fast DIAMOND alignments with Hadoop parallelism
Feb 24, 2017
Journal Of Biotechnology
The introduction of next generation sequencing has caused a steady increase in the amounts of data that have to be processed in modern life science. Sequence alignment plays a key role in the analysis of sequencing data e.g. within whole genome sequencing or metagenome projects. BLAST is a commonly used alignment tool that was the standard approach for more than two decades, but in the last years faster alternatives have been proposed including RapSearch, GHOSTX, and DIAMOND. Here we introduce HAMOND, an application that uses Apache Hadoop to parallelize DIAMOND computation in order to scale-out the calculation of alignments. HAMOND is fault tolerant and scalable by utilizing large cloud computing infrastructures like Amazon Web Services. HAMOND has been tested in comparative genomics analyses and showed promising results both in efficiency and accuracy.Copyright © 2017. Published by Elsevier B.V.
Improvement of succinate production by release of end-product inhibition in Corynebacterium glutamicum
Feb 24, 2017   Metabolic Engineering
Chung SC, Park JS, Yun J, Park JH
Improvement of succinate production by release of end-product inhibition in Corynebacterium glutamicum
Feb 24, 2017
Metabolic Engineering
Succinate is a renewable-based platform chemical that may be used to produce a wide range of chemicals including 1,4-butanediol, tetrahydrofurane, and γ-butyrolactone. However, industrial fermentation of organic acids is often subject to end-product inhibition, which significantly retards cell growth and limits metabolic activities and final productivity. In this study, we report the development of metabolically engineered Corynebacterium glutamicum for high production of succinate by release of end-product inhibition coupled with an increase of key metabolic flux. It was found that the rates of glucose consumption and succinate production were significantly reduced by extracellular succinate in an engineered strain, S003. To understand the mechanism underlying the inhibition by succinate, comparative transcriptome analysis was performed. Among the downregulated genes, overexpression of the NCgl0275 gene was found to suppress the inhibition of glucose consumption and succinate production, resulting in a 37.7% increase in succinate production up to 55.4g/L in fed-batch fermentation. Further improvement was achieved by increasing the metabolic flux from PEP to OAA. The final engineered strain was able to produce 152.2g/L succinate, the highest production reported to date, with a yield of 1.1g/g glucose under anaerobic condition. These results suggest that the release of end-product inhibition coupled with an increase in key metabolic flux is a promising strategy for enhancing production of succinate.Copyright © 2017. Published by Elsevier Inc.
Genomic analysis of 63,220 tumors reveals insights into tumor uniqueness and targeted cancer immunotherapy strategies
Feb 24, 2017   Genome Medicine
Hartmaier RJ, Charo J, Fabrizio D, Goldberg ME, Albacker LA, Pao W, Chmielecki J
Genomic analysis of 63,220 tumors reveals insights into tumor uniqueness and targeted cancer immunotherapy strategies
Feb 24, 2017
Genome Medicine
BACKGROUND: The integration of genomics with immunotherapy has potential value for cancer vaccine development. Given the clinical successes of immune checkpoint modulators, interest in cancer vaccines as therapeutic options has been revived. Current data suggest that each tumor contains a unique set of mutations (mutanome), thus requiring the creation of individualized cancer vaccines. However, rigorous analysis of non-individualized cancer immunotherapy approaches across multiple cancer types and in the context of known driver alterations has yet to be reported. We therefore set out to determine the feasibility of a generalizable cancer vaccine strategy based on targeting multiple neoantigens in an HLA-A/B subtype-directed manner. METHODS: A cancer gene-focused, hybrid capture-based genomic analysis was performed on 63,220 unique tumors. Neoantigens were predicted using a combined peptide processing and MHC-I binding prediction tool (IEDB) for all recurrent (>10 tumors) missense alterations and non-frameshift indels for the two most common HLA-A/B subtypes in North American/European populations. RESULTS: Despite being overwhelmingly unique overall, many mutanomes (~45%) contain at least one mutation from a set of ten mutations chosen to maximize the number of unique tumors. This held true for tumors driven by KRAS G12C (n = 1799), PIK3CA E545K (n = 1713), or EGFR L858R (n = 478) alterations, which define distinct sample subsets. We therefore hypothesized that sets of carefully selected mutations/neoantigens may allow the development of broadly applicable semi-universal cancer vaccines. To test the feasibility of such an approach, antigen processing and MHC-I binding prediction was applied for HLA subtypes A*01:01/B*08:01 and A*02:01/B*44:02. In tumors with a specific HLA type, 0.7 and 2.5% harbored at least one of a set of ten neoantigens predicted to bind to each subtype, respectively. In comparison, KRAS G12C-driven tumors produced similar results (0.8 and 2.6% for each HLA subtype, respectively), indicating that neoantigen targets still remain highly diverse even within the context of major driver mutations. CONCLUSIONS: This "best case scenario" analysis of a large tumor set across multiple cancer types and in the context of driver alterations reveals that semi-universal, HLA-specific cancer vaccine strategies will be relevant to only a small subset of the general population. Similar analysis of whole exome/genome sequencing, although not currently feasible at scale in a clinical setting, will likely uncover further diversity.
Unravelling the metabolic impact of SBS-associated microbial dysbiosis: Insights from the piglet short bowel syndrome model
Feb 23, 2017   Scientific Reports
Pereira-Fantini PM, Byars SG, Pitt J, Lapthorne S, Fouhy F, Cotter PD, Bines JE
Unravelling the metabolic impact of SBS-associated microbial dysbiosis: Insights from the piglet short bowel syndrome model
Feb 23, 2017
Scientific Reports
Liver disease is a major source of morbidity and mortality in children with short bowel syndrome (SBS). SBS-associated microbial dysbiosis has recently been implicated in the development of SBS-associated liver disease (SBS-ALD), however the pathological implications of this association have not been explored. In this study high-throughput sequencing of colonic content from the well-validated piglet SBS-ALD model was examined to determine alterations in microbial communities, and concurrent metabolic alterations identified in urine samples via targeted mass spectrometry approaches (GC-MS, LC-MS, FIA-MS) further uncovered impacts of microbial disturbance on metabolic outcomes in SBS-ALD. Multi-variate analyses were performed to elucidate contributing SBS-ALD microbe and metabolite panels and to identify microbe-metabolite interactions. A unique SBS-ALD microbe panel was clearest at the genus level, with discriminating bacteria predominantly from the Firmicutes and Bacteroidetes phyla. The SBS-ALD metabolome included important alterations in the microbial metabolism of amino acids and the mitochondrial metabolism of branched chain amino acids. Correlation analysis defined microbe-metabolite clustering patterns unique to SBS-ALD and identified a metabolite panel that correlates with dysbiosis of the gut microbiome in SBS.

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