Fiziev, Petko; Akdemir, Kadir C; Miller, John P; Keung, Emily Z; Samant, Neha S; Sharma, Sneha; Natale, Christopher A; Terranova, Christopher J; Maitituoheti, Mayinuer; Amin, Samirkumar B; Martinez-Ledesma, Emmanuel; Dhamdhere, Mayura; Axelrad, Jacob B; Shah, Amiksha; Cheng, Christine S; Mahadeshwar, Harshad; Seth, Sahil; Barton, Michelle C; Protopopov, Alexei; Tsai, Kenneth Y; Davies, Michael A; Garcia, Benjamin A; Amit, Ido; Chin, Lynda; Ernst, Jason; Rai, Kunal
The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Tuikue Ndam, Nicaise; Bischoff, Emmanuel; Proux, Caroline
BACKGROUND: Pregnancy-associated malaria (PAM) causing maternal anemia and low birth weight is among the multiple manifestations of Plasmodium falciparum malaria. Infected erythrocytes (iEs) can acquire various adhesive properties that mediate the clinical severity of malaria. Recent advances...
Macé, Aurélien; Tuke, Marcus A; Deelen, Patrick
There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations ...
Tan, Shangjin; Zhou, Jin; Zhu, Xiaoshan; Yu, Shichen; Zhan, Wugen; Wang, Bo; Cai, Zhonghua
Algal blooms are a worldwide phenomenon and the biological interactions that underlie their regulation are only just beginning to be understood. It is established that algal microorganisms associate with many other ubiquitous, oceanic organisms, but the interactions that lead to the dynamics of bloom formation are currently unknown. To address this gap, we used network approaches to investigate the association patterns among microeukaryotes and bacterioplankton in response to a natural Scrippsiella trochoidea bloom. This is the first study to apply network approaches to bloom dynamics. To this end, terminal restriction fragment (T-RF) length polymorphism analysis showed dramatic changes in community compositions of microeukaryotes and bacterioplankton over the blooming period. A variance ratio test revealed significant positive overall associations both within and between microeukaryotic and bacterioplankton communities. An association network generated from significant correlations between T-RFs revealed that S. trochoidea had few connections to other microeukaryotes and bacterioplankton and was placed on the edge. This lack of connectivity allowed for the S. trochoidea sub-network to break off from the overall network. These results allowed us to propose a conceptual model for explaining how changes in microbial associations regulate the dynamics of an algal bloom. In addition, key T-RFs were screened by principal components analysis, correlation coefficients, and network analysis. Dominant T-RFs were then identified through 18S and 16S rRNA gene clone libraries. Results showed that microeukaryotes clustered predominantly with Dinophyceae and Perkinsea while the majority of bacterioplankton identified were Alphaproteobacteria, Gammaproteobacteria, and Bacteroidetes. The ecologi-cal roles of both were discussed in the context of these findings. © 2014 Phycological Society of America.
Tambor, V; Kacerovsky, M; Lenco, J; Bhat, G; Menon, R
The presence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) is associated with adverse neonatal outcomes in pregnancies complicated by preterm prelabor rupture of membranes (pPROM). Therefore, there is an urgent need to identify new biomarkers revealing these conditions. The objective of this study is to identify possible biomarkers and their underlying biofunctions in pPROM pregnancies with and without MIAC and HCA. A total of 72 women with pPROM were recruited. Only women with both MIAC and HCA (n = 19) and all women without these complications (n = 19) having the same range of gestational ages at sampling were included in the study. Samples of amniotic fluid were obtained by transabdominal amniocentesis, processed and analyzed using quantitative shotgun proteomics. Ingenuity pathway analysis was used to identify molecular networks that involve altered proteins. Network interaction identified by ingenuity pathway analysis revealed immunological disease and the inflammatory response as the top functions and disease associated with pPROM in the presence of MIAC and HCA. The proteins involved in these pathways were significantly altered between the groups with and without the presence of both MIAC and HCA. Proteins involved included histones H3, H4, H2B, cathelicidin antimicrobial peptide, myeloperoxidase, neutrophil gelatinase-associated lipocalin, matrix metalloproteinase-9, peptidoglycan recognition protein-1 and neutrophil defensin 1, all of which were found to be up-regulated in the presence of MIAC and HCA. Bioinformatic analysis of proteomics data allowed us to project likely biomolecular pathology resulting in pPROM complicated by MIAC and HCA. As inflammation is not a homogeneous phenomenon, we provide evidence for oxidative-stress-associated DNA damage and biomarkers of reactive oxygen species generation as factors associated with inflammation and proteolysis. Copyright © 2012 Elsevier Ltd. All rights reserved.
Xie, Jianbo; Tian, Jiaxing; Du, Qingzhang; Chen, Jinhui; Li, Ying; Yang, Xiaohui; Li, Bailian; Zhang, Deqiang
Gibberellins (GAs) regulate a wide range of important processes in plant growth and development, including photosynthesis. However, the mechanism by which GAs regulate photosynthesis remains to be understood. Here, we used multi-gene association to investigate the effect of genes in the GA-responsive pathway, as constructed by RNA sequencing, on photosynthesis, growth, and wood property traits, in a population of 435 Populus tomentosa By analyzing changes in the transcriptome following GA treatment, we identified many key photosynthetic genes, in agreement with the observed increase in measurements of photosynthesis. Regulatory motif enrichment analysis revealed that 37 differentially expressed genes related to photosynthesis shared two essential GA-related cis-regulatory elements, the GA response element and the pyrimidine box. Thus, we constructed a GA-responsive pathway consisting of 47 genes involved in regulating photosynthesis, including GID1, RGA, GID2, MYBGa, and 37 photosynthetic differentially expressed genes. Single nucleotide polymorphism (SNP)-based association analysis showed that 142 SNPs, representing 40 candidate genes in this pathway, were significantly associated with photosynthesis, growth, and wood property traits. Epistasis analysis uncovered interactions between 310 SNP-SNP pairs from 37 genes in this pathway, revealing possible genetic interactions. Moreover, a structural gene-gene matrix based on a time-course of transcript abundances provided a better understanding of the multi-gene pathway affecting photosynthesis. The results imply a functional role for these genes in mediating photosynthesis, growth, and wood properties, demonstrating the potential of combining transcriptome-based regulatory pathway construction and genetic association approaches to detect the complex genetic networks underlying quantitative traits. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights
Lanktree, Matthew B.; Guo, Yiran; Murtaza, Muhammed; Glessner, Joseph T.; Bailey, Swneke D.; Onland-Moret, N. Charlotte; Lettre, Guillaume; Ongen, Halit; Rajagopalan, Ramakrishnan; Johnson, Toby; Shen, Haiqing; Nelson, Christopher P.; Klopp, Norman; Baumert, Jens; Padmanabhan, Sandosh; Pankratz, Nathan; Pankow, James S.; Shah, Sonia; Taylor, Kira; Barnard, John; Peters, Bas J.; Maloney, Cliona M.; Lobmeyer, Maximilian T.; Stanton, Alice; Zafarmand, M. Hadi; Romaine, Simon P. R.; Mehta, Amar; van Iperen, Erik P. A.; Gong, Yan; Price, Tom S.; Smith, Erin N.; Kim, Cecilia E.; Li, Yun R.; Asselbergs, Folkert W.; Atwood, Larry D.; Bailey, Kristian M.; Bhatt, Deepak; Bauer, Florianne; Behr, Elijah R.; Bhangale, Tushar; Boer, Jolanda M. A.; Boehm, Bernhard O.; Bradfield, Jonathan P.; Brown, Morris; Braund, Peter S.; Burton, Paul R.; Carty, Cara; Chandrupatla, Hareesh R.; Chen, Wei; Connell, John; Dalgeorgou, Chrysoula; de Boer, Anthonius; Drenos, Fotios; Elbers, Clara C.; Fang, James C.; Fox, Caroline S.; Frackelton, Edward C.; Fuchs, Barry; Furlong, Clement E.; Gibson, Quince; Gieger, Christian; Goel, Anuj; Grobbee, Diederik E.; Hastie, Claire; Howard, Philip J.; Huang, Guan-Hua; Johnson, W. Craig; Li, Qing; Kleber, Marcus E.; Klein, Barbara E. K.; Klein, Ronald; Kooperberg, Charles; Ky, Bonnie; LaCroix, Andrea; Lanken, Paul; Lathrop, Mark; Li, Mingyao; Marshall, Vanessa; Melander, Olle; Mentch, Frank D.; Meyer, Nuala J.; Monda, Keri L.; Montpetit, Alexandre; Murugesan, Gurunathan; Nakayama, Karen; Nondahl, Dave; Onipinla, Abiodun; Rafelt, Suzanne; Newhouse, Stephen J.; Otieno, F. George; Patel, Sanjey R.; Putt, Mary E.; Rodriguez, Santiago; Safa, Radwan N.; Sawyer, Douglas B.; Schreiner, Pamela J.; Simpson, Claire; Sivapalaratnam, Suthesh; Srinivasan, Sathanur R.; Suver, Christine; Swergold, Gary; Sweitzer, Nancy K.; Thomas, Kelly A.; Thorand, Barbara; Timpson, Nicholas J.; Tischfield, Sam; Tobin, Martin; Tomaszewski, Maciej; Tomaszweski, Maciej; Verschuren, W. M. Monique; Wallace, Chris; Winkelmann, Bernhard; Zhang, Haitao; Zheng, Dongling; Zhang, Li; Zmuda, Joseph M.; Clarke, Robert; Balmforth, Anthony J.; Danesh, John; Day, Ian N.; Schork, Nicholas J.; de Bakker, Paul I. W.; Delles, Christian; Duggan, David; Hingorani, Aroon D.; Hirschhorn, Joel N.; Hofker, Marten H.; Humphries, Steve E.; Kivimaki, Mika; Lawlor, Debbie A.; Kottke-Marchant, Kandice; Mega, Jessica L.; Mitchell, Braxton D.; Morrow, David A.; Palmen, Jutta; Redline, Susan; Shields, Denis C.; Shuldiner, Alan R.; Sleiman, Patrick M.; Smith, George Davey; Farrall, Martin; Jamshidi, Yalda; Christiani, David C.; Casas, Juan P.; Hall, Alistair S.; Doevendans, Pieter A.; Christie, Jason D.; Berenson, Gerald S.; Murray, Sarah S.; Illig, Thomas; Dorn, Gerald W.; Cappola, Thomas P.; Boerwinkle, Eric; Sever, Peter; Rader, Daniel J.; Reilly, Muredach P.; Caulfield, Mark; Talmud, Philippa J.; Topol, Eric; Engert, James C.; Wang, Kai; Dominiczak, Anna; Hamsten, Anders; Curtis, Sean P.; Silverstein, Roy L.; Lange, Leslie A.; Sabatine, Marc S.; Trip, Mieke; Saleheen, Danish; Peden, John F.; Cruickshanks, Karen J.; März, Winfried; O'Connell, Jeffrey R.; Klungel, Olaf H.; Wijmenga, Cisca; Maitland-van der Zee, Anke Hilse; Schadt, Eric E.; Johnson, Julie A.; Jarvik, Gail P.; Papanicolaou, George J.; Grant, Struan F. A.; Munroe, Patricia B.; North, Kari E.; Samani, Nilesh J.; Koenig, Wolfgang; Gaunt, Tom R.; Anand, Sonia S.; van der Schouw, Yvonne T.; Soranzo, Nicole; FitzGerald, Garret A.; Reiner, Alex; Hegele, Robert A.; Hakonarson, Hakon; Keating, Brendan J.
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and
Full Text Available Aim: The objective of this study is to characterize differential proteomic expression among well-differentiation and poor-differentiation colorectal carcinoma tissues and normal mucous epithelium. Materials and Methods: The study is based on quantitative 2-dimensional gel electrophoresis and analyzed by PDquest. Results: Excluding redundancies due to proteolysis and posttranslational modified isoforms of over 600 protein spots, 11 proteins were revealed as regulated with statistical variance being within the 95 th confidence level and were identified by peptide mass fingerprinting in matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Progression-associated proteins belong to the functional complexes of tumorigenesis, proliferation, differentiation, metabolism, and the regulation of major histocompatibility complex processing and other functions. Partial but significant overlap was revealed with previous proteomics and transcriptomics studies in CRC. Among various differentiation stage of CRC tissues, we identified calreticulin precursor, MHC class I antigen (human leukocyte antigen A , glutathione S-transferase pi1, keratin 8, heat shock protein 27, tubulin beta chain, triosephosphate, fatty acid-binding protein, hemoglobin (deoxy mutant with val b 1 replaced by met (HBB, and zinc finger protein 312 (FEZF2. Conclusions: Their functional networks were analyzed by Ingenuity systems Ingenuity Pathways Analysis and revealed the potential roles as novel biomarkers for progression in various differentiation stages of CRC.
Xu, Jidi; Zhou, Shasha; Gong, Xiaoqing; Song, Yi; van Nocker, Steve; Ma, Fengwang; Guan, Qingmei
Cytosine methylation is an essential feature of epigenetic regulation and is involved in various biological processes. Although cytosine methylation has been analysed at the genomic scale for several plant species, there is a general lack of understanding of the dynamics of global and genic DNA methylation in plants growing in environments challenged with biotic and abiotic stresses. In this study, we mapped cytosine methylation at single-base resolution in the genome of commercial apple (Malus x domestica), and analysed changes in methylation patterns associated with water deficit in representative drought-sensitive and drought-tolerant cultivars. We found that the apple genome exhibits ~54%, ~38% and ~8.5% methylation at CG, CHG and CHH sequence contexts, respectively. We additionally documented changes in gene expression associated with water deficit in an attempt to link methylation and gene expression changes. Global methylation and transcription analysis revealed that promoter-unmethylated genes showed higher expression levels than promoter-methylated genes. Gene body methylation appears to be positively correlated with gene expression. Water deficit stress was associated with changes in methylation at a multitude of genes, including those encoding transcription factors (TFs) and transposable elements (TEs). These results present a methylome map of the apple genome and reveal widespread DNA methylation alterations in response to water deficit stress. These data will be helpful for understanding potential linkages between DNA methylation and gene expression in plants growing in natural environments and challenged with abiotic and biotic stresses. © 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.
Fejzo, Marlena Schoenberg; Myhre, Ronny; Colodro-Conde, Lucía; MacGibbon, Kimber W; Sinsheimer, Janet S; Reddy, M V Prasad Linga; Pajukanta, Päivi; Nyholt, Dale R; Wright, Margaret J; Martin, Nicholas G; Engel, Stephanie M; Medland, Sarah E; Magnus, Per; Mullin, Patrick M
Hyperemesis Gravidarum (HG), severe nausea/vomiting in pregnancy (NVP), can cause poor maternal/fetal outcomes. Genetic predisposition suggests the genetic component is essential in discovering an etiology. We performed whole-exome sequencing of 5 families followed by analysis of variants in 584 cases/431 controls. Variants in RYR2 segregated with disease in 2 families. The novel variant L3277R was not found in any case/control. The rare variant, G1886S was more common in cases (p = 0.046) and extreme cases (p = 0.023). Replication of G1886S using Norwegian/Australian data was supportive. Common variants rs790899 and rs1891246 were significantly associated with HG and weight loss. Copy-number analysis revealed a deletion in a patient. RYR2 encodes an intracellular calcium release channel involved in vomiting, cyclic-vomiting syndrome, and is a thyroid hormone target gene. Additionally, RYR2 is a downstream drug target of Inderal, used to treat HG and CVS. Thus, herein we provide genetic evidence for a pathway and therapy for HG. Copyright Â© 2016 Elsevier Ireland Ltd. All rights reserved.
Kuttappan, Vivek A; Bottje, Walter; Ramnathan, Ranjith; Hartson, Steven D; Coon, Craig N; Kong, Byung-Whi; Owens, Casey M; Vazquez-Añon, Mercedes; Hargis, Billy M
White Striping (WS) and Woody Breast (WB) are 2 conditions that adversely affect consumer acceptance as well as quality of poultry meat and meat products. Both WS and WB are characterized with degenerative myopathic changes. Previous studies showed that WS and WB in broiler fillets could result in higher ultimate pH, increased drip loss, and decreased marinade uptake. The main objective of the present study was to compare the proteomic profiles of muscle tissue (n = 5 per group) with either NORM (no or few minor myopathic lesions) or SEV (with severe myopathic changes). Proteins were extracted from these samples and analyzed using a hybrid LTQ-OrbitrapXL mass spectrometer (LC-MS/MS). Over 800 proteins were identified in the muscle samples, among which 141 demonstrated differential (P < 0.05) expression between NORM and SEV. The set of differentially (P < 0.05) expressed proteins was uploaded to Ingenuity Pathway Analysis® (IPA) software to determine the associated biological networks and pathways. The IPA analysis showed that eukaryotic initiation factor-2 (eIF-2) signaling, mechanistic target of rapamycin (mTOR) signaling, as well as regulation of eIF4 and p70S6K signaling were the major canonical pathways up-regulated (P < 0.05) in SEV muscle compared to NORM. The up-regulation of these pathways indicate an increase in protein synthesis which could be part of the rapid growth as well as cellular stress associated with ongoing muscle degeneration and the attempt to repair tissue damage in SEV birds. Furthermore, IPA analysis revealed that glycolysis and gluconeogenesis were the major down-regulated (P < 0.05) canonical pathways in SEV with respect to NORM muscle. Down-regulation of these pathways could be the reason for higher ultimate pH seen in SEV muscle samples indicating reduced glycolytic potential. In conclusion, comparison of proteomic profiles of NORM and SEV muscle samples showed differences in protein profile which explains some of the observed
Li, Shu-Fen; Zhang, Guo-Jun; Zhang, Xue-Jin; Yuan, Jin-Hong; Deng, Chuan-Liang; Gao, Wu-Jun
Garden asparagus (Asparagus officinalis) is a highly valuable vegetable crop of commercial and nutritional interest. It is also commonly used to investigate the mechanisms of sex determination and differentiation in plants. However, the sex expression mechanisms in asparagus remain poorly understood. De novo transcriptome sequencing via Illumina paired-end sequencing revealed more than 26 billion bases of high-quality sequence data from male and female asparagus flower buds. A total of 72,626 unigenes with an average length of 979 bp were assembled. In comparative transcriptome analysis, 4876 differentially expressed genes (DEGs) were identified in the possible sex-determining stage of female and male/supermale flower buds. Of these DEGs, 433, including 285 male/supermale-biased and 149 female-biased genes, were annotated as flower related. Of the male/supermale-biased flower-related genes, 102 were probably involved in anther development. In addition, 43 DEGs implicated in hormone response and biosynthesis putatively associated with sex expression and reproduction were discovered. Moreover, 128 transcription factor (TF)-related genes belonging to various families were found to be differentially expressed, and this finding implied the essential roles of TF in sex determination or differentiation in asparagus. Correlation analysis indicated that miRNA-DEG pairs were also implicated in asparagus sexual development. Our study identified a large number of DEGs involved in the sex expression and reproduction of asparagus, including known genes participating in plant reproduction, plant hormone signaling, TF encoding, and genes with unclear functions. We also found that miRNAs might be involved in the sex differentiation process. Our study could provide a valuable basis for further investigations on the regulatory networks of sex determination and differentiation in asparagus and facilitate further genetic and genomic studies on this dioecious species.
Arun Prabhu Dhanapal
Full Text Available Nitrogen is a primary plant nutrient that plays a major role in achieving maximum economic yield. Insufficient availability most often limits soybean [ (L. Merr.] crop growth. Symbiotic N fixation in soybean is highly sensitive to limited water availability, and breeding for reduced N fixation sensitivity to drought is considered an important objective to improve yields under drought. The objective of this study was to identify single nucleotide polymorphism (SNP markers associated with N traits. A collection of 373 diverse soybean genotypes were grown in four field environments (2 yr and two locations and characterized for N derived from atmosphere (Ndfa, N concentration ([N], and C/N ratio. The population structure of 373 soybean genotypes was assessed based on 31,145 SNPs and genome-wide association analysis using a unified mixed model identified SNPs associated with Ndfa, [N], and C/N ratio. Although the Ndfa, [N], and C/N ratio values were significantly different between the two locations in both years, results were consistent among genotypes across years and locations. While numerous SNPs were identified by association analysis for each trait in only one of the four environments, 17, 19, and 24 SNPs showed a significant association with Ndfa, [N], and C/N ratio, respectively, in at least two environments as well as with the average across all four environments. These markers represent an important resource for pyramiding favorable alleles for drought tolerance and for identifying extremes for comparative physiological studies.
Zorrilla-Vaca, Andrés; Healy, Ryan Jacob; Silva-Medina, Melissa M.
The association between cerebrovascular accidents (CVA) and weather has been described across several studies showing multiple conflicting results. In this paper, we aim to conduct a meta-analysis to further clarify this association, as well as to find the potential sources of heterogeneity. PubMed, EMBASE, and Google Scholar were searched from inception through 2015, for articles analyzing the correlation between the incidence of CVA and temperature. A pooled effect size (ES) was estimated using random effects model and expressed as absolute values. Subgroup analyses by type of CVA were also performed. Heterogeneity and influence of covariates—including geographic latitude of the study site, male percentage, average temperature, and time interval—were assessed by meta-regression analysis. Twenty-six articles underwent full data extraction and scoring. A total of 19,736 subjects with CVA from 12 different countries were included and grouped as ischemic strokes (IS; n = 14,199), intracerebral hemorrhages (ICH; n = 3798), and subarachnoid hemorrhages (SAH; n = 1739). Lower ambient temperature was significantly associated with increase in incidence of overall CVA when using unadjusted (pooled ES = 0.23, P < 0.001) and adjusted data (pooled ES = 0.03, P = 0.003). Subgroup analyses showed that lower temperature has higher impact on the incidence of ICH (pooled ES = 0.34, P < 0.001), than that of IS (pooled ES = 0.22, P < 0.001) and SAH (pooled ES = 0.11, P = 0.012). In meta-regression analysis, the geographic latitude of the study site was the most influencing factor on this association ( Z-score = 8.68). Synthesis of the existing data provides evidence supporting that a lower ambient temperature increases the incidence of CVA. Further population-based studies conducted at negative latitudes are needed to clarify the influence of this factor.
Huang, Yong-Zhen; Zhan, Zhao-Yang; Li, Xin-Yi; Wu, Sheng-Ru; Sun, Yu-Jia; Xue, Jing; Lan, Xian-Yong; Lei, Chu-Zhao; Zhang, Chun-Lei; Jia, Yu-Tang; Chen, Hong
Insulin-like growth factor 2 (IGF2) is a potent cell growth and differentiation factor and is implicated in mammals' growth and development. The objective of this study was to evaluate the effects of the mutations in the bovine IGF2 with growth traits in Chinese Qinchuan cattle. Four single nucleotide polymorphisms (SNPs) were detected of the bovine IGF2 by DNA pool sequencing and forced polymerase chain reaction-restriction fragment length polymorphism (forced PCR-RFLP) methods. We also investigated haplotype structure and linkage disequilibrium (LD) coefficients for four SNPs in 817 individuals representing two main cattle breeds from China. The result of haplotype analysis showed eight different haplotypes and 27 combined genotypes within the study population. The statistical analyses indicated that the four SNPs, combined genotypes and haplotypes are associated with the withers height, body length, chest breadth, chest depth and body weight in Qinchuan cattle population (P growth traits; the heterozygote diplotype was associated with higher growth traits compared to wild-type homozygote. Our results provide evidence that polymorphisms in the IGF2 gene are associated with growth traits, and may be used for marker-assisted selection in beef cattle breeding program.
Soanes, Darren M.; Alam, Intikhab; Cornell, Mike; Wong, Han Min; Hedeler, Cornelia; Paton, Norman W.; Rattray, Magnus; Hubbard, Simon J.; Oliver, Stephen G.; Talbot, Nicholas J.
Fungi and oomycetes are the causal agents of many of the most serious diseases of plants. Here we report a detailed comparative analysis of the genome sequences of thirty-six species of fungi and oomycetes, including seven plant pathogenic species, that aims to explore the common genetic features associated with plant disease-causing species. The predicted translational products of each genome have been clustered into groups of potential orthologues using Markov Chain Clustering and the data integrated into the e-Fungi object-oriented data warehouse (http://www.e-fungi.org.uk/). Analysis of the species distribution of members of these clusters has identified proteins that are specific to filamentous fungal species and a group of proteins found only in plant pathogens. By comparing the gene inventories of filamentous, ascomycetous phytopathogenic and free-living species of fungi, we have identified a set of gene families that appear to have expanded during the evolution of phytopathogens and may therefore serve important roles in plant disease. We have also characterised the predicted set of secreted proteins encoded by each genome and identified a set of protein families which are significantly over-represented in the secretomes of plant pathogenic fungi, including putative effector proteins that might perturb host cell biology during plant infection. The results demonstrate the potential of comparative genome analysis for exploring the evolution of eukaryotic microbial pathogenesis. PMID:18523684
Eric K Johnson
Full Text Available Mutations affecting the expression of dystrophin result in progressive loss of skeletal muscle function and cardiomyopathy leading to early mortality. Interestingly, clinical studies revealed no correlation in disease severity or age of onset between cardiac and skeletal muscles, suggesting that dystrophin may play overlapping yet different roles in these two striated muscles. Since dystrophin serves as a structural and signaling scaffold, functional differences likely arise from tissue-specific protein interactions. To test this, we optimized a proteomics-based approach to purify, identify and compare the interactome of dystrophin between cardiac and skeletal muscles from as little as 50 mg of starting material. We found selective tissue-specific differences in the protein associations of cardiac and skeletal muscle full length dystrophin to syntrophins and dystrobrevins that couple dystrophin to signaling pathways. Importantly, we identified novel cardiac-specific interactions of dystrophin with proteins known to regulate cardiac contraction and to be involved in cardiac disease. Our approach overcomes a major challenge in the muscular dystrophy field of rapidly and consistently identifying bona fide dystrophin-interacting proteins in tissues. In addition, our findings support the existence of cardiac-specific functions of dystrophin and may guide studies into early triggers of cardiac disease in Duchenne and Becker muscular dystrophies.
Johnson, Eric K.; Zhang, Liwen; Adams, Marvin E.; Phillips, Alistair; Freitas, Michael A.; Froehner, Stanley C.; Green-Church, Kari B.; Montanaro, Federica
Mutations affecting the expression of dystrophin result in progressive loss of skeletal muscle function and cardiomyopathy leading to early mortality. Interestingly, clinical studies revealed no correlation in disease severity or age of onset between cardiac and skeletal muscles, suggesting that dystrophin may play overlapping yet different roles in these two striated muscles. Since dystrophin serves as a structural and signaling scaffold, functional differences likely arise from tissue-specific protein interactions. To test this, we optimized a proteomics-based approach to purify, identify and compare the interactome of dystrophin between cardiac and skeletal muscles from as little as 50 mg of starting material. We found selective tissue-specific differences in the protein associations of cardiac and skeletal muscle full length dystrophin to syntrophins and dystrobrevins that couple dystrophin to signaling pathways. Importantly, we identified novel cardiac-specific interactions of dystrophin with proteins known to regulate cardiac contraction and to be involved in cardiac disease. Our approach overcomes a major challenge in the muscular dystrophy field of rapidly and consistently identifying bona fide dystrophin-interacting proteins in tissues. In addition, our findings support the existence of cardiac-specific functions of dystrophin and may guide studies into early triggers of cardiac disease in Duchenne and Becker muscular dystrophies. PMID:22937058
Full Text Available Fat mass and obesity-associated protein (FTO is α-ketoglutarate-dependent dioxygenase and responsible for demethylating N6-methyladenosine (m6A in mRNA, 3-methylthymine (m3T in single-stranded DNA (ssDNA and 3-methyluracil (m3U in single-stranded RNA (ssRNA. Its other function remains unknown but thousands of mammalian DNA show 5-methyl-2'-deoxycytidine (5mdC modification and 5mdC demethylases are required for mammalian energy homeostasis and fertility. Here, we aimed to confirm whether FTO proteins can demethylate 5mdC in DNA. However, we found that FTO exhibits no potent demethylation activity against 5mdC in vitro and in vivo by using liquid chromatography-tandem mass spectrometry (LC-MS-MS. The result showed FTO demethylase has the characteristics of high substrates specificity and selectivity. In addition, we also used immunofluorescence technique to demonstrate overexpression of wild type TET2, but not FTO and mutant TET2 in Hela cells results in higher levels of 5-hydroxymethyl-2'-deoxycytidine (5hmdC generated from 5mdC. In conclusion, our results not only reveal the enzymatic activity of FTO, but also may facilitate the future discovery of proteins involved in epigenetic modification function.
Jun, Se-Ran; Wassenaar, Trudy M; Nookaew, Intawat; Hauser, Loren; Wanchai, Visanu; Land, Miriam; Timm, Collin M; Lu, Tse-Yuan S; Schadt, Christopher W; Doktycz, Mitchel J; Pelletier, Dale A; Ussery, David W
The Pseudomonas genus contains a metabolically versatile group of organisms that are known to occupy numerous ecological niches, including the rhizosphere and endosphere of many plants. Their diversity influences the phylogenetic diversity and heterogeneity of these communities. On the basis of average amino acid identity, comparative genome analysis of >1,000 Pseudomonas genomes, including 21 Pseudomonas strains isolated from the roots of native Populus deltoides (eastern cottonwood) trees resulted in consistent and robust genomic clusters with phylogenetic homogeneity. All Pseudomonas aeruginosa genomes clustered together, and these were clearly distinct from other Pseudomonas species groups on the basis of pangenome and core genome analyses. In contrast, the genomes of Pseudomonas fluorescens were organized into 20 distinct genomic clusters, representing enormous diversity and heterogeneity. Most of our 21 Populus-associated isolates formed three distinct subgroups within the major P. fluorescens group, supported by pathway profile analysis, while two isolates were more closely related to Pseudomonas chlororaphis and Pseudomonas putida. Genes specific to Populus-associated subgroups were identified. Genes specific to subgroup 1 include several sensory systems that act in two-component signal transduction, a TonB-dependent receptor, and a phosphorelay sensor. Genes specific to subgroup 2 contain hypothetical genes, and genes specific to subgroup 3 were annotated with hydrolase activity. This study justifies the need to sequence multiple isolates, especially from P. fluorescens, which displays the most genetic variation, in order to study functional capabilities from a pangenomic perspective. This information will prove useful when choosing Pseudomonas strains for use to promote growth and increase disease resistance in plants. Copyright © 2015 Jun et al.
Full Text Available In this study, 796 male Duroc pigs were used to identify genomic regions controlling growth traits. Three production traits were studied: food conversion ratio, days to 100 KG, and average daily gain, using a panel of 39,436 single nucleotide polymorphisms. In total, we detected 11 genome-wide and 162 chromosome-wide single nucleotide polymorphism trait associations. The Gene ontology analysis identified 14 candidate genes close to significant single nucleotide polymorphisms, with growth-related functions: six for days to 100 KG (WT1, FBXO3, DOCK7, PPP3CA, AGPAT9, and NKX6-1, seven for food conversion ratio (MAP2, TBX15, IVL, ARL15, CPS1, VWC2L, and VAV3, and one for average daily gain (COL27A1. Gene ontology analysis indicated that most of the candidate genes are involved in muscle, fat, bone or nervous system development, nutrient absorption, and metabolism, which are all either directly or indirectly related to growth traits in pigs. Additionally, we found four haplotype blocks composed of suggestive single nucleotide polymorphisms located in the growth trait-related quantitative trait loci and further narrowed down the ranges, the largest of which decreased by ~60 Mb. Hence, our results could be used to improve pig production traits by increasing the frequency of favorable alleles via artificial selection.
Xiao, Zhiliang; Hu, Yang; Zhang, Xiaoli; Xue, Yuqian; Fang, Zhiyuan; Yang, Limei; Zhang, Yangyong; Liu, Yumei; Li, Zhansheng; Liu, Xing; Liu, Zezhou; Lv, Honghao; Zhuang, Mu
Hybrid lethality is a deleterious phenotype that is vital to species evolution. We previously reported hybrid lethality in cabbage ( Brassica oleracea ) and performed preliminary mapping of related genes. In the present study, the fine mapping of hybrid lethal genes revealed that BoHL1 was located on chromosome C1 between BoHLTO124 and BoHLTO130, with an interval of 101 kb. BoHL2 was confirmed to be between insertion-deletion (InDels) markers HL234 and HL235 on C4, with a marker interval of 70 kb. Twenty-eight and nine annotated genes were found within the two intervals of BoHL1 and BoHL2 , respectively. We also applied RNA-Seq to analyze hybrid lethality in cabbage. In the region of BoHL1 , seven differentially expressed genes (DEGs) and five resistance (R)-related genes (two in common, i.e., Bo1g153320 and Bo1g153380 ) were found, whereas in the region of BoHL2 , two DEGs and four R-related genes (two in common, i.e., Bo4g173780 and Bo4g173810 ) were found. Along with studies in which R genes were frequently involved in hybrid lethality in other plants, these interesting R-DEGs may be good candidates associated with hybrid lethality. We also used SNP/InDel analyses and quantitative real-time PCR to confirm the results. This work provides new insight into the mechanisms of hybrid lethality in cabbage.
He, Hua; Liu, Xiao-lin; Zhang, Hui-lin; Yang, Jing; Niu, Fu-biao; Li, Zhi-xiong; Liu, Yu; Chen, Ling
The cysteine and glycine-rich protein 1 and 2 genes (CSRP1 and CSRP2) are an effective growth factor in promoting skeletal muscle growth in vitro and vivo. However, in cattle, the information on the CSRP1 and CSRP2 genes is very limited. The aim of this study was to examine the association of the CSRP1 and CSRP2 variants with growth and carcass traits in cattle breeds. Three single nucleotide variants (SNVs) were identified within the bovine CSRP1 gene, whereas CSRP2 gene has not detected any SNVs, using DNA pooled sequencing, PCR-RFLP, and forced PCR-RFLP methods. These SNVs include g. 801T>C (Intron 2), g. 46T>C (Exon 3) and g. 99C>G (Intron 3). Besides, we also investigated haplotype frequencies and linkage disequilibrium (LD) coefficients for three SNVs in all study populations. LD and haplotype structure of CSRP1 were different between breeds. The result of haplotype analysis demonstrated eight haplotype present in QC (Qinchuan) and one haplotype in CH (Chinese Holstein). Only haplotype 1 (TTC), shared by all two populations, comprised 10.74% and 100.00%, of all haplotypes observed in QC and CH, respectively. Haplotype 5 (CTC) had the highest haplotype frequencies in QC (30.98%) and haplotype 1 had the highest haplotype frequencies in CH (100.00%). The statistical analyses indicated that one single SNV and 19 combined haplotypes were significantly or highly significantly associated with growth and carcass traits in the QC cattle population (P<0.05 or P<0.01). Quantitative real-time PCR (qRT-PCR) analyses showed that the bovine CSRP1 and CSRP2 genes were widely expressed in many tissues. The results of this study suggest that the CSRP1 gene possibly is a strong candidate gene that affects growth and carcass traits in the Chinese beef cattle breeding. Copyright © 2013 Elsevier B.V. All rights reserved.
Waldera-Lupa, Daniel M.; Kalfalah, Faiza; Florea, Ana-Maria; Sass, Steffen; Kruse, Fabian; Rieder, Vera; Tigges, Julia; Fritsche, Ellen; Krutmann, Jean; Busch, Hauke; Boerries, Melanie; Meyer, Helmut E.; Boege, Fritz; Theis, Fabian
We analyzed an ex vivo model of in situ aged human dermal fibroblasts, obtained from 15 adult healthy donors from three different age groups using an unbiased quantitative proteome-wide approach applying label-free mass spectrometry. Thereby, we identified 2409 proteins, including 43 proteins with an age-associated abundance change. Most of the differentially abundant proteins have not been described in the context of fibroblasts’ aging before, but the deduced biological processes confirmed known hallmarks of aging and led to a consistent picture of eight biological categories involved in fibroblast aging, namely proteostasis, cell cycle and proliferation, development and differentiation, cell death, cell organization and cytoskeleton, response to stress, cell communication and signal transduction, as well as RNA metabolism and translation. The exhaustive analysis of protein and mRNA data revealed that 77% of the age-associated proteins were not linked to expression changes of the corresponding transcripts. This is in line with an associated miRNA study and led us to the conclusion that most of the age-associated alterations detected at the proteome level are likely caused post-transcriptionally rather than by differential gene expression. In summary, our findings led to the characterization of novel proteins potentially associated with fibroblast aging and revealed that primary cultures of in situ aged fibroblasts are characterized by moderate age-related proteomic changes comprising the multifactorial process of aging. PMID:25411231
Full Text Available The vaginal microbiome plays an influential role in several disease states in reproductive age women, including bacterial vaginosis (BV. While demographic characteristics are associated with differences in vaginal microbiome community structure, little is known about the influence of sexual and hygiene habits. Furthermore, associations between the vaginal microbiome and risk symptoms of bacterial vaginosis have not been fully elucidated. Using Bayesian network (BN analysis of 16S rRNA gene sequence results, demographic and extensive questionnaire data, we describe both novel and previously documented associations between habits of women and their vaginal microbiome. The BN analysis approach shows promise in uncovering complex associations between disparate data types. Our findings based on this approach support published associations between specific microbiome members (e.g., Eggerthella, Gardnerella, Dialister, Sneathia and Ruminococcaceae, the Nugent score (a BV diagnostic and vaginal pH (a risk symptom of BV. Additionally, we found that several microbiome members were directly connected to other risk symptoms of BV (such as vaginal discharge, odor, itch, irritation, and yeast infection including L. jensenii, Corynebacteria, and Proteobacteria. No direct connections were found between the Nugent Score and risk symptoms of BV other than pH, indicating that the Nugent Score may not be the most useful criteria for assessment of clinical BV. We also found that demographics (i.e., age, ethnicity, previous pregnancy were associated with the presence/absence of specific vaginal microbes. The resulting BN revealed several as-yet undocumented associations between birth control usage, menstrual hygiene practices and specific microbiome members. Many of these complex relationships were not identified using common analytical methods, i.e., ordination and PERMANOVA. While these associations require confirmatory follow-up study, our findings strongly
Noyes, Noelle; Cho, Kyu-Chul; Ravel, Jacques; Forney, Larry J; Abdo, Zaid
The vaginal microbiome plays an influential role in several disease states in reproductive age women, including bacterial vaginosis (BV). While demographic characteristics are associated with differences in vaginal microbiome community structure, little is known about the influence of sexual and hygiene habits. Furthermore, associations between the vaginal microbiome and risk symptoms of bacterial vaginosis have not been fully elucidated. Using Bayesian network (BN) analysis of 16S rRNA gene sequence results, demographic and extensive questionnaire data, we describe both novel and previously documented associations between habits of women and their vaginal microbiome. The BN analysis approach shows promise in uncovering complex associations between disparate data types. Our findings based on this approach support published associations between specific microbiome members (e.g., Eggerthella, Gardnerella, Dialister, Sneathia and Ruminococcaceae), the Nugent score (a BV diagnostic) and vaginal pH (a risk symptom of BV). Additionally, we found that several microbiome members were directly connected to other risk symptoms of BV (such as vaginal discharge, odor, itch, irritation, and yeast infection) including L. jensenii, Corynebacteria, and Proteobacteria. No direct connections were found between the Nugent Score and risk symptoms of BV other than pH, indicating that the Nugent Score may not be the most useful criteria for assessment of clinical BV. We also found that demographics (i.e., age, ethnicity, previous pregnancy) were associated with the presence/absence of specific vaginal microbes. The resulting BN revealed several as-yet undocumented associations between birth control usage, menstrual hygiene practices and specific microbiome members. Many of these complex relationships were not identified using common analytical methods, i.e., ordination and PERMANOVA. While these associations require confirmatory follow-up study, our findings strongly suggest that future
Full Text Available Evidence suggests that animal patterns (motifs function in camouflage. Irregular mottled patterns can facilitate concealment when stationary in cluttered habitats, whereas regular patterns typically prevent capture during movement in open habitats. Bird plumage patterns have predominantly converged on just four types—mottled (irregular, scales, bars and spots (regular—and habitat could be driving convergent evolution in avian patterning. Based on sensory ecology, we therefore predict that irregular patterns would be associated with visually noisy closed habitats and that regular patterns would be associated with open habitats. Regular patterns have also been shown to function in communication for sexually competing males to stand-out and attract females, so we predict that male breeding plumage patterns evolved in both open and closed habitats. Here, taking phylogenetic relatedness into account, we investigate ecological selection for bird plumage patterns across the class Aves. We surveyed plumage patterns in 80% of all avian species worldwide. Of these, 2,756 bird species have regular and irregular plumage patterns as well as habitat information. In this subset, we tested whether adult breeding/non-breeding plumages in each sex, and juvenile plumages, were associated with the habitat types found within the species’ geographical distributions. We found no evidence for an association between habitat and plumage patterns across the world’s birds and little phylogenetic signal. We also found that species with regular and irregular plumage patterns were distributed randomly across the world’s eco-regions without being affected by habitat type. These results indicate that at the global spatial and taxonomic scale, habitat does not predict convergent evolution in bird plumage patterns, contrary to the camouflage hypothesis.
Xia, Xi; Wu, Congming; Cui, Yaowen; Kang, Mengjiao; Li, Xiaowei; Ding, Shuangyang; Shen, Jianzhong
Mycoplasma gallisepticum is a significant pathogenic bacterium that infects poultry, causing chronic respiratory disease and sinusitis in chickens and turkeys, respectively. M. gallisepticum infection poses a substantial economic threat to the poultry industry, and this threat is made worse by the emergence of antibiotic-resistant strains. The mechanisms of resistance are often difficult to determine; for example, little is known about antibiotic resistance of M. gallisepticum at the proteome level. In this study, we performed comparative proteomic analyses of an antibiotic (tylosin)-resistant M. gallisepticum mutant and a susceptible parent strain using a combination of two-dimensional differential gel electrophoresis and nano-liquid chromatography-quadrupole-time of flight mass spectrometry. Thirteen proteins were identified as differentially expressed in the resistant strain compared to the susceptible strain. Most of these proteins were related to catalytic activity, including catalysis that promotes the formylation of initiator tRNA and energy production. Elongation factors Tu and G were over-expressed in the resistant strains, and this could promote the binding of tRNA to ribosomes and catalyze ribosomal translocation, the coordinated movement of tRNA, and conformational changes in the ribosome. Taken together, our results indicate that M. gallisepticum develops resistance to tylosin by regulating associated enzymatic activities.
Wang, Z P; Liu, R F; Wang, A R; Li, J Y; Deng, X M
Biliverdin is responsible for the coloration of blue eggs and is secreted onto the eggshell by the shell gland. Previous studies confirmed that a significant difference exists in biliverdin content between blue eggs and brown eggs, although the reasons are still unknown. Because the pigment is derived from oxidative degradation of heme catalyzed by heme oxygenase (HO), this study compared heme oxygenase (decycling) 1 (HMOX1), the gene encoding HO expression and HO activity, in the shell glands of the Dongxiang blue-shelled chicken (n = 12) and the Dongxiang brown-shelled chicken (n = 12). Results showed that HMOX1 was highly expressed at the mRNA (1.58-fold; P 0.05). Taken together, these results show that blue egg formation is associated with high expression of HMOX1 in the shell gland of Dongxiang blue-shelled chickens, and suggest that differential expression of HMOX1 in the 2 groups of chickens is most likely to arise from an alteration in the trans-acting factor.
Estruch, Sara B; Graham, Sarah A; Quevedo, Martí; Vino, Arianna; Dekkers, Dick H W; Deriziotis, Pelagia; Sollis, Elliot; Demmers, Jeroen; Poot, Raymond A; Fisher, Simon E
FOXP transcription factors play important roles in neurodevelopment, but little is known about how their transcriptional activity is regulated. FOXP proteins cooperatively regulate gene expression by forming homo- and hetero-dimers with each other. Physical associations with other transcription factors might also modulate the functions of FOXP proteins. However, few FOXP-interacting transcription factors have been identified so far. Therefore, we sought to discover additional transcription factors that interact with the brain-expressed FOXP proteins, FOXP1, FOXP2 and FOXP4, through affinity-purifications of protein complexes followed by mass spectrometry. We identified seven novel FOXP-interacting transcription factors (NR2F1, NR2F2, SATB1, SATB2, SOX5, YY1 and ZMYM2), five of which have well-estabslished roles in cortical development. Accordingly, we found that these transcription factors are co-expressed with FoxP2 in the deep layers of the cerebral cortex and also in the Purkinje cells of the cerebellum, suggesting that they may cooperate with the FoxPs to regulate neural gene expression in vivo. Moreover, we demonstrated that etiological mutations of FOXP1 and FOXP2, known to cause neurodevelopmental disorders, severely disrupted the interactions with FOXP-interacting transcription factors. Additionally, we pinpointed specific regions within FOXP2 sequence involved in mediating these interactions. Thus, by expanding the FOXP interactome we have uncovered part of a broader neural transcription factor network involved in cortical development, providing novel molecular insights into the transcriptional architecture underlying brain development and neurodevelopmental disorders.
Aijaz A Wani
Full Text Available BACKGROUND: Mitochondrial encephalomyopathies are a heterogeneous group of clinical disorders generally caused due to mutations in either mitochondrial DNA (mtDNA or nuclear genes encoding oxidative phosphorylation (OXPHOS. We analyzed the mtDNA sequences from a group of 23 pediatric patients with clinical and morphological features of mitochondrial encephalopathies and tried to establish a relationship of identified variants with the disease. METHODOLOGY/PRINCIPLE FINDINGS: Complete mitochondrial genomes were amplified by PCR and sequenced by automated DNA sequencing. Sequencing data was analyzed by SeqScape software and also confirmed by BLASTn program. Nucleotide sequences were compared with the revised Cambridge reference sequence (CRS and sequences present in mitochondrial databases. The data obtained shows that a number of known and novel mtDNA variants were associated with the disease. Most of the non-synonymous variants were heteroplasmic (A4136G, A9194G and T11916A suggesting their possibility of being pathogenic in nature. Some of the missense variants although homoplasmic were showing changes in highly conserved amino acids (T3394C, T3866C, and G9804A and were previously identified with diseased conditions. Similarly, two other variants found in tRNA genes (G5783A and C8309T could alter the secondary structure of Cys-tRNA and Lys-tRNA. Most of the variants occurred in single cases; however, a few occurred in more than one case (e.g. G5783A and A10149T. CONCLUSIONS AND SIGNIFICANCE: The mtDNA variants identified in this study could be the possible cause of mitochondrial encephalomyopathies with childhood onset in the patient group. Our study further strengthens the pathogenic score of known variants previously reported as provisionally pathogenic in mitochondrial diseases. The novel variants found in the present study can be potential candidates for further investigations to establish the relationship between their incidence and role
Agulleiro María J
Full Text Available Abstract Background The Senegalese sole (Solea senegalensis is a marine flatfish of increasing commercial interest. However, the reproduction of this species in captivity is not yet controlled mainly because of the poor knowledge on its reproductive physiology, as it occurs for other non-salmonid marine teleosts that exhibit group-synchronous ovarian follicle development. In order to investigate intra-ovarian molecular mechanisms in Senegalese sole, the aim of the present study was to identify differentially expressed genes in the ovary during oocyte growth (vitellogenesis, maturation and ovarian follicle atresia using a recently developed oligonucleotide microarray. Results Microarray analysis led to the identification of 118 differentially expressed transcripts, of which 20 and 8 were monitored by real-time PCR and in situ hybridization, respectively. During vitellogenesis, many up-regulated ovarian transcripts had putative mitochondrial function/location suggesting high energy production (NADH dehydrogenase subunits, cytochromes and increased antioxidant protection (selenoprotein W2a, whereas other regulated transcripts were related to cytoskeleton and zona radiata organization (zona glycoprotein 3, alpha and beta actin, keratin 8, intracellular signalling pathways (heat shock protein 90, Ras homolog member G, cell-to-cell and cell-to-matrix interactions (beta 1 integrin, thrombospondin 4b, and the maternal RNA pool (transducer of ERBB2 1a, neurexin 1a. Transcripts up-regulated in the ovary during oocyte maturation included ion transporters (Na+-K+-ATPase subunits, probably required for oocyte hydration, as well as a proteinase inhibitor (alpha-2-macroglobulin and a vesicle calcium sensor protein (extended synaptotagmin-2-A. During follicular atresia, few transcripts were found to be up-regulated, but remarkably most of them were localized in follicular cells of atretic follicles, and they had inferred roles in lipid transport (apolipoprotein
Full Text Available Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.
Mols, Maarten; van Kranenburg, Richard; van Melis, Clint C J; Moezelaar, Roy; Abee, Tjakko
Acid stress resistance of the food-borne human pathogen Bacillus cereus may contribute to its survival in acidic environments, such as encountered in soil, food and the human gastrointestinal tract. The acid stress responses of B. cereus strains ATCC 14579 and ATCC 10987 were analysed in aerobically grown cultures acidified to pH values ranging from pH 5.4 to pH 4.4 with HCl. Comparative phenotype and transcriptome analyses revealed three acid stress-induced responses in this pH range: growth rate reduction, growth arrest and loss of viability. These physiological responses showed to be associated with metabolic shifts and the induction of general stress response mechanisms with a major oxidative component, including upregulation of catalases and superoxide dismutases. Flow cytometry analysis in combination with the hydroxyl (OH.) and peroxynitrite (ONOO(-))-specific fluorescent probe 3'-(p-hydroxyphenyl) fluorescein (HPF) showed excessive radicals to be formed in both B. cereus strains in bactericidal conditions only. Our study shows that radicals can indicate acid-induced malfunctioning of cellular processes that lead to cell death.
Abdelbary, Mohamed M. H.; Wittenberg, Anne; Cuny, Christiane
-allelic polymorphisms, and phylogenetic analyses revealed that an epidemic sub-clone within CC398 (dubbed 'clade (C)') has spread within and between equine hospitals, where it causes nosocomial infections in horses and colonises the personnel. While clade (C) was strongly associated with S. aureus from horses...
Chu, Pu; Yan, Gui Xia; Yang, Qing; Zhai, Li Na; Zhang, Cheng; Zhang, Feng Qi; Guan, Rong Zhan
Photosynthesis, the primary source of plant biomass, is important for plant growth and crop yield. Chlorophyll is highly abundant in plant leaves and plays essential roles in photosynthesis. We recently isolated a chlorophyll-deficient mutant (cde1) from ethyl methanesulfonate (EMS) mutagenized Brassica napus. Herein, quantitative proteomics analysis using the iTRAQ approach was conducted to investigate cde1-induced changes in the proteome. We identified 5069 proteins from B. napus leaves, of which 443 showed differential accumulations between the cde1 mutant and its corresponding wild-type. The differentially accumulated proteins were found to be involved in photosynthesis, porphyrin and chlorophyll metabolism, biosynthesis of secondary metabolites, carbon fixation, spliceosome, mRNA surveillance and RNA degradation. Our results suggest that decreased abundance of chlorophyll biosynthetic enzymes and photosynthetic proteins, impaired carbon fixation efficiency and disturbed redox homeostasis might account for the reduced chlorophyll contents, impaired photosynthetic capacity and increased lipid peroxidation in this mutant. Epigenetics was implicated in the regulation of gene expression in cde1, as proteins involved in DNA/RNA/histone methylation and methylation-dependent chromatin silencing were up-accumulated in the mutant. Biological significance Photosynthesis produces more than 90% of plant biomass and is an important factor influencing potential crop yield. The pigment chlorophyll plays essential roles in light harvesting and energy transfer during photosynthesis. Mutants deficient in chlorophyll synthesis have been used extensively to investigate the chlorophyll metabolism, development and photosynthesis. However, limited information is available with regard to the changes of protein profiles upon chlorophyll deficiency. Here, a combined physiological, histological, proteomics and molecular analysis revealed several important pathways associated with
Meda, Shashwath A.; Ruaño, Gualberto; Windemuth, Andreas; O’Neil, Kasey; Berwise, Clifton; Dunn, Sabra M.; Boccaccio, Leah E.; Narayanan, Balaji; Kocherla, Mohan; Sprooten, Emma; Keshavan, Matcheri S.; Tamminga, Carol A.; Sweeney, John A.; Clementz, Brett A.; Calhoun, Vince D.; Pearlson, Godfrey D.
The brain’s default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging–genetic relationships. ICA identified three DMNs. Hypo-connectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases. PMID:24778245
Full Text Available Abstract Background The inhalation of allergens by allergic asthmatics results in the early asthmatic response (EAR, which is characterized by acute airway obstruction beginning within a few minutes. The EAR is the earliest indicator of the pathological progression of allergic asthma. Because the molecular mechanism underlying the EAR is not fully defined, this study will contribute to a better understanding of asthma. Methods In order to gain insight into the molecular basis of the EAR, we examined changes in protein expression patterns in the lung tissue of asthmatic rats during the EAR using 2-DE/MS-based proteomic techniques. Bioinformatic analysis of the proteomic data was then performed using PPI Spider and KEGG Spider to investigate the underlying molecular mechanism. Results In total, 44 differentially expressed protein spots were detected in the 2-DE gels. Of these 44 protein spots, 42 corresponded to 36 unique proteins successfully identified using mass spectrometry. During subsequent bioinformatic analysis, the gene ontology classification, the protein-protein interaction networking and the biological pathway exploration demonstrated that the identified proteins were mainly involved in glycolysis, calcium binding and mitochondrial activity. Using western blot and semi-quantitative RT-PCR, we confirmed the changes in expression of five selected proteins, which further supports our proteomic and bioinformatic analyses. Conclusions Our results reveal that the allergen-induced EAR in asthmatic rats is associated with glycolysis, calcium binding and mitochondrial activity, which could establish a functional network in which calcium binding may play a central role in promoting the progression of asthma.
Mohapatra, Chinmayee; Chand, Ramesh; Navathe, Sudhir; Sharma, Sandeep
Powdery mildew caused by Erysiphe pisi is one of the important diseases responsible for heavy yield losses in pea crop worldwide. The most effective method of controlling the disease is the use of resistant varieties. The resistance to powdery mildew in pea is recessive and governed by a single gene er1. The objective of present study is to investigate if er1 mediated powdery mildew resistance is associated with changes in the redox status of the pea plant. 16 pea genotypes were screened for powdery mildew resistance in field condition for two years and, also, analyzed for the presence/absence of er1 gene. Histochemical analysis with DAB and NBT staining indicates accumulation of reactive oxygen species (ROS) in surrounding area of powdery mildew infection which was higher in susceptible genotypes as compared to resistant genotypes. A biochemical study revealed that the activity of superoxide dismutase (SOD) and catalase, enzymes involved in scavenging ROS, was increased in, both, resistant and susceptible genotypes after powdery mildew infection. However, both enzymes level was always higher in resistant than susceptible genotypes throughout time course of infection. Moreover, irrespective of any treatment, the total phenol (TP) and malondialdehyde (MDA) content was significantly high and low in resistant genotypes, respectively. The powdery mildew infection elevated the MDA content but decreased the total phenol in pea genotypes. Statistical analysis showed a strong positive correlation between AUDPC and MDA; however, a negative correlation was observed between AUDPC and SOD, CAT and TP. Heritability of antioxidant was also high. The study identified few novel genotypes resistant to powdery mildew infection that carried the er1 gene and provided further clue that er1 mediated defense response utilizes antioxidant machinery to confer powdery mildew resistance in pea. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
Full Text Available BACKGROUND: Colonisation of sessile eukaryotic host surfaces (e.g. invertebrates and seaweeds by bacteria is common in the marine environment and is expected to create significant inter-species competition and other interactions. The bacterium Pseudoalteromonas tunicata is a successful competitor on marine surfaces owing primarily to its ability to produce a number of inhibitory molecules. As such P. tunicata has become a model organism for the studies into processes of surface colonisation and eukaryotic host-bacteria interactions. METHODOLOGY/PRINCIPAL FINDINGS: To gain a broader understanding into the adaptation to a surface-associated life-style, we have sequenced and analysed the genome of P. tunicata and compared it to the genomes of closely related strains. We found that the P. tunicata genome contains several genes and gene clusters that are involved in the production of inhibitory compounds against surface competitors and secondary colonisers. Features of P. tunicata's oxidative stress response, iron scavenging and nutrient acquisition show that the organism is well adapted to high-density communities on surfaces. Variation of the P. tunicata genome is suggested by several landmarks of genetic rearrangements and mobile genetic elements (e.g. transposons, CRISPRs, phage. Surface attachment is likely to be mediated by curli, novel pili, a number of extracellular polymers and potentially other unexpected cell surface proteins. The P. tunicata genome also shows a utilisation pattern of extracellular polymers that would avoid a degradation of its recognised hosts, while potentially causing detrimental effects on other host types. In addition, the prevalence of recognised virulence genes suggests that P. tunicata has the potential for pathogenic interactions. CONCLUSIONS/SIGNIFICANCE: The genome analysis has revealed several physiological features that would provide P. tunciata with competitive advantage against other members of the surface-associated
Noyes, Noelle; Cho, Kyu-Chul; Ravel, Jacques; Forney, Larry J.; Abdo, Zaid
The vaginal microbiome plays an influential role in several disease states in reproductive age women, including bacterial vaginosis (BV). While demographic characteristics are associated with differences in vaginal microbiome community structure, little is known about the influence of sexual and hygiene habits. Furthermore, associations between the vaginal microbiome and risk symptoms of bacterial vaginosis have not been fully elucidated. Using Bayesian network (BN) analysis of 16S rRNA gene ...
Xu, Ke; Zhang, Xinyu; Wang, Zuoheng; Hu, Ying; Sinha, Rajita
Chronic stress has a significant impact on obesity. However, how stress influences obesity remains unclear. We conducted an epigenome-wide DNA methylation association analysis of obesity (N=510) and examined whether cumulative stress influenced the DNA methylation on body weight. We identified 20 CpG sites associated with body mass index at the false discovery rate qstress contributed to variations in body weight (p=0.002). Individuals with at least five major life events and lower methylation of cg1818703 showed a 1.38-fold higher risk of being obese (95%CI: 1.17-1.76). Our findings suggest that aberrant in DNA methylation is associated with body weight and that methylation of SOCS3 moderates the effect of cumulative stress on obesity. Copyright © 2016 Elsevier B.V. All rights reserved.
Zhang, Yuji; Tao, Cui; Jiang, Guoqian; Nair, Asha A; Su, Jian; Chute, Christopher G; Liu, Hongfang
A huge amount of associations among different biological entities (e.g., disease, drug, and gene) are scattered in millions of biomedical articles. Systematic analysis of such heterogeneous data can infer novel associations among different biological entities in the context of personalized medicine and translational research. Recently, network-based computational approaches have gained popularity in investigating such heterogeneous data, proposing novel therapeutic targets and deciphering disease mechanisms. However, little effort has been devoted to investigating associations among drugs, diseases, and genes in an integrative manner. We propose a novel network-based computational framework to identify statistically over-expressed subnetwork patterns, called network motifs, in an integrated disease-drug-gene network extracted from Semantic MEDLINE. The framework consists of two steps. The first step is to construct an association network by extracting pair-wise associations between diseases, drugs and genes in Semantic MEDLINE using a domain pattern driven strategy. A Resource Description Framework (RDF)-linked data approach is used to re-organize the data to increase the flexibility of data integration, the interoperability within domain ontologies, and the efficiency of data storage. Unique associations among drugs, diseases, and genes are extracted for downstream network-based analysis. The second step is to apply a network-based approach to mine the local network structure of this heterogeneous network. Significant network motifs are then identified as the backbone of the network. A simplified network based on those significant motifs is then constructed to facilitate discovery. We implemented our computational framework and identified five network motifs, each of which corresponds to specific biological meanings. Three case studies demonstrate that novel associations are derived from the network topology analysis of reconstructed networks of significant
Lee, Janice S; Ward, William O; Ren, Hongzu; Vallanat, Beena; Darlington, Gretchen J; Han, Eun-Soo; Laguna, Juan C; DeFord, James H; Papaconstantinou, John; Selman, Colin; Corton, J Christopher
Aging is associated with a loss of cellular homeostasis, a decline in physiological function and an increase in various pathologies. Employing a meta-analysis, hepatic gene expression profiles from four independent mouse aging studies were interrogated. There was little overlap in the number of genes or canonical pathways perturbed, suggesting that independent study-specific factors may play a significant role in determining age-dependent gene expression. However, 43 genes were consistently altered during aging in three or four of these studies, including those that (1) exhibited progressively increased expression starting from 12 months of age, (2) exhibited similar expression changes in models of progeria at young ages and dampened or no changes in old longevity mouse models, (3) were associated with inflammatory tertiary lymphoid neogenesis (TLN) associated with formation of ectopic lymphoid structures observed in chronically inflamed tissues, and (4) overlapped with genes perturbed by aging in brain, muscle, and lung. Surprisingly, around half of the genes altered by aging in wild-type mice exhibited similar expression changes in adult long-lived mice compared to wild-type controls, including those associated with intermediary metabolism and feminization of the male-dependent gene expression pattern. Genes unique to aging in wild-type mice included those linked to TLN. Published by Elsevier Ireland Ltd.
Yu, Dong; Hui, Yiming; Zai, Xiaodong; Xu, Junjie; Liang, Long; Wang, Bingxiang; Yue, Junjie; Li, Shanhu
The Brucella abortus strain 104M, a spontaneously attenuated strain, has been used as a vaccine strain in humans against brucellosis for 6 decades in China. Despite many studies, the molecular mechanisms that cause the attenuation are still unclear. Here, we determined the whole-genome sequence of 104M and conducted a comprehensive comparative analysis against the whole genome sequences of the virulent strain, A13334, and other reference strains. This analysis revealed a highly similar genome structure between 104M and A13334. The further comparative genomic analysis between 104M and A13334 revealed a set of genes missing in 104M. Some of these genes were identified to be directly or indirectly associated with virulence. Similarly, a set of mutations in the virulence-related genes was also identified, which may be related to virulence alteration. This study provides a set of candidate genes associated with virulence attenuation in B.abortus vaccine strain 104M.
Full Text Available Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD, caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD is a high-risk breed for canine AD (CAD. In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1 × 10(-5 in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3, which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n cases = 91, n controls = 88. IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0 × 10(-9, thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (praw = 3.1 × 10(-7, pgenome = 0.03. The total associated region was defined as a ~1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The ~209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.
Zhang, Nan; Yang, Dongqing; Kendall, Joshua R. A.; Borriss, Rainer; Druzhinina, Irina S.; Kubicek, Christian P.; Shen, Qirong; Zhang, Ruifu
Bacillus subtilis and its sister species B. amyloliquefaciens comprise an evolutionary compact but physiologically versatile group of bacteria that includes strains isolated from diverse habitats. Many of these strains are used as plant growth-promoting rhizobacteria (PGPR) in agriculture and a plant-specialized subspecies of B. amyloliquefaciens—B. amyloliquefaciens subsp. plantarum, has recently been recognized, here we used 31 whole genomes [including two newly sequenced PGPR strains: B. amyloliquefaciens NJN-6 isolated from Musa sp. (banana) and B. subtilis HJ5 from Gossypium sp. (cotton)] to perform comparative analysis and investigate the genomic characteristics and evolution traits of both species in different niches. Phylogenomic analysis indicated that strains isolated from plant-associated (PA) habitats could be distinguished from those from non-plant-associated (nPA) niches in both species. The core genomes of PA strains are more abundant in genes relevant to intermediary metabolism and secondary metabolites biosynthesis as compared with those of nPA strains, and they also possess additional specific genes involved in utilization of plant-derived substrates and synthesis of antibiotics. A further gene gain/loss analysis indicated that only a few of these specific genes (18/192 for B. amyloliquefaciens and 53/688 for B. subtilis) were acquired by PA strains at the initial divergence event, but most were obtained successively by different subgroups of PA stains during the evolutional process. This study demonstrated the genomic differences between PA and nPA B. amyloliquefaciens and B. subtilis from different niches and the involved evolutional traits, and has implications for screening of PGPR strains in agricultural production. PMID:28066362
Sznajder, Anna; Pfeiffer, Daniel
Identification of proteins that were present in a polyhydroxybutyrate (PHB) granule fraction isolated from Ralstonia eutropha but absent in the soluble, membrane, and membrane-associated fractions revealed the presence of only 12 polypeptides with PHB-specific locations plus 4 previously known PHB-associated proteins with multiple locations. None of the previously postulated PHB depolymerase isoenzymes (PhaZa2 to PhaZa5, PhaZd1, and PhaZd2) and none of the two known 3-hydroxybutyrate oligomer hydrolases (PhaZb and PhaZc) were significantly present in isolated PHB granules. Four polypeptides were found that had not yet been identified in PHB granules. Three of the novel proteins are putative α/β-hydrolases, and two of those (A0671 and B1632) have a PHB synthase/depolymerase signature. The third novel protein (A0225) is a patatin-like phospholipase, a type of enzyme that has not been described for PHB granules of any PHB-accumulating species. No function has been ascribed to the fourth protein (A2001), but its encoding gene forms an operon with phaB2 (acetoacetyl-coenzyme A [CoA] reductase) and phaC2 (PHB synthase), and this is in line with a putative function in PHB metabolism. The localization of the four new proteins at the PHB granule surface was confirmed in vivo by fluorescence microscopy of constructed fusion proteins with enhanced yellow fluorescent protein (eYFP). Deletion of A0671 and B1632 had a minor but detectable effect on the PHB mobilization ability in the stationary growth phase of nutrient broth (NB)-gluconate cells, confirming the functional involvement of both proteins in PHB metabolism. PMID:25548058
Yoo, DongAhn; Bagon, Bernadette B; Valeriano, Valerie Diane V; Oh, Ju Kyoung; Kim, Heebal; Cho, Seoae; Kang, Dae-Kyung
Research findings on probiotics highlight their importance in repressing harmful bacteria, leading to more extensive research on their potential applications. We analysed the genome of Lactobacillus fermentum SK152, which was isolated from the Korean traditional fermented vegetable dish kimchi, to determine the genetic makeup and genetic factors responsible for the antimicrobial activity of L. fermentum SK152 and performed a comparative genome analysis with other L. fermentum strains. The genome of L. fermentum SK152 was found to comprise a complete circular chromosome of 2092 273 bp, with an estimated GC content of 51.9% and 2184 open reading frames. It consisted of 2038 protein-coding genes and 73 RNA-coding genes. Moreover, a gene encoding a putative endolysin was found. A comparative genome analysis with other L. fermentum strains showed that SK152 is closely related to L. fermentum 3872 and F-6. An evolutionary analysis identified five positively selected genes that encode proteins associated with transport, survival and stress resistance. These positively selected genes may be essential for L. fermentum to colonise and survive in the stringent environment of the human gut and exert its beneficial effects. Our findings highlight the potential benefits of SK152. © FEMS 2017. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Full Text Available The regulation of complex cellular activities in palmitate treated HepG2 cells, and the ensuing cytotoxic phenotype, involves cooperative interactions between genes. While previous approaches have largely focused on identifying individual target genes, elucidating interacting genes has thus far remained elusive. We applied the concept of information synergy to reconstruct a "gene-cooperativity" network for palmititate-induced cytotoxicity in liver cells. Our approach integrated gene expression data with metabolic profiles to select a subset of genes for network reconstruction. Subsequent analysis of the network revealed insulin signaling as the most significantly enriched pathway, and desmoplakin (DSP as its top neighbor. We determined that palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. Insulin resistance is a common pathological feature of fatty liver and related ailments, whereas loss of DSP has been noted in liver carcinoma. Reduced DSP expression can lead to loss of cell-cell adhesion via desmosomes, and disrupt the keratin intermediate filament network. Our findings suggest that DSP expression may be perturbed by palmitate and, along with insulin resistance, may play a role in palmitate induced cytotoxicity, and serve as potential targets for further studies on non-alcoholic fatty liver disease (NAFLD.
Andrade, Jonathan de Magalhães; Toledo, Tatiana Torres; Nogueira, Silvia Beserra; Cordenunsi, Beatriz Rosana; Lajolo, Franco Maria; do Nascimento, João Roberto Oliveira
A comparative proteomic investigation between the pre-climacteric and climacteric mango fruits (cv. Keitt) was performed to identify protein species with variable abundance during ripening. Proteins were phenol-extracted from fruits, cyanine-dye-labeled, and separated on 2D gels at pH 4-7. Total spot count of about 373 proteins spots was detected in each gel and forty-seven were consistently different between pre-climacteric and climacteric fruits and were subjected to LC-MS/MS analysis. Functional classification revealed that protein species involved in carbon fixation and hormone biosynthesis decreased during ripening, whereas those related to catabolism and the stress-response, including oxidative stress and abiotic and pathogen defense factors, accumulated. In relation to fruit quality, protein species putatively involved in color development and pulp softening were also identified. This study on mango proteomics provides an overview of the biological processes that occur during ripening. Copyright © 2012 Elsevier B.V. All rights reserved.
Chundi Vinay Kumar
Full Text Available The T118M mutation in PMP22 gene is associated with Charcot Marie Tooth, type 1A (CMT1A. CMT1A is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Mutations in CMT related disorder are seen to increase the stability of the protein resulting in the diseased state. We performed SNP analysis for all the nsSNPs of PMP22 protein and carried out molecular dynamics simulation for T118M mutation to compare the stability difference between the wild type protein structure and the mutant protein structure. The mutation T118M resulted in the overall increase in the stability of the mutant protein. The superimposed structure shows marked structural variation between the wild type and the mutant protein structures.
Full Text Available Efficient use of feed resources is a challenge in the pork industry because the largest variability in expenditure is attributed to the cost of fodder. Efficiency of feeding is directly related to feeding behavior. In order to identify genomic regions controlling feeding behavior and eating efficiency traits, 338 Duroc boars were used in this study. The Illumina Porcine SNP60K BeadChip was used for genotyping. Data pertaining to individual daily feed intake (DFI, total daily time spent in feeder (TPD, number of daily visits to feeder (NVD, average duration of each visit (TPV, mean feed intake per visit (FPV, mean feed intake rate (FR, and feed conversion ratio (FCR were collected for these pigs. Despite the limited sample size, the genome-wide association study was acceptable to detect candidate regions association with feeding behavior and eating efficiency traits in pigs. We detected three genome-wide (P < 1.40E-06 and 11 suggestive (P < 2.79E-05 single nucleotide polymorphism (SNP-trait associations. Six SNPs were located in genomic regions where quantitative trait loci (QTLs have previously been reported for feeding behavior and eating efficiency traits in pigs. Five candidate genes (SERPINA3, MYC, LEF1, PITX2, and MAP3K14 with biochemical and physiological roles that were relevant to feeding behavior and eating efficiency were discovered proximal to significant or suggestive markers. Gene ontology analysis indicated that most of the candidate genes were involved in the development of the hypothalamus (GO:0021854, P < 0.0398. Our results provide new insights into the genetic basis of feeding behavior and eating efficiency in pigs. Furthermore, some significant SNPs identified in this study could be incorporated into artificial selection programs for Duroc-related pigs to select for increased feeding efficiency.
Larval growth of the polychaete worm Pseudopolydora vexillosa involves the formation of segment-specific structures. When larvae attain competency to settle, they discard swimming chaetae and secrete mucus. The larvae build tubes around themselves and metamorphose into benthic juveniles. Understanding the molecular processes, which regulate this complex and unique transition, remains a major challenge because of the limited molecular information available. To improve this situation, we conducted high-throughput RNA sequencing and quantitative proteome analysis of the larval stages of P. vexillosa. Based on gene ontology (GO) analysis, transcripts related to cellular and metabolic processes, binding, and catalytic activities were highly represented during larval-adult transition. Mitogen-activated protein kinase (MAPK), calcium-signaling, Wnt/β-catenin, and notch signaling metabolic pathways were enriched in transcriptome data. Quantitative proteomics identified 107 differentially expressed proteins in three distinct larval stages. Fourteen and 53 proteins exhibited specific differential expression during competency and metamorphosis, respectively. Dramatic up-regulation of proteins involved in signaling, metabolism, and cytoskeleton functions were found during the larval-juvenile transition. Several proteins involved in cell signaling, cytoskeleton and metabolism were up-regulated, whereas proteins related to transcription and oxidative phosphorylation were down-regulated during competency. The integration of high-throughput RNA sequencing and quantitative proteomics allowed a global scale analysis of larval transcripts/proteins associated molecular processes in the metamorphosis of polychaete worms. Further, transcriptomic and proteomic insights provide a new direction to understand the fundamental mechanisms that regulate larval metamorphosis in polychaetes. © 2013 American Chemical Society.
Conlan, Sean; Mijares, Lilia A; Becker, Jesse; Blakesley, Robert W; Bouffard, Gerard G; Brooks, Shelise; Coleman, Holly; Gupta, Jyoti; Gurson, Natalie; Park, Morgan; Schmidt, Brian; Thomas, Pamela J; Otto, Michael; Kong, Heidi H; Murray, Patrick R; Segre, Julia A
While Staphylococcus epidermidis is commonly isolated from healthy human skin, it is also the most frequent cause of nosocomial infections on indwelling medical devices. Despite its importance, few genome sequences existed and the most frequent hospital-associated lineage, ST2, had not been fully sequenced. We cultivated 71 commensal S. epidermidis isolates from 15 skin sites and compared them with 28 nosocomial isolates from venous catheters and blood cultures. We produced 21 commensal and 9 nosocomial draft genomes, and annotated and compared their gene content, phylogenetic relatedness and biochemical functions. The commensal strains had an open pan-genome with 80% core genes and 20% variable genes. The variable genome was characterized by an overabundance of transposable elements, transcription factors and transporters. Biochemical diversity, as assayed by antibiotic resistance and in vitro biofilm formation, demonstrated the varied phenotypic consequences of this genomic diversity. The nosocomial isolates exhibited both large-scale rearrangements and single-nucleotide variation. We showed that S. epidermidis genomes separate into two phylogenetic groups, one consisting only of commensals. The formate dehydrogenase gene, present only in commensals, is a discriminatory marker between the two groups. Commensal skin S. epidermidis have an open pan-genome and show considerable diversity between isolates, even when derived from a single individual or body site. For ST2, the most common nosocomial lineage, we detect variation between three independent isolates sequenced. Finally, phylogenetic analyses revealed a previously unrecognized group of S. epidermidis strains characterized by reduced virulence and formate dehydrogenase, which we propose as a clinical molecular marker.
Chen, Linghua; Huang, Yining; Xu, Ming; Cheng, Zuxin; Zhang, Dasheng; Zheng, Jingui
Black rice (Oryza sativa L.), whose pericarp is rich in anthocyanins (ACNs), is considered as a healthier alternative to white rice. Molecular species of ACNs in black rice have been well documented in previous studies; however, information about the metabolic mechanisms underlying ACN biosynthesis during black rice grain development is unclear. The aim of the present study was to determine changes in the metabolic pathways that are involved in the dynamic grain proteome during the development of black rice indica cultivar, (Oryza sativa L. indica var. SSP). Isobaric tags for relative and absolute quantification (iTRAQ) MS/MS were employed to identify statistically significant alterations in the grain proteome. Approximately 928 proteins were detected, of which 230 were differentially expressed throughout 5 successive developmental stages, starting from 3 to 20 days after flowering (DAF). The greatest number of differentially expressed proteins was observed on 7 and 10 DAF, including 76 proteins that were upregulated and 39 that were downregulated. The biological process analysis of gene ontology revealed that the 230 differentially expressed proteins could be sorted into 14 functional groups. Proteins in the largest group were related to metabolic process, which could be integrated into multiple biochemical pathways. Specifically, proteins with a role in ACN biosynthesis, sugar synthesis, and the regulation of gene expression were upregulated, particularly from the onset of black rice grain development and during development. In contrast, the expression of proteins related to signal transduction, redox homeostasis, photosynthesis and N-metabolism decreased during grain maturation. Finally, 8 representative genes encoding different metabolic proteins were verified via quantitative real-time polymerase chain reaction (qRT-PCR) analysis, these genes had differed in transcriptional and translational expression during grain development. Expression analyses of
Chen, Linghua; Huang, Yining; Xu, Ming; Cheng, Zuxin; Zhang, Dasheng; Zheng, Jingui
Background Black rice (Oryza sativa L.), whose pericarp is rich in anthocyanins (ACNs), is considered as a healthier alternative to white rice. Molecular species of ACNs in black rice have been well documented in previous studies; however, information about the metabolic mechanisms underlying ACN biosynthesis during black rice grain development is unclear. Results The aim of the present study was to determine changes in the metabolic pathways that are involved in the dynamic grain proteome during the development of black rice indica cultivar, (Oryza sativa L. indica var. SSP). Isobaric tags for relative and absolute quantification (iTRAQ) MS/MS were employed to identify statistically significant alterations in the grain proteome. Approximately 928 proteins were detected, of which 230 were differentially expressed throughout 5 successive developmental stages, starting from 3 to 20 days after flowering (DAF). The greatest number of differentially expressed proteins was observed on 7 and 10 DAF, including 76 proteins that were upregulated and 39 that were downregulated. The biological process analysis of gene ontology revealed that the 230 differentially expressed proteins could be sorted into 14 functional groups. Proteins in the largest group were related to metabolic process, which could be integrated into multiple biochemical pathways. Specifically, proteins with a role in ACN biosynthesis, sugar synthesis, and the regulation of gene expression were upregulated, particularly from the onset of black rice grain development and during development. In contrast, the expression of proteins related to signal transduction, redox homeostasis, photosynthesis and N-metabolism decreased during grain maturation. Finally, 8 representative genes encoding different metabolic proteins were verified via quantitative real-time polymerase chain reaction (qRT-PCR) analysis, these genes had differed in transcriptional and translational expression during grain development. Conclusions
Zeng, Xue; Zhao, Jingjing; Wu, Xiaohong; Shi, Hongbo; Liu, Wali; Cui, Bingnan; Yang, Li; Ding, Xu; Song, Ping
Psoriasis is an inflammatory skin disease. Deceleration in keratinocyte apoptosis is the most significant pathological change observed in psoriasis. To detect a meaningful correlation between the genes and gene functions associated with the mechanism underlying psoriasis, 927 differentially expressed genes (DEGs) were identified using the Gene Expression Omnibus database, GSE13355 [false discovery rate (FDR) 1] with the package in R langue. The selected DEGs were further constructed using the search tool for the retrieval of interacting genes, in order to analyze the interaction network between the DEGs. Subsequent to PageRank analysis, 14 topological hub genes were identified, and the functions and pathways in the hub genes network were analyzed. The top‑ranked hub gene, estrogen receptor‑1 (ESR1) is downregulated in psoriasis, exhibited binding sites enriched with genes possessing anti‑apoptotic functions. The ESR1 gene encodes estrogen receptor α (ERα); a reduced level of ERα expression provides a crucial foundation in response to the anti‑apoptotic activity of psoriatic keratinocytes by activating the expression of anti‑apoptotic genes. Furthermore, it was detected that the pathway that is associated most significantly with psoriasis is the pathways in cancer. Pathways in cancer may protect psoriatic cells from apoptosis by inhibition of ESR1 expression. The present study provides support towards the investigation of ESR1 gene function and elucidates that the interaction with anti‑apoptotic genes is involved in the underlying biological mechanisms of resistance to apoptosis in psoriasis. However, further investigation is required to confirm the present results.
Cziesielski, Maha J.
Corals and their endosymbiotic dinoflagellates of the genus Symbiodinium have a fragile relationship that breaks down under heat stress, an event known as bleaching. However, many coral species have adapted to high temperature environments such as the Red Sea (RS). To investigate mechanisms underlying temperature adaptation in zooxanthellate cnidarians we compared transcriptome- and proteome-wide heat stress response (24 h at 32°C) of three strains of the model organism Aiptasia pallida from regions with differing temperature profiles; North Carolina (CC7), Hawaii (H2) and the RS. Correlations between transcript and protein levels were generally low but inter-strain comparisons highlighted a common core cnidarian response to heat stress, including protein folding and oxidative stress pathways. RS anemones showed the strongest increase in antioxidant gene expression and exhibited significantly lower reactive oxygen species (ROS) levels in hospite However, comparisons of antioxidant gene and protein expression between strains did not show strong differences, indicating similar antioxidant capacity across the strains. Subsequent analysis of ROS production in isolated symbionts confirmed that the observed differences of ROS levels in hospite were symbiont-driven. Our findings indicate that RS anemones do not show increased antioxidant capacity but may have adapted to higher temperatures through association with more thermally tolerant symbionts.
Belstrøm, Daniel; Constancias, Florentin; Liu, Yang
relative abundance of traditional periodontal pathogens such as Porphyromonas gingivalis and Filifactor alocis and salivary microbial activity of F. alocis was associated with periodontitis. Significantly higher relative abundance of caries-associated bacteria such as Streptococcus mutans and Lactobacillus...
Nwugo, Chika C; Doud, Melissa S; Duan, Yong-Ping; Lin, Hong
Citrus Huanglongbing (HLB), which is linked to the bacterial pathogen 'Ca. Liberibacter asiaticus' (Las), is the most devastating disease of citrus plants, and longer-term control measures via breeding or genetic engineering have been unwieldy because all cultivated citrus species are susceptible to the disease. However, the degree of susceptibility varies among citrus species, which has prompted efforts to identify potential Las resistance/tolerance-related genes in citrus plants for application in breeding or genetic engineering programs. Plant exposure to one form of stress has been shown to serendipitously induce innate resistance to other forms of stress and a recent study showed that continuous heat treatment (40 to 42 °C) reduced Las titer and HLB-associated symptoms in citrus seedlings. The goal of the present study was to apply comparative proteomics analysis via 2-DE and mass spectrometry to elucidate the molecular processes associated with heat-induced mitigation of HLB in citrus plants. Healthy or Las-infected citrus grapefruit plants were exposed to room temperature or to continuous heat treatment of 40 °C for 6 days. An exhaustive total protein extraction process facilitated the identification of 107 differentially-expressed proteins in response to Las and/or heat treatment, which included a strong up-regulation of chaperones including small (23.6, 18.5 and 17.9 kDa) heat shock proteins, a HSP70-like protein and a ribulose-1,5-bisphosphate carboxylase oxygenase (RuBisCO)-binding 60 kDa chaperonin, particularly in response to heat treatment. Other proteins that were generally down-regulated due to Las infection but up-regulated in response to heat treatment include RuBisCO activase, chlorophyll a/b binding protein, glucosidase II beta subunit-like protein, a putative lipoxygenase protein, a ferritin-like protein, and a glutathione S-transferase. The differentially-expressed proteins identified in this study highlights a premier characterization
Derow Catherine K
Full Text Available Abstract Background Gene expression signatures are typically identified by correlating gene expression patterns to a disease phenotype of interest. However, individual gene-based signatures usually suffer from low reproducibility and interpretability. Results We have developed a novel algorithm Iterative Clique Enumeration (ICE for identifying relatively independent maximal cliques as co-expression modules and a module-based approach to the analysis of gene expression data. Applying this approach on a public breast cancer dataset identified 19 modules whose expression levels were significantly correlated with tumor grade. The correlations were reproducible for 17 modules in an independent breast cancer dataset, and the reproducibility was considerably higher than that based on individual genes or modules identified by other algorithms. Sixteen out of the 17 modules showed significant enrichment in certain Gene Ontology (GO categories. Specifically, modules related to cell proliferation and immune response were up-regulated in high-grade tumors while those related to cell adhesion was down-regulated. Further analyses showed that transcription factors NYFB, E2F1/E2F3, NRF1, and ELK1 were responsible for the up-regulation of the cell proliferation modules. IRF family and ETS family proteins were responsible for the up-regulation of the immune response modules. Moreover, inhibition of the PPARA signaling pathway may also play an important role in tumor progression. The module without GO enrichment was found to be associated with a potential genomic gain in 8q21-23 in high-grade tumors. The 17-module signature of breast tumor progression clustered patients into subgroups with significantly different relapse-free survival times. Namely, patients with lower cell proliferation and higher cell adhesion levels had significantly lower risk of recurrence, both for all patients (p = 0.004 and for those with grade 2 tumors (p = 0.017. Conclusions The ICE
Fehringer, G. (Gordon); P. Kraft (Peter); P.D.P. Pharoah (Paul); R. Eeles (Rosalind); Chatterjee, N. (Nilanjan); F.R. Schumacher (Fredrick R); J.M. Schildkraut (Joellen); S. Lindstrom (Stephen); P. Brennan (Paul); H. Bickeböller (Heike); R. Houlston (Richard); M.T. Landi (Maria Teresa); N.E. Caporaso (Neil); Risch, A. (Angela); A.A. Al Olama (Ali Amin); S.I. Berndt (Sonja); Giovannucci, E.L. (Edward L.); H. Grönberg (Henrik); Z. Kote-Jarai; Ma, J. (Jing); K.R. Muir (K.); M.J. Stampfer (Meir J.); Stevens, V.L. (Victoria L.); F. Wiklund (Fredrik); W.C. Willett (Walter C.); E.L. Goode (Ellen); Permuth, J.B. (Jennifer B.); H. Risch (Harvey); Reid, B.M. (Brett M.); Bezieau, S. (Stephane); H. Brenner (Hermann); Chan, A.T. (Andrew T.); J. Chang-Claude (Jenny); T.J. Hudson (Thomas); Kocarnik, J.K. (Jonathan K.); P. Newcomb (Polly); Schoen, R.E. (Robert E.); Slattery, M.L. (Martha L.); White, E. (Emily); M.A. Adank (Muriel); H. Ahsan (Habibul); K. Aittomäki (Kristiina); Baglietto, L. (Laura); Blomquist, C. (Carl); F. Canzian (Federico); K. Czene (Kamila); I. dos Santos Silva (Isabel); Eliassen, A.H. (A. Heather); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); O. Fletcher (Olivia); M. García-Closas (Montserrat); M.M. Gaudet (Mia); Johnson, N. (Nichola); P. Hall (Per); A. Hazra (Aditi); R. Hein (Rebecca); Hofman, A. (Albert); J.L. Hopper (John); A. Irwanto (Astrid); M. Johansson (Mattias); R. Kaaks (Rudolf); M.G. Kibriya (Muhammad); P. Lichtner (Peter); J. Liu (Jianjun); E. Lund (Eiliv); Makalic, E. (Enes); A. Meindl (Alfons); B. Müller-Myhsok (B.); Muranen, T.A. (Taru A.); H. Nevanlinna (Heli); P.H.M. Peeters; J. Peto (Julian); R. Prentice (Ross); N. Rahman (Nazneen); M.-J. Sanchez (Maria-Jose); D.F. Schmidt (Daniel); R.K. Schmutzler (Rita); M.C. Southey (Melissa); Tamimi, R. (Rulla); S.P.L. Travis (Simon); C. Turnbull (Clare); Uitterlinden, A.G. (Andre G.); Z. Wang (Zhaoming); A.S. Whittemore (Alice); X.R. Yang (Xiaohong); W. Zheng (Wei); D. Buchanan (Daniel); G. Casey (Graham); G. Conti (Giario); C.K. Edlund (Christopher); S. Gallinger (Steve); R. Haile (Robert); M. Jenkins (Mark); Marchand, L. (Loïcle); Li, L. (Li); N.M. Lindor (Noralane); Schmit, S.L. (Stephanie L.); S.N. Thibodeau (Stephen); M.O. Woods (Michael); T. Rafnar (Thorunn); J. Gudmundsson (Julius); S.N. Stacey (Simon); Stefansson, K. (Kari); P. Sulem (Patrick); Chen, Y.A. (Y. Ann); J.P. Tyrer (Jonathan); Christiani, D.C. (David C.); Wei, Y. (Yongyue); H. Shen (Hongbing); Z. Hu (Zhibin); X.-O. Shu (Xiao-Ou); Shiraishi, K. (Kouya); A. Takahashi (Atsushi); Y. Bossé (Yohan); M. Obeidat; D.C. Nickle (David C.); W. Timens (Wim); M. Freedman (Matthew); Li, Q. (Qiyuan); D. Seminara (Daniela); S.J. Chanock (Stephen); Gong, J. (Jian); U. Peters (Ulrike); S.B. Gruber (Stephen); Amos, C.I. (Christopher I.); T.A. Sellers (Thomas A.); D.F. Easton (Douglas F.); D. Hunter (David); C.A. Haiman (Christopher A.); B.E. Henderson (Brian); R.J. Hung (Rayjean)
textabstractIdentifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851
Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fredrick R.; Schildkraut, Joellen M.; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Al Olama, Ali Amin; Berndt, Sonja I.; Giovannucci, Edward L.; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J.; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter C.; Goode, Ellen L.; Permuth, Jennifer B.; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine D.; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Buchanan, Daniel D.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Gallinger, Steven; Haile, Robert W.; Jenkins, Mark; Marchand, Loïcle; Li, Li; Lindor, Noralene M.; Schmit, Stephanie L.; Thibodeau, Stephen N.; Woods, Michael O.; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.
Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820
Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fredrick R.; Schildkraut, Joellen M.; Lindstrom, Sara; Brennan, Paul; Bickeboller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Al Olama, Ali Amin; Berndt, Sonja I.; Giovannucci, Edward L.; Gronberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J.; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter C.; Goode, Ellen L.; Permuth, Jennifer B.; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomaki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine D.; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Muller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Buchanan, Daniel D.; Casey, Graham; Conti, David V.; Edlund, Christopher K.; Gallinger, Steven; Haile, Robert W.; Jenkins, Mark; Le Marchand, Loic; Li, Li; Lindor, Noralene M.; Schmit, Stephanie L.; Thibodeau, Stephen N.; Woods, Michael O.; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bosse, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.
Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820
Bonàs-Guarch, Sílvia; Guindo-Martínez, Marta; Miguel-Escalada, Irene
The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associ...
Docherty, Sophia J; Kovas, Yulia; Petrill, Stephen A; Plomin, Robert
The Generalist Genes Hypothesis is based upon quantitative genetic findings which indicate that many of the same genes influence diverse cognitive abilities and disabilities across age. In a recent genome-wide association study of mathematical ability in 10-year-old children, 43 SNP associations were nominated from scans of pooled DNA, 10 of which were validated in an individually genotyped sample. The 4927 children in this genotyped sample have also been studied at 7, 9 and 12 years of age on measures of mathematical ability, as well as on other cognitive and learning abilities. Using these data we have explored the Generalist Genes Hypothesis by assessing the association of the available measures of ability at age 10 and other ages with two composite 'SNP-set' scores, formed from the full set of 43 nominated SNPs and the sub-set of 10 SNPs that were previously found to be associated with mathematical ability at age 10. Both SNP sets yielded significant associations with mathematical ability at ages 7, 9 and 12, as well as with reading and general cognitive ability at age 10. Although effect sizes are small, our results correspond with those of quantitative genetic research in supporting the Generalist Genes Hypothesis. SNP sets identified on the basis of their associations with mathematical ability at age 10 show associations with mathematical ability at earlier and later ages and show associations of similar magnitude with reading and general cognitive ability. With small effect sizes expected in such complex traits, future studies may be able to capitalise on power by searching for 'generalist genes' using longitudinal and multivariate approaches.
Taylor, Kimberly E; Wong, Quenna; Levine, David M; McHugh, Caitlin; Laurie, Cathy; Doheny, Kimberly; Lam, Mi Y; Baer, Alan N; Challacombe, Stephen; Lanfranchi, Hector; Schiødt, Morten; Srinivasan, M; Umehara, Hisanori; Vivino, Frederick B; Zhao, Yan; Shiboski, Stephen C; Daniels, Troy E; Greenspan, John S; Shiboski, Caroline H; Criswell, Lindsey A
The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets. We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations. We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10 -42 , P = 3 × 10 -14 , and P = 9 × 10 -10 , respectively), and several novel suggestive regions (those with 2 or more associations at P ancestry (P = 4 × 10 -15 and P = 4 × 10 -5 , respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations. Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes. © 2017, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.
Aging is associated with a predictable loss of cellular homeostasis, a decline in physiological function and an increase in various diseases. We hypothesized that similar age-related gene expression profiles would be observed in mice across independent studies. Employing a metaan...
Khankhanian, Pouya; Cozen, Wendy; Himmelstein, Daniel S.; Madireddy, Lohith; Din, Lennox; van den Berg, Anke; Matsushita, Takuya; Glaser, Sally L.; More, Jayaji M.; Smedby, Karin E.; Baranzini, Sergio E.; Mack, Thomas M.; Lizee, Antoine; de Sanjose, Silvia; Gourraud, Pierre-Antoine; Nieters, Alexandra; Hauser, Stephen L.; Cocco, Pierluigi; Maynadie, Marc; Foretova, Lenka; Staines, Anthony; Delahaye-Sourdeix, Manon; Li, Dalin; Bhatia, Smita; Melbye, Mads; Onel, Kenan; Jarrett, Ruth; McKay, James D.; Oksenberg, Jorge R.; Hjalgrim, Henrik
Background: Based on epidemiological commonalities, multiple sclerosis (MS) and Hodgkin lymphoma (HL), two clinically distinct conditions, have long been suspected to be aetiologically related. MS and HL occur in roughly the same age groups, both are associated with Epstein-Barr virus infection and
Sheen, Patricia; Requena, David; Gushiken, Eduardo; Gilman, Robert H; Antiparra, Ricardo; Lucero, Bryan; Lizárraga, Pilar; Cieza, Basilio; Roncal, Elisa; Grandjean, Louis; Pain, Arnab; McNerney, Ruth; Clark, Taane G; Moore, David; Zimic, Mirko
Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear. We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion. These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.
Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.
Conlan, Sean; Mijares, Lilia A; Becker, Jesse; Blakesley, Robert W; Bouffard, Gerard G; Brooks, Shelise; Coleman, Holly; Gupta, Jyoti; Gurson, Natalie; Park, Morgan; Schmidt, Brian; Thomas, Pamela J; Otto, Michael; Kong, Heidi H; Murray, Patrick R
Background While Staphylococcus epidermidis is commonly isolated from healthy human skin, it is also the most frequent cause of nosocomial infections on indwelling medical devices. Despite its importance, few genome sequences existed and the most frequent hospital-associated lineage, ST2, had not been fully sequenced. Results We cultivated 71 commensal S. epidermidis isolates from 15 skin sites and compared them with 28 nosocomial isolates from venous catheters and blood cultures. We produced...
Fujibayashi, Shugo; Sasajima, Junpei; Goto, Takuma; Tanaka, Hiroki; Kawabata, Hidemasa; Fujii, Tsuneshi; Nakamura, Kazumasa; Chiba, Atsushi; Yanagawa, Nobuyuki; Moriichi, Kentaro; Fujiya, Mikihiro; Kohgo, Yutaka
The pathogenesis of autoimmune pancreatitis is unknown. In the present study we used high-throughput sequencing with next generation sequencing to identify the candidate genes associated with AIP. A total of 27 type 1 AIP patients and 30 healthy blood donors were recruited, and DNA samples were isolated from their mononuclear cells. A high-throughput sequencer with an original custom panel of 1031 genes was used to detect the genetic variants in each sample. Polymorphisms of CACNA1S (c.4642C>T), rs41554316, rs2231119, rs1042131, rs2838171, P2RX3 (c.195delG), rs75639061, SMAD7 (c.624delC) and TOP1 (c.2007delG), were identified as candidate genetic variants in patients with type 1 AIP. P2RX3 and TOP1 were significantly associated with AIP, even after adjusting bay means of Bonferroni's correction. In addition, we also identified eight candidate genetic variants that were associated with the relapse of type 1 AIP, namely: rs1143146, rs1050716, HLA-C (c.759_763delCCCCCinsTCCCG), rs1050451, rs4154112, rs1049069, CACNA1C (c.5996delC) and CXCR3 (c.630_631delGC). Finally polymorphisms of rs1050716 and rs111493987 were identified as candidate genetic variants associated with extra-pancreatic lesions in patients with type 1 AIP. These candidates might be used as markers of AIP susceptibility and could contribute to the pathogenesis of type 1 AIP.
Ma, Yunlong; Fan, Rongli; Li, Ming D
Although many studies have analyzed the association of 3'-untranslated region variable-number tandem repeat (VNTR) polymorphism in SLC6A3 with alcohol dependence (AD), the results remain controversial. This study aimed to determine whether this variant indeed has any genetic effect on AD by integrating 17 reported studies with 5,929 participants included. The A9-dominant genetic model that considers A9-repeat and non-A9 repeat as 2 genotypes and compared their frequencies in alcoholics with that in controls was adopted. Considering the potential influence of ethnicity, differences in diagnostic criteria of AD, and alcoholic subgroups, stratified meta-analyses were conducted. There existed no evidence for the presence of heterogeneity among the studied samples, indicating the results under the fixed-effects model are acceptable. We found a significant association of VNTR A9 genotypes with AD in all ethnic populations (pooled odds ratio [OR] 1.12; 95% confidence interval [CI] 1.00, 1.25; p = 0.045) and the Caucasian population (pooled OR 1.15; 95% CI 1.01, 1.31; p = 0.036). We also found VNTR A9 genotypes to be significantly associated with alcoholism as defined by the DSM-IV criteria (pooled OR 1.18; 95% CI 1.03, 1.36; p = 0.02). Further, we found a significant association between VNTR A9 genotypes and alcoholism associated with alcohol withdrawal seizure or delirium tremens (pooled OR 1.55; 95% CI 1.24, 1.92; p = 1.0 × 10(-4) ). In all these meta-analyses, no evidence of publication bias was detected. We concluded that the VNTR polymorphism has an important role in the etiology of AD, and individuals with at least 1 A9 allele are more likely to be dependent on alcohol than persons carrying the non-A9 allele. Copyright © 2016 by the Research Society on Alcoholism.
Wester, Vincent L; Noppe, Gerard; Savas, Mesut; van den Akker, Erica L T; de Rijke, Yolanda B; van Rossum, Elisabeth F C
Scalp hair is increasingly used to measure the long-term exposure to endogenous glucocorticoids hormones. Long-term cortisone (HairE) and cortisol (HairF) have been associated with obesity, metabolic syndrome, cardiovascular disease and psychopathology. However, little is known about the influence of the use of local corticosteroids and major stressful life events on hair glucocorticoids. We determined HairE and HairF using liquid chromatography - tandem mass spectrometry in 295 adult participants of the population-based Lifelines cohort study (75% females, median age 42). We collected anthropometry and fasting metabolic laboratory values, questionnaires on hair characteristics, recent use of corticosteroids, and recent major stressful life events. After adjustment for covariates, hair glucocorticoids increased with age, male sex, black or brown hair color, and frequency of sweating on the scalp, and decreased with higher hair washing frequency (PHairE was decreased in participants who used systemic corticosteroids (5.4 vs. 8.5pg/mg hair, P=0.041), and in participants who only used local agents such as inhaled, topical and nasal corticosteroids (6.8 vs. 8.5pg/mg, P=0.005). Recent life events were positively associated with HairF after adjustment for age and sex (P=0.026), but this association lost significance after adjustment for hair related characteristics (P>0.05). HairE can be a useful marker to detect mild adrenal suppression due to corticosteroid use in the general population, even when only inhaled, nasal or topical corticosteroids are used, which suggests that these commonly used agents induce systemic effects. Copyright © 2017 Elsevier Ltd. All rights reserved.
Zhao, Wei; Liu, Zhongjie; Yu, Xujiao; Lai, Luying; Li, Haobo; Liu, Zipeng; Li, Le; Jiang, Shan; Xia, Zhengyuan; Xu, Shi-yuan
Bupivacaine, a commonly used local anesthetic, has potential neurotoxicity through diverse signaling pathways. However, the key mechanism of bupivacaine-induced neurotoxicity remains unclear. Cultured human SH-SY5Y neuroblastoma cells were treated (bupivacaine) or untreated (control) with bupivacaine for 24 h. Compared to the control group, bupivacaine significantly increased cyto-inhibition, cellular reactive oxygen species, DNA damage, mitochondrial injury, apoptosis (increased TUNEL-positive cells, cleaved caspase 3, and Bcl-2/Bax), and activated autophagy (enhanced LC3II/LC3I ratio). To explore changes in protein expression and intercommunication among the pathways involved in bupivacaine-induced neurotoxicity, an 8-plex iTRAQ proteomic technique and bioinformatics analysis were performed. Compared to the control group, 241 differentially expressed proteins were identified, of which, 145 were up-regulated and 96 were down-regulated. Bioinformatics analysis of the cross-talk between the significant proteins with altered expression in bupivacaine-induced neurotoxicity indicated that phosphatidyl-3-kinase (PI3K) was the most frequently targeted protein in each of the interactions. We further confirmed these results by determining the downstream targets of the identified signaling pathways (PI3K, Akt, FoxO1, Erk, and JNK). In conclusion, our study demonstrated that PI3K may play a central role in contacting and regulating the signaling pathways that contribute to bupivacaine-induced neurotoxicity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Zhao, Shilin; Li, Rongxia; Cai, Xiaofan; Chen, Wanjia; Li, Qingrun; Xing, Tao; Zhu, Wenjie; Chen, Y Eugene; Zeng, Rong; Deng, Yueyi
Body fluid proteome is the most informative proteome from a medical viewpoint. But the lack of accurate quantitation method for complicated body fluid limited its application in disease research and biomarker discovery. To address this problem, we introduced a novel strategy, in which SILAC-labeled mouse serum was used as internal standard for human serum and urine proteome analysis. The SILAC-labeled mouse serum was mixed with human serum and urine, and multidimensional separation coupled with tandem mass spectrometry (IEF-LC-MS/MS) analysis was performed. The shared peptides between two species were quantified by their SILAC pairs, and the human-only peptides were quantified by mouse peptides with coelution. The comparison for the results from two replicate experiments indicated the high repeatability of our strategy. Then the urine from Immunoglobulin A nephropathy patients treated and untreated was compared by this quantitation strategy. Fifty-three peptides were found to be significantly changed between two groups, including both known diagnostic markers for IgAN and novel candidates, such as Complement C3, Albumin, VDBP, ApoA,1 and IGFBP7. In conclusion, we have developed a practical and accurate quantitation strategy for comparison of complicated human body fluid proteome. The results from such strategy could provide potential disease-related biomarkers for evaluation of treatment.
Correa, Katharina; Lhorente, Jean P; López, María E; Bassini, Liane; Naswa, Sudhir; Deeb, Nader; Di Genova, Alex; Maass, Alejandro; Davidson, William S; Yáñez, José M
Pisciricketssia salmonis is the causal agent of Salmon Rickettsial Syndrome (SRS), which affects salmon species and causes severe economic losses. Selective breeding for disease resistance represents one approach for controlling SRS in farmed Atlantic salmon. Knowledge concerning the architecture of the resistance trait is needed before deciding on the most appropriate approach to enhance artificial selection for P. salmonis resistance in Atlantic salmon. The purpose of the study was to dissect the genetic variation in the resistance to this pathogen in Atlantic salmon. 2,601 Atlantic salmon smolts were experimentally challenged against P. salmonis by means of intra-peritoneal injection. These smolts were the progeny of 40 sires and 118 dams from a Chilean breeding population. Mortalities were recorded daily and the experiment ended at day 40 post-inoculation. Fish were genotyped using a 50K Affymetrix® Axiom® myDesignTM Single Nucleotide Polymorphism (SNP) Genotyping Array. A Genome Wide Association Analysis was performed on data from the challenged fish. Linear regression and logistic regression models were tested. Genome Wide Association Analysis indicated that resistance to P. salmonis is a moderately polygenic trait. There were five SNPs in chromosomes Ssa01 and Ssa17 significantly associated with the traits analysed. The proportion of the phenotypic variance explained by each marker is small, ranging from 0.007 to 0.045. Candidate genes including interleukin receptors and fucosyltransferase have been found to be physically linked with these genetic markers and may play an important role in the differential immune response against this pathogen. Due to the small amount of variance explained by each significant marker we conclude that genetic resistance to this pathogen can be more efficiently improved with the implementation of genetic evaluations incorporating genotype information from a dense SNP array.
Full Text Available Fusarium proliferatum and F. verticillioides are considered as minor pathogens of pea (Pisum sativum L.. Both species can survive in seed material without visible disease symptoms, but still contaminating it with fumonisins. Two populations of pea-derived F. proliferatum and F. verticillioides strains were subjected to FUM1 sequence divergence analysis, forming a distinct group when compared to the collection strains originating from different host species. Furthermore, the mycotoxigenic abilities of those strains were evaluated on the basis of in planta and in vitro fumonisin biosynthesis. No differences were observed in fumonisin B (FB levels measured in pea seeds (maximum level reached 1.5 μg g−1; however, in rice cultures, the majority of F. proliferatum genotypes produced higher amounts of FB1–FB3 than F. verticillioides strains.
Horner, Stacy M; Wilkins, Courtney; Badil, Samantha; Iskarpatyoti, Jason; Gale, Michael
RIG-I pathway signaling of innate immunity against RNA virus infection is organized between the ER and mitochondria on a subdomain of the ER called the mitochondrial-associated ER membrane (MAM). The RIG-I adaptor protein MAVS transmits downstream signaling of antiviral immunity, with signaling complexes assembling on the MAM in association with mitochondria and peroxisomes. To identify components that regulate MAVS signalosome assembly on the MAM, we characterized the proteome of MAM, ER, and cytosol from cells infected with either chronic (hepatitis C) or acute (Sendai) RNA virus infections, as well as mock-infected cells. Comparative analysis of protein trafficking dynamics during both chronic and acute viral infection reveals differential protein profiles in the MAM during RIG-I pathway activation. We identified proteins and biochemical pathways recruited into and out of the MAM in both chronic and acute RNA viral infections, representing proteins that drive immunity and/or regulate viral replication. In addition, by using this comparative proteomics approach, we identified 3 new MAVS-interacting proteins, RAB1B, VTN, and LONP1, and defined LONP1 as a positive regulator of the RIG-I pathway. Our proteomic analysis also reveals a dynamic cross-talk between subcellular compartments during both acute and chronic RNA virus infection, and demonstrates the importance of the MAM as a central platform that coordinates innate immune signaling to initiate immunity against RNA virus infection.
Full Text Available The MYC oncogene has been implicated in the regulation of up to thousands of genes involved in many cellular programs including proliferation, growth, differentiation, self-renewal, and apoptosis. MYC is thought to induce cancer through an exaggerated effect on these physiologic programs. Which of these genes are responsible for the ability of MYC to initiate and/or maintain tumorigenesis is not clear. Previously, we have shown that upon brief MYC inactivation, some tumors undergo sustained regression. Here we demonstrate that upon MYC inactivation there are global permanent changes in gene expression detected by microarray analysis. By applying StepMiner analysis, we identified genes whose expression most strongly correlated with the ability of MYC to induce a neoplastic state. Notably, genes were identified that exhibited permanent changes in mRNA expression upon MYC inactivation. Importantly, permanent changes in gene expression could be shown by chromatin immunoprecipitation (ChIP to be associated with permanent changes in the ability of MYC to bind to the promoter regions. Our list of candidate genes associated with tumor maintenance was further refined by comparing our analysis with other published results to generate a gene signature associated with MYC-induced tumorigenesis in mice. To validate the role of gene signatures associated with MYC in human tumorigenesis, we examined the expression of human homologs in 273 published human lymphoma microarray datasets in Affymetrix U133A format. One large functional group of these genes included the ribosomal structural proteins. In addition, we identified a group of genes involved in a diverse array of cellular functions including: BZW2, H2AFY, SFRS3, NAP1L1, NOLA2, UBE2D2, CCNG1, LIFR, FABP3, and EDG1. Hence, through our analysis of gene expression in murine tumor models and human lymphomas, we have identified a novel gene signature correlated with the ability of MYC to maintain tumorigenesis.
Murphy, Derek M
BACKGROUND: Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is a major cause of childhood cancer related deaths. The single most important prognostic indicator of poor clinical outcome in this disease is genomic amplification of MYCN, a member of a family of oncogenic transcription factors. METHODOLOGY: We applied MYCN chromatin immunoprecipitation to microarrays (ChIP-chip) using MYCN amplified\\/non-amplified cell lines as well as a conditional knockdown cell line to determine the distribution of MYCN binding sites within all annotated promoter regions. CONCLUSION: Assessment of E-box usage within consistently positive MYCN binding sites revealed a predominance for the CATGTG motif (p<0.0016), with significant enrichment of additional motifs CATTTG, CATCTG, CAACTG in the MYCN amplified state. For cell lines over-expressing MYCN, gene ontology analysis revealed enrichment for the binding of MYCN at promoter regions of numerous molecular functional groups including DNA helicases and mRNA transcriptional regulation. In order to evaluate MYCN binding with respect to other genomic features, we determined the methylation status of all annotated CpG islands and promoter sequences using methylated DNA immunoprecipitation (MeDIP). The integration of MYCN ChIP-chip and MeDIP data revealed a highly significant positive correlation between MYCN binding and DNA hypermethylation. This association was also detected in regions of hemizygous loss, indicating that the observed association occurs on the same homologue. In summary, these findings suggest that MYCN binding occurs more commonly at CATGTG as opposed to the classic CACGTG E-box motif, and that disease associated over expression of MYCN leads to aberrant binding to additional weaker affinity E-box motifs in neuroblastoma. The co-localization of MYCN binding and DNA hypermethylation further supports the dual role of MYCN, namely that of a classical transcription factor affecting the
Yen Ling Low
Full Text Available Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p(global = 0.034 and endometrial (p(global = 0.052 cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p(global = 0.008 and endometrial cancer (p(global = 0.014. The sub-pathway association was validated in the Finnish sample of breast cancer (p(global = 0.015. Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (p(global = 0.0003. Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite
Duy Ngoc Do
Full Text Available Residual feed intake (RFI is a complex trait that is economically important for livestock production; however, the genetic and biological mechanisms regulating RFI are largely unknown in pigs. Therefore, the study aimed to identify single nucleotide polymorphisms (SNPs, candidate genes and biological pathways involved in regulating RFI using Genome-wide association (GWA and pathway analyses. A total of 596 Yorkshire boars with phenotypes for two different measures of RFI (RFI1 and 2 and 60k genotypic data was used. Genome-wide association analysis was performed using a univariate mixed model and 12 and 7 SNPs were found to be significantly associated with RFI1 and RFI2, respectively. Several genes such as XIRP2, TTC29, SOGA1, MAS1, GRK5, PROX1, GPR155 and ZFYVE26 were identified as putative candidates for RFI based on their genomic location in the vicinity of these SNPs. Genes located within 50 kilo base pairs of SNPs significantly associated with RFI and RFI2 (q-value ≤ 0.2 were subsequently used for pathway analyses. These analyses were performed by assigning genes to biological pathways and then testing the association of individual pathways with RFI using a Fisher’s exact test. Metabolic pathway was significantly associated with both RFIs. Other biological pathways regulating phagosome, tight junctions, olfactory transduction, and insulin secretion were significantly associated with both RFI traits when relaxed threshold for cut-off p-value was used (p ≤ 0.05. These results implied porcine RFI is regulated by multiple biological mechanisms, although the metabolic processes might be the most important. Olfactory transduction pathway controlling the perception of feed via smell, insulin pathway controlling food intake might be important pathways for RFI. Furthermore, our study revealed key genes and genetic variants that control feed efficiency that could potentially be useful for genetic selection of more feed efficient pigs.
Su, Hsun-Cheng; Khatun, Jainab; Kanavy, Dona M; Giddings, Morgan C
The alarming rise of ciprofloxacin-resistant Pseudomonas aeruginosa has been reported in several clinical studies. Though the mutation of resistance genes and their role in drug resistance has been researched, the process by which the bacterium acquires high-level resistance is still not well understood. How does the genomic evolution of P. aeruginosa affect resistance development? Could the exposure of antibiotics to the bacteria enrich genomic variants that lead to the development of resistance, and if so, how are these variants distributed through the genome? To answer these questions, we performed 454 pyrosequencing and a whole genome analysis both before and after exposure to ciprofloxacin. The comparative sequence data revealed 93 unique resistance strain variation sites, which included a mutation in the DNA gyrase subunit A gene. We generated variation-distribution maps comparing the wild and resistant types, and isolated 19 candidates from three discrete resistance-associated high variability regions that had available transposon mutants, to perform a ciprofloxacin exposure assay. Of these region candidates with transposon disruptions, 79% (15/19) showed a reduction in the ability to gain high-level resistance, suggesting that genes within these high variability regions might enrich for certain functions associated with resistance development.
Sung, Uhna; Jennings, Jennifer L.; Link, Andrew J.; Blakely, Randy D.
The norepinephrine transporter (NET) terminates noradrenergic signals by clearing released NE at synapses. NET regulation by receptors and intracellular signaling pathways is supported by a growing list of associated proteins including syntaxin1A, protein phosphatase 2A (PP2A) catalytic subunit (PP2A-C), PICK1, and Hic-5. In the present study, we sought evidence for additional partnerships by mass spectrometry-based analysis of proteins co-immunoprecipitated with human NET (hNET) stably expressed in a mouse noradrenergic neuroblastoma cell line. Our initial proteomic analyses reveal multiple peptides derived from hNET, peptides arising from the mouse PP2A anchoring subunit (PP2A-Ar) and peptides derived from 14-3-3 proteins. We verified physical association of NET with PP2A-Ar via co-immunoprecipitation studies using mouse vas deferens extracts and with 14-3-3 via a fusion pull-down approach, implicating specifically the hNET NH 2 -terminus for interactions. The transporter complexes described likely support mechanisms regulating transporter activity, localization, and trafficking
Bainard, Jillian D; Bainard, Luke D; Henry, Thomas A; Fazekas, Aron J; Newmaster, Steven G
Genome size (C-value) and endopolyploidy (endoreduplication index, EI) are known to correlate with various morphological and ecological traits, in addition to phylogenetic placement. A phylogenetically controlled multivariate analysis was used to explore the relationships between DNA content and phenotype in angiosperms. Seeds from 41 angiosperm species (17 families) were grown in a common glasshouse experiment. Genome size (2C-value and 1Cx-value) and EI (in four tissues: leaf, stem, root, petal) were determined using flow cytometry. The phylogenetic signal was calculated for each measure of DNA content, and phylogenetic canonical correlation analysis (PCCA) explored how the variation in genome size and EI was correlated with 18 morphological and ecological traits. Phylogenetic signal (λ) was strongest for EI in all tissues, and λ was stronger for the 2C-value than the 1Cx-value. PCCA revealed that EI was correlated with pollen length, stem height, seed mass, dispersal mechanism, arbuscular mycorrhizal association, life history and flowering time, and EI and genome size were both correlated with stem height and life history. PCCA provided an effective way to explore multiple factors of DNA content variation and phenotypic traits in a phylogenetic context. Traits that were correlated significantly with DNA content were linked to plant competitive ability. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.
Full Text Available Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS (prototype for AED-resistant epilepsy; juvenile myoclonic epilepsy (JME (prototype for AED-responsive epilepsy; and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004. This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004 and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05 cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with greater tendency
Heid, Iris M; Jackson, Anne U; Randall, Joshua C; Winkler, Thomas W; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M Carola; Speliotes, Elizabeth K; Mägi, Reedik; Workalemahu, Tsegaselassie; White, Charles C; Bouatia-Naji, Nabila; Harris, Tamara B; Berndt, Sonja I; Ingelsson, Erik; Willer, Cristen J; Weedon, Michael N; Luan, Jian'an; Vedantam, Sailaja; Esko, Tõnu; Kilpeläinen, Tuomas O; Kutalik, Zoltán; Li, Shengxu; Monda, Keri L; Dixon, Anna L; Holmes, Christopher C; Kaplan, Lee M; Liang, Liming; Min, Josine L; Moffatt, Miriam F; Molony, Cliona; Nicholson, George; Schadt, Eric E; Zondervan, Krina T; Feitosa, Mary F; Ferreira, Teresa; Lango Allen, Hana; Weyant, Robert J; Wheeler, Eleanor; Wood, Andrew R; Estrada, Karol; Goddard, Michael E; Lettre, Guillaume; Mangino, Massimo; Nyholt, Dale R; Purcell, Shaun; Smith, Albert Vernon; Visscher, Peter M; Yang, Jian; McCarroll, Steven A; Nemesh, James; Voight, Benjamin F; Absher, Devin; Amin, Najaf; Aspelund, Thor; Coin, Lachlan; Glazer, Nicole L; Hayward, Caroline; Heard-Costa, Nancy L; Hottenga, Jouke-Jan; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kapur, Karen; Ketkar, Shamika; Knowles, Joshua W; Kraft, Peter; Kraja, Aldi T; Lamina, Claudia; Leitzmann, Michael F; McKnight, Barbara; Morris, Andrew P; Ong, Ken K; Perry, John R B; Peters, Marjolein J; Polasek, Ozren; Prokopenko, Inga; Rayner, Nigel W; Ripatti, Samuli; Rivadeneira, Fernando; Robertson, Neil R; Sanna, Serena; Sovio, Ulla; Surakka, Ida; Teumer, Alexander; van Wingerden, Sophie; Vitart, Veronique; Zhao, Jing Hua; Cavalcanti-Proença, Christine; Chines, Peter S; Fisher, Eva; Kulzer, Jennifer R; Lecoeur, Cecile; Narisu, Narisu; Sandholt, Camilla; Scott, Laura J; Silander, Kaisa; Stark, Klaus; Tammesoo, Mari-Liis; Teslovich, Tanya M; Timpson, Nicholas John; Watanabe, Richard M; Welch, Ryan; Chasman, Daniel I; Cooper, Matthew N; Jansson, John-Olov; Kettunen, Johannes; Lawrence, Robert W; Pellikka, Niina; Perola, Markus; Vandenput, Liesbeth; Alavere, Helene; Almgren, Peter; Atwood, Larry D; Bennett, Amanda J; Biffar, Reiner; Bonnycastle, Lori L; Bornstein, Stefan R; Buchanan, Thomas A; Campbell, Harry; Day, Ian N M; Dei, Mariano; Dörr, Marcus; Elliott, Paul; Erdos, Michael R; Eriksson, Johan G; Freimer, Nelson B; Fu, Mao; Gaget, Stefan; Geus, Eco J C; Gjesing, Anette P; Grallert, Harald; Grässler, Jürgen; Groves, Christopher J; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Havulinna, Aki S; Herzig, Karl-Heinz; Hicks, Andrew A; Hui, Jennie; Igl, Wilmar; Jousilahti, Pekka; Jula, Antti; Kajantie, Eero; Kinnunen, Leena; Kolcic, Ivana; Koskinen, Seppo; Kovacs, Peter; Kroemer, Heyo K; Krzelj, Vjekoslav; Kuusisto, Johanna; Kvaloy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lathrop, G Mark; Lokki, Marja-Liisa; Luben, Robert N; Ludwig, Barbara; McArdle, Wendy L; McCarthy, Anne; Morken, Mario A; Nelis, Mari; Neville, Matt J; Paré, Guillaume; Parker, Alex N; Peden, John F; Pichler, Irene; Pietiläinen, Kirsi H; Platou, Carl G P; Pouta, Anneli; Ridderstråle, Martin; Samani, Nilesh J; Saramies, Jouko; Sinisalo, Juha; Smit, Jan H; Strawbridge, Rona J; Stringham, Heather M; Swift, Amy J; Teder-Laving, Maris; Thomson, Brian; Usala, Gianluca; van Meurs, Joyce B J; van Ommen, Gert-Jan; Vatin, Vincent; Volpato, Claudia B; Wallaschofski, Henri; Walters, G Bragi; Widen, Elisabeth; Wild, Sarah H; Willemsen, Gonneke; Witte, Daniel R; Zgaga, Lina; Zitting, Paavo; Beilby, John P; James, Alan L; Kähönen, Mika; Lehtimäki, Terho; Nieminen, Markku S; Ohlsson, Claes; Palmer, Lyle J; Raitakari, Olli; Ridker, Paul M; Stumvoll, Michael; Tönjes, Anke; Viikari, Jorma; Balkau, Beverley; Ben-Shlomo, Yoav; Bergman, Richard N; Boeing, Heiner; Smith, George Davey; Ebrahim, Shah; Froguel, Philippe; Hansen, Torben; Hengstenberg, Christian; Hveem, Kristian; Isomaa, Bo; Jørgensen, Torben; Karpe, Fredrik; Khaw, Kay-Tee; Laakso, Markku; Lawlor, Debbie A; Marre, Michel; Meitinger, Thomas; Metspalu, Andres; Midthjell, Kristian; Pedersen, Oluf; Salomaa, Veikko; Schwarz, Peter E H; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Valle, Timo T; Wareham, Nicholas J; Arnold, Alice M; Beckmann, Jacques S; Bergmann, Sven; Boerwinkle, Eric; Boomsma, Dorret I; Caulfield, Mark J; Collins, Francis S; Eiriksdottir, Gudny; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Hattersley, Andrew T; Hofman, Albert; Hu, Frank B; Illig, Thomas; Iribarren, Carlos; Jarvelin, Marjo-Riitta; Kao, W H Linda; Kaprio, Jaakko; Launer, Lenore J; Munroe, Patricia B; Oostra, Ben; Penninx, Brenda W; Pramstaller, Peter P; Psaty, Bruce M; Quertermous, Thomas; Rissanen, Aila; Rudan, Igor; Shuldiner, Alan R; Soranzo, Nicole; Spector, Timothy D; Syvanen, Ann-Christine; Uda, Manuela; Uitterlinden, André; Völzke, Henry; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Wright, Alan F; Abecasis, Gonçalo R; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Groop, Leif C; Haritunians, Talin; Hunter, David J; Kaplan, Robert C; North, Kari E; O'Connell, Jeffrey R; Peltonen, Leena; Schlessinger, David; Strachan, David P; Hirschhorn, Joel N; Assimes, Themistocles L; Wichmann, H-Erich; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Stefansson, Kari; Cupples, L Adrienne; Loos, Ruth J F; Barroso, Inês; McCarthy, Mark I; Fox, Caroline S; Mohlke, Karen L; Lindgren, Cecilia M
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Kouprina, Natalay; Noskov, Vladimir N.; Waterfall, Joshua J.; Walker, Robert L.; Meltzer, Paul S.; Topol, Eric J.; Larionov, Vladimir
Tandem segmental duplications (SDs) greater than 10 kb are widespread in complex genomes. They provide material for gene divergence and evolutionary adaptation, while formation of specific de novo SDs is a hallmark of cancer and some human diseases. Most SDs map to distinct genomic regions termed ‘duplication blocks’. SDs organization within these blocks is often poorly characterized as they are mosaics of ancestral duplicons juxtaposed with younger duplicons arising from more recent duplication events. Structural and functional analysis of SDs is further hampered as long repetitive DNA structures are underrepresented in existing BAC and YAC libraries. We applied Transformation-Associated Recombination (TAR) cloning, a versatile technique for large DNA manipulation, to selectively isolate the coronary artery disease (CAD) interval sequence within the 9p21.3 chromosome locus from a patient with coronary artery disease and normal individuals. Four tandem head-to-tail duplicons, each ∼50 kb long, were recovered in the patient but not in normal individuals. Sequence analysis revealed that the repeats varied by 10-15 SNPs between each other and by 82 SNPs between the human genome sequence (version hg19). SNPs polymorphism within the junctions between repeats allowed two junction types to be distinguished, Type 1 and Type 2, which were found at a 2:1 ratio. The junction sequences contained an Alu element, a sequence previously shown to play a role in duplication. Knowledge of structural variation in the CAD interval from more patients could help link this locus to cardiovascular diseases susceptibility, and maybe relevant to other cases of regional amplification, including cancer. PMID:29632643
Full Text Available Cymbidium ensifolium belongs to the genus Cymbidium of the orchid family. Owing to its spectacular flower morphology, C. ensifolium has considerable ecological and cultural value. However, limited genetic data is available for this non-model plant, and the molecular mechanism underlying floral organ identity is still poorly understood. In this study, we characterize the floral transcriptome of C. ensifolium and present, for the first time, extensive sequence and transcript abundance data of individual floral organs. After sequencing, over 10 Gb clean sequence data were generated and assembled into 111,892 unigenes with an average length of 932.03 base pairs, including 1,227 clusters and 110,665 singletons. Assembled sequences were annotated with gene descriptions, gene ontology, clusters of orthologous group terms, the Kyoto Encyclopedia of Genes and Genomes, and the plant transcription factor database. From these annotations, 131 flowering-associated unigenes, 61 CONSTANS-LIKE (COL unigenes and 90 floral homeotic genes were identified. In addition, four digital gene expression libraries were constructed for the sepal, petal, labellum and gynostemium, and 1,058 genes corresponding to individual floral organ development were identified. Among them, eight MADS-box genes were further investigated by full-length cDNA sequence analysis and expression validation, which revealed two APETALA1/AGL9-like MADS-box genes preferentially expressed in the sepal and petal, two AGAMOUS-like genes particularly restricted to the gynostemium, and four DEF-like genes distinctively expressed in different floral organs. The spatial expression of these genes varied distinctly in different floral mutant corresponding to different floral morphogenesis, which validated the specialized roles of them in floral patterning and further supported the effectiveness of our in silico analysis. This dataset generated in our study provides new insights into the molecular mechanisms
Kitawi, Rose C; Hunja, Carol W; Aman, Rashid; Ogutu, Bernhards R; Muigai, Anne W T; Kokwaro, Gilbert O; Ochieng, Washingtone
HIV-1 is highly variable genetically and at protein level, a property it uses to subvert antiviral immunity and treatment. The aim of this study was to assess if HIV subtype differences were associated with variations in glycosylation patterns and co-receptor tropism among HAART patients experiencing different virologic treatment outcomes. A total of 118 HIV env C2V3 sequence isolates generated previously from 59 Kenyan patients receiving highly active antiretroviral therapy (HAART) were examined for tropism and glycosylation patterns. For analysis of Potential N-linked glycosylation sites (PNGs), amino acid sequences generated by the NCBI's Translate tool were applied to the HIVAlign and the N-glycosite tool within the Los Alamos Database. Viral tropism was assessed using Geno2Pheno (G2P), WebPSSM and Phenoseq platforms as well as using Raymond's and Esbjörnsson's rules. Chi square test was used to determine independent variables association and ANOVA applied on scale variables. At respective False Positive Rate (FPR) cut-offs of 5% (p = 0.045), 10% (p = 0.016) and 20% (p = 0.005) for CXCR4 usage within the Geno2Pheno platform, HIV-1 subtype and viral tropism were significantly associated in a chi square test. Raymond's rule (p = 0.024) and WebPSSM (p = 0.05), but not Phenoseq or Esbjörnsson showed significant associations between subtype and tropism. Relative to other platforms used, Raymond's and Esbjörnsson's rules showed higher proportions of X4 variants, while WebPSSM resulted in lower proportions of X4 variants across subtypes. The mean glycosylation density differed significantly between subtypes at positions, N277 (p = 0.034), N296 (p = 0.036), N302 (p = 0.034) and N366 (p = 0.004), with HIV-1D most heavily glycosylated of the subtypes. R5 isolates had fewer PNGs than X4 isolates, but these differences were not significant except at position N262 (p = 0.040). Cell-associated isolates from virologic treatment
Zhang, Lei; Zhu, Junwei; Chen, Yong; Zhao, Jianning
This study is to evaluate the association between the catechol-O-methyltransferase (COMT) gene val(158)met polymorphism and FM risk. We performed a meta-analysis of 8 case-control studies that included 589 FM cases and 527 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, this meta-analysis showed that the COMT gene val(158)met polymorphism was not associated with FM risk in all genetic models, i.e., allele (met vs. val: OR=1.46, 95% CI=0.80-2.66, P heterpgeneitysubgroup analyses by ethnicity and HWE. No publication bias was found in the present study. This meta-analysis suggests that the COMT gene val(158)met polymorphism is not associated with FM risk. Further large and well-designed studies are needed to confirm this association.
Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associ...
Full Text Available Previous studies in narcolepsy, an autoimmune disorder affecting hypocretin (orexin neurons and recently associated with H1N1 influenza, have demonstrated significant associations with five loci. Using a well-characterized Chinese cohort, we refined known associations in TRA@ and P2RY11-DNMT1 and identified new associations in the TCR beta (TRB@; rs9648789 max P = 3.7 × 10(-9 OR 0.77, ZNF365 (rs10995245 max P = 1.2 × 10(-11 OR 1.23, and IL10RB-IFNAR1 loci (rs2252931 max P = 2.2 × 10(-9 OR 0.75. Variants in the Human Leukocyte Antigen (HLA- DQ region were associated with age of onset (rs7744020 P = 7.9×10(-9 beta -1.9 years and varied significantly among cases with onset after the 2009 H1N1 influenza pandemic compared to previous years (rs9271117 P = 7.8 × 10(-10 OR 0.57. These reflected an association of DQB1*03:01 with earlier onset and decreased DQB1*06:02 homozygosity following 2009. Our results illustrate how genetic association can change in the presence of new environmental challenges and suggest that the monitoring of genetic architecture over time may help reveal the appearance of novel triggers for autoimmune diseases.
Kilarski, L. L.; Achterberg, S.; Devan, W. J.; Traylor, M.; Malik, R.; Lindgren, A.; Pare, G.; Sharma, P.; Slowik, A.; Thijs, V.; Walters, M.; Worrall, B. B.; Sale, M. M.; Algra, A.; Kappelle, L. J.
textabstractResults: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p 5 7.12 3 10-11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p 5 0.695).Conclusion: Our resu...
I.M. Heid (Iris); A.U. Jackson (Anne); J.C. Randall (Joshua); T.W. Winkler (Thomas); L. Qi (Lu); V. Ssteinthorsdottir (Valgerdur); G. Tthorleifsson (Ggudmar); M.C. Zillikens (Carola); E.K. Sspeliotes (Eelizabeth); R. Mägi (Reedik); T. Workalemahu (Tsegaselassie); C.C. White (Charles); N. Bouatia-Naji (Nabila); T.B. Harris (Tamara); S.I. Berndt (Sonja); E. Ingelsson (Erik); C.J. Willer (Cristen); J. Luan; S. Vedantam (Sailaja); T. Eesko (Tõnu); T.O. Kilpeläinen (Tuomas); Z. Kutalik (Zoltán); S. Li (Shengxu); K.L. Monda (Keri); A.L. Dixon (Anna); C. Holmes (Christopher); R.C. Kaplan (Robert); L. Liang (Liming); J. Min (Josine); M.F. Moffatt (Miriam); C. Molony (Cliona); G. Nicholson (Ggeorge); E.E. Sschadt (Eeric); K.T. Zondervan (Krina); M.F. Feitosa (Mary Furlan); T. Ferreira (Teresa); H.L. Allen; R.J. Weyant (Robert); E. Wheeler (Eleanor); A.R. Wood (Andrew); K. Eestrada (Karol); M.E. Goddard (Michael); G. Lettre (Guillaume); M. Mangino (Massimo); D.R. Nyholt (Dale); S. Purcell (Shaun); A.V. Ssmith; P.M. Visscher (Peter); J. Yang (Joanna); S.A. McCcarroll (Ssteven); J. Nemesh (James); B.F. Voight (Benjamin); D. Absher (Devin); N. Amin (Najaf); T. Aspelund (Thor); L. Coin (Lachlan); N.L. Glazer (Nicole); C. Hayward (Caroline); N. Heard-Ccosta (Nancy); J.J. Hottenga (Jouke Jan); A. Johansson (Åsa); T. Johnson (Toby); M. Kaakinen (Marika); K. Kapur (Karen); S. Ketkar (Shamika); J.W. Knowles (Joshua); P. Kraft (Peter); A. Kraja (Aldi); C. Lamina (Claudia); M.F. Leitzmann (Michael); B. McKknight (Barbara); A.D. Morris (Andrew); K. Oong (Ken); J.R.B. Perry (John); M.J. Peters (Marjolein); O. Polasek (Ozren); I. Prokopenko (Inga); N.W. Rayner (Nigel William); S. Ripatti (Samuli); F. Rivadeneira Ramirez (Fernando); N.R. Robertson (Neil); S. Sanna (Serena); U. Sovio (Ulla); I. Surakka (Ida); A. Teumer (Alexander); S. van Wingerden (Sophie); V. Vitart (Veronique); J.H. Zhao (Jing Hua); C. Cavalcanti-Proença (Christine); P.S. Chines (Peter); E. Fisher (Eeva); J.R. Kulzer (Jennifer); C. Lecoeur (Cécile); N. Narisu (Narisu); C. Sandholt (Camilla); L.J. Scott (Laura); K. Silander (Kaisa); K. Stark (Klaus); M.L. Tammesoo; T.M. Teslovich (Tanya); N.J. Timpson (Nicholas); R.P. Welch (Ryan); D.I. Chasman (Daniel); M.N. Cooper (Matthew); J.O. Jansson; J. Kettunen (Johannes); R. Wlawrence (Robert); N. Pellikka (Niina); M. Perola (Markus); L. Vandenput (Liesbeth); H. Alavere (Helene); P. Almgren (Peter); L.D. Atwood (Larry); A.J. Bennett (Amanda); R. Biffar (Reiner); L.L. Bonnycastle (Lori); S.R. Bornstein (Stefan); T.A. Buchanan (Thomas); H. Campbell (Harry); I.N.M. Day (Ian); M. Dei (Mariano); M. Dörr (Marcus); P. Eelliott (Paul); M.R. Eerdos (Micheal); J.G. Eeriksson (Johan); N.B. Freimer (Nelson); M. Fu (Mao); S. Gaget (Stefan); E.J.C. Geus (Eco); A.P. Gjesing (Anette); H. Grallert (Harald); J. Gräßler (Jürgen); C.J. Groves (Christopher); C. Guiducci (Candace); A.L. Hartikainen; N. Hassanali (Neelam); A.S. Havulinna (Aki); K.H. Herzig; A.A. Hicks (Andrew); J. Hui (Jennie); W. Igl (Wilmar); P. Jousilahti (Pekka); A. Jula (Antti); E. Kajantie (Eero); L. Kinnunen (Leena); I. Kolcic (Ivana); S. Koskinen (Seppo); P. Kovacs (Peter); H.K. Kroemer (Heyo); V. Krzelj (Vjekoslav); J. Kuusisto (Johanna); K. Kvaløy (Kirsti); J. Laitinen (Jaana); O. Lantieri (Olivier); G.M. Lathrop (Mark); M.L. Lokki; R.N. Luben (Robert); B. Ludwig (Barbara); W.L. McArdle (Wendy); A. McCcarthy (Anne); M.A. Morken (Mario); M. Nelis (Mari); M.J. Neville (Matthew); G. Paré (Guillaume); A.N. Parker (Alex); J. Peden (John); I. Pichler (Irene); K.H. Pietilainen (Kirsi Hannele); C.P. Platou (Carl); A. Pouta (Anneli); M. Ridderstråle (Martin); N.J. Samani (Nilesh); J. Saramies (Jouko); J. Sinisalo (Juha); J.H. Smit (Jan); R.J. Strawbridge (Rona); H.M. Stringham (Heather); A.J. Swift (Amy); M. Teder-Llaving (Maris); B. Thomson (Brian); G. Usala; J.B.J. van Meurs (Joyce); G.J. van Ommen (Gert); V. Vatin (Vincent); C.B. Volpato; H. Wallaschofski (Henri); G.B. Walters (Bragi); E. Widen (Elisabeth); S.H. Wild (Sarah); G.A.H.M. Willemsen (Gonneke); D.R. Witte (Deniel); L. Zgaga (Lina); P. Zitting (Paavo); J.P. Beilby (John); A. James (Alan); M. Kähönen (Mika); T. Lehtimäki (Terho); M.S. Nieminen (Markku); C. Ohlsson (Claes); C. Palmer (Cameron); O. Raitakari (Olli); P.M. Ridker (Paul); M. Stumvoll (Michael); A. Tönjes (Anke); J. Viikari (Jorma); B. Balkau (Beverley); Y. Ben-Shlomo; R.N. Bergman (Richard); H. Boeing (Heiner); A.V. Smith (Albert Vernon); S. Eebrahim (Shah); P. Froguel (Philippe); T. Hansen (Torben); C. Hengstenberg (Christian); K. Hveem (Kristian); B. Isomaa (Bo); T. Jørgensen (Torben); F. Karpe (Fredrik); K-T. Khaw (Kay-Tee); M. Laakso (Markku); D.A. Lawlor (Debbie); M. Marre (Michel); T. Meitinger (Thomas); A. Metspalu (Andres); K. Midthjell (Kristian); O. Pedersen (Oluf); V. Salomaa (Veikko); P.E.H. Schwarz (Peter); T. Tuomi (Tiinamaija); J. Tuomilehto (Jaakko); T.T. Valle (Timo); N.J. Wareham (Nick); A.M. Arnold (Alice); J.S. Beckmann (Jacques); S.M. Bergmann (Sven); E.A. Boerwinkle (Eric); D.I. Boomsma (Dorret); M. Caulfield (Mark); F.S. Collins (Francis); G. Eeiriksdottir (Gudny); V. Gudnason (Vilmundur); U. Gyllensten (Ulf); A. Hamsten (Anders); A.T. Hattersley (Andrew); A. Hofman (Albert); F.B. Hu (Frank); T. Illig (Thomas); C. Iribarren (Carlos); M.R. Järvelin; W.H.L. Kao (Wen); J. Kaprio (Jaakko); L.J. Launer (Lenore); P. Munroe (Patricia); B.A. Oostra (Ben); B.W.J.H. Penninx (Brenda); P.P. Pramstaller (Peter Paul); B.M. Psaty (Bruce); T. Quertermous (Thomas); A. Rissanen (Aila); I. Rudan (Igor); A.R. Shuldiner (Alan); N. Soranzo (Nicole); T.D. Spector (Timothy); A.C. Syvanen; M. Uda (Manuela); A.G. Uitterlinden (André); H. Völzke (Henry); P. Vollenweider (Peter); J.F. Wilson (James); J.C.M. Witteman (Jacqueline); A.F. Wright (Alan); G.R. Abecasis (Gonçalo); M. Boehnke (Michael); I.B. Borecki (Ingrid); P. Deloukas (Panagiotis); T.M. Frayling (Timothy); L. Groop (Leif); T. Haritunians (Talin); D.J. Hunter (David); K.E. North (Kari); J.R. O'Cconnell (Jeffrey); L. Peltonen (Leena Johanna); D. Schlessinger; D.P. Strachan (David); J.N. Hirschhorn (Joel); T.L. Assimes (Themistocles); H.E. Wichmann (Heinz Erich); U. Thorsteinsdottir (Unnur); C.M. van Duijn (Cornelia); K. Stefansson (Kari); L.A. Cupples (Adrienne); R.J.F. Loos (Ruth); I. Barroso (Inês); C.S. Fox (Caroline); K.L. Mohlke (Karen); C.M. Lindgren (Cecilia); R.M. Watanabe (Richard); M.N. Weedon (Michael)
textabstractWaist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association
Heid, Iris M.; Jackson, Anne U.; Randall, Joshua C.; Winkler, Thomas W.; Qi, Lu; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Zillikens, M. Carola; Speliotes, Elizabeth K.; Maegi, Reedik; Workalemahu, Tsegaselassie; White, Charles C.; Bouatia-Naji, Nabila; Harris, Tamara B.; Berndt, Sonja I.; Ingelsson, Erik; Willer, Cristen J.; Weedon, Michael N.; Luan, Jianan; Vedantam, Sailaja; Esko, Tonu; Kilpelaeinen, Tuomas O.; Kutalik, Zoltan; Li, Shengxu; Monda, Keri L.; Dixon, Anna L.; Holmes, Christopher C.; Kaplan, Lee M.; Liang, Liming; Min, Josine L.; Moffatt, Miriam F.; Molony, Cliona; Nicholson, George; Schadt, Eric E.; Zondervan, Krina T.; Feitosa, Mary F.; Ferreira, Teresa; Allen, Hana Lango; Weyant, Robert J.; Wheeler, Eleanor; Wood, Andrew R.; Estrada, Karol; Goddard, Michael E.; Lettre, Guillaume; Mangino, Massimo; Nyholt, Dale R.; Purcell, Shaun; Smith, Albert Vernon; Visscher, Peter M.; Yang, Jian; McCarroll, Steven A.; Nemesh, James; Voight, Benjamin F.; Absher, Devin; Amin, Najaf; Aspelund, Thor; Coin, Lachlan; Glazer, Nicole L.; Hayward, Caroline; Heard-Costa, Nancy L.; Hottenga, Jouke-Jan; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kapur, Karen; Ketkar, Shamika; Knowles, Joshua W.; Kraft, Peter; Kraja, Aldi T.; Lamina, Claudia; Leitzmann, Michael F.; McKnight, Barbara; Morris, Andrew P.; Ong, Ken K.; Perry, John R. B.; Peters, Marjolein J.; Polasek, Ozren; Prokopenko, Inga; Rayner, Nigel W.; Ripatti, Samuli; Rivadeneira, Fernando; Robertson, Neil R.; Sanna, Serena; Sovio, Ulla; Surakka, Ida; Teumer, Alexander; van Wingerden, Sophie; Vitart, Veronique; Zhao, Jing Hua; Cavalcanti-Proenca, Christine; Chines, Peter S.; Fisher, Eva; Kulzer, Jennifer R.; Lecoeur, Cecile; Narisu, Narisu; Sandholt, Camilla; Scott, Laura J.; Silander, Kaisa; Stark, Klaus; Tammesoo, Mari-Liis; Teslovich, Tanya M.; Timpson, Nicholas John; Watanabe, Richard M.; Welch, Ryan; Chasman, Daniel I.; Cooper, Matthew N.; Jansson, John-Olov; Kettunen, Johannes; Lawrence, Robert W.; Pellikka, Niina; Perola, Markus; Vandenput, Liesbeth; Alavere, Helene; Almgren, Peter; Atwood, Larry D.; Bennett, Amanda J.; Biffar, Reiner; Bonnycastle, Lori L.; Bornstein, Stefan R.; Buchanan, Thomas A.; Campbell, Harry; Day, Ian N. M.; Dei, Mariano; Doerr, Marcus; Elliott, Paul; Erdos, Michael R.; Eriksson, Johan G.; Freimer, Nelson B.; Fu, Mao; Gaget, Stefan; Geus, Eco J. C.; Gjesing, Anette P.; Grallert, Harald; Graessler, Juergen; Groves, Christopher J.; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Havulinna, Aki S.; Herzig, Karl-Heinz; Hicks, Andrew A.; Hui, Jennie; Igl, Wilmar; Jousilahti, Pekka; Jula, Antti; Kajantie, Eero; Kinnunen, Leena; Kolcic, Ivana; Koskinen, Seppo; Kovacs, Peter; Kroemer, Heyo K.; Krzelj, Vjekoslav; Kuusisto, Johanna; Kvaloy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lathrop, G. Mark; Lokki, Marja-Liisa; Luben, Robert N.; Ludwig, Barbara; McArdle, Wendy L.; McCarthy, Anne; Morken, Mario A.; Nelis, Mari; Neville, Matt J.; Pare, Guillaume; Parker, Alex N.; Peden, John F.; Pichler, Irene; Pietilainen, Kirsi H.; Platou, Carl G. P.; Pouta, Anneli; Ridderstrale, Martin; Samani, Nilesh J.; Saramies, Jouko; Sinisalo, Juha; Smit, Jan H.; Strawbridge, Rona J.; Stringham, Heather M.; Swift, Amy J.; Teder-Laving, Maris; Thomson, Brian; Usala, Gianluca; van Meurs, Joyce B. J.; van Ommen, Gert-Jan; Vatin, Vincent; Volpato, Claudia B.; Wallaschofski, Henri; Walters, G. Bragi; Widen, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Witte, Daniel R.; Zgaga, Lina; Zitting, Paavo; Beilby, John P.; James, Alan L.; Kahonen, Mika; Lehtimaki, Terho; Nieminen, Markku S.; Ohlsson, Claes; Palmer, Lyle J.; Raitakari, Olli; Ridker, Paul M.; Stumvoll, Michael; Toenjes, Anke; Viikari, Jorma; Balkau, Beverley; Ben-Shlomo, Yoav; Bergman, Richard N.; Boeing, Heiner; Smith, George Davey; Ebrahim, Shah; Froguel, Philippe; Hansen, Torben; Hengstenberg, Christian; Hveem, Kristian; Isomaa, Bo; Jorgensen, Torben; Karpe, Fredrik; Khaw, Kay-Tee; Laakso, Markku; Lawlor, Debbie A.; Marre, Michel; Meitinger, Thomas; Metspalu, Andres; Midthjell, Kristian; Pedersen, Oluf; Salomaa, Veikko; Schwarz, Peter E. H.; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Valle, Timo T.; Wareham, Nicholas J.; Arnold, Alice M.; Beckmann, Jacques S.; Bergmann, Sven; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Collins, Francis S.; Eiriksdottir, Gudny; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Hattersley, Andrew T.; Hofman, Albert; Hu, Frank B.; Illig, Thomas; Iribarren, Carlos; Jarvelin, Marjo-Riitta; Kao, W. H. Linda; Kaprio, Jaakko; Launer, Lenore J.; Munroe, Patricia B.; Oostra, Ben; Penninx, Brenda W.; Pramstaller, Peter P.; Psaty, Bruce M.; Quertermous, Thomas; Rissanen, Aila; Rudan, Igor; Shuldiner, Alan R.; Soranzo, Nicole; Spector, Timothy D.; Syvanen, Ann-Christine; Uda, Manuela; Uitterlinden, Andre; Voelzke, Henry; Vollenweider, Peter; Wilson, James F.; Witteman, Jacqueline C.; Wright, Alan F.; Abecasis, Goncalo R.; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Frayling, Timothy M.; Groop, Leif C.; Haritunians, Talin; Hunter, David J.; Kaplan, Robert C.; North, Kari E.; O'Connell, Jeffrey R.; Peltonen, Leena; Schlessinger, David; Strachan, David P.; Hirschhorn, Joel N.; Assimes, Themistocles L.; Wichmann, H-Erich; Thorsteinsdottir, Unnur; van Duijn, Cornelia M.; Stefansson, Kari; Cupples, L. Adrienne; Loos, Ruth J. F.; Barroso, Ines; McCarthy, Mark I.; Fox, Caroline S.; Mohlke, Karen L.; Lindgren, Cecilia M.
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR
K. Estrada Gil (Karol); U. Styrkarsdottir (Unnur); E. Evangelou (Evangelos); Y.-H. Hsu (Yi-Hsiang); E.L. Duncan (Emma); E.E. Ntzani (Evangelia); L. Oei (Ling); O.M.E. Albagha (Omar M.); N. Amin (Najaf); J.P. Kemp (John); D.L. Koller (Daniel); G. Li (Guo); C.-T. Liu (Ching-Ti); R.L. Minster (Ryan); A. Moayyeri (Alireza); L. Vandenput (Liesbeth); D. Willner (Dana); S.-M. Xiao (Su-Mei); L.M. Yerges-Armstrong (Laura); H.-F. Zheng (Hou-Feng); N. Alonso (Nerea); J. Eriksson (Joel); C.M. Kammerer (Candace); S. Kaptoge (Stephen); P.J. Leo (Paul); G. Thorleifsson (Gudmar); S.G. Wilson (Scott); J.F. Wilson (James); V. Aalto (Ville); T.A. van Alen (Theo); A.K. Aragaki (Aaron); T. Aspelund (Thor); J.R. Center (Jacqueline); Z. Dailiana (Zoe); C. Duggan; M. Garcia (Melissa); N. Garcia-Giralt (Natàlia); S. Giroux (Sylvie); G. Hallmans (Göran); L.J. Hocking (Lynne); L.B. Husted (Lise Bjerre); K. Jameson (Karen); R. Khusainova (Rita); G.S. Kim (Ghi Su); C. Kooperberg (Charles); T. Koromila (Theodora); M. Kruk (Marcin); M. Laaksonen (Marika); A.Z. LaCroix (Andrea); S.U. Lee (Seung); P.C. Leung (Ping); J.R. Lewis (Joshua); L. Masi (Laura); S. Mencej-Bedrac (Simona); T.V. Nguyen (Tuan); X. Nogues (Xavier); M.S. Patel (Millan); J. Prezelj (Janez); L.M. Rose (Lynda); S. Scollen (Serena); K. Siggeirsdottir (Kristin); G.D. Smith; O. Svensson (Olle); S. Trompet (Stella); O. Trummer (Olivia); N.M. van Schoor (Natasja); M.M. Woo (Margaret M.); K. Zhu (Kun); S. Balcells (Susana); M.L. Brandi; B.M. Buckley (Brendan M.); S. Cheng (Sulin); C. Christiansen; C. Cooper (Charles); G.V. Dedoussis (George); I. Ford (Ian); M. Frost (Morten); D. Goltzman (David); J. González-Macías (Jesús); M. Kähönen (Mika); M. Karlsson (Magnus); E.K. Khusnutdinova (Elza); J.-M. Koh (Jung-Min); P. Kollia (Panagoula); B.L. Langdahl (Bente); W.D. Leslie (William); P. Lips (Paul); O. Ljunggren (Östen); R. Lorenc (Roman); J. Marc (Janja); D. Mellström (Dan); B. Obermayer-Pietsch (Barbara); D. Olmos (David); U. Pettersson-Kymmer (Ulrika); D.M. Reid (David); J.A. Riancho (José); P.M. Ridker (Paul); M.F. Rousseau (Francois); P.E.S. Lagboom (P Eline); N.L.S. Tang (Nelson L.); R. Urreizti (Roser); W. Van Hul (Wim); J. Viikari (Jorma); M.T. Zarrabeitia (María); Y.S. Aulchenko (Yurii); M.C. Castaño Betancourt (Martha); E. Grundberg (Elin); L. Herrera (Lizbeth); T. Ingvarsson (Torvaldur); H. Johannsdottir (Hrefna); T. Kwan (Tony); R. Li (Rui); R.N. Luben (Robert); M.C. Medina-Gomez (Carolina); S. Th Palsson (Stefan); S. Reppe (Sjur); J.I. Rotter (Jerome); G. Sigurdsson (Gunnar); J.B.J. van Meurs (Joyce); D.J. Verlaan (Dominique); F.M. Williams (Frances); A.R. Wood (Andrew); Y. Zhou (Yanhua); K.M. Gautvik (Kaare); T. Pastinen (Tomi); S. Raychaudhuri (Soumya); J.A. Cauley (Jane); D.I. Chasman (Daniel); G.R. Clark (Graeme); S. Cummings; P. Danoy (Patrick); E.M. Dennison (Elaine); R. Eastell (Richard); J.A. Eisman (John); V. Gudnason (Vilmundur); A. Hofman (Albert); R.D. Jackson (Rebecca); G. Jones (Graeme); J.W. Jukema (Jan Wouter); K-T. Khaw (Kay-Tee); T. Lehtimäki (Terho); Y. Liu (YongMei); M. Lorentzon (Mattias); E.V. McCloskey (Eugene); B.D. Mitchell (Braxton); K. Nandakumar (Kannabiran); G.C. Nicholson (Geoffrey); B.A. Oostra (Ben); M. Peacock (Munro); H.A.P. Pols (Huib); R.L. Prince (Richard); O. Raitakari (Olli); I.R. Reid (Ian); J. Robbins (John); P.N. Sambrook (Philip); P.C. Sham (Pak); A.R. Shuldiner (Alan); F.A. Tylavsky (Frances); C.M. van Duijn (Cornelia); N.J. Wareham (Nick); L.A. Cupples (Adrienne); M.J. Econs (Michael); D.M. Evans (David); T.B. Harris (Tamara); A.W.C. Kung (Annie); B.M. Psaty (Bruce); J. Reeve (Jonathan); T.D. Spector (Timothy); E.A. Streeten (Elizabeth); M.C. Zillikens (Carola); U. Thorsteinsdottir (Unnur); C. Ohlsson (Claes); D. Karasik (David); J.B. Richards (Brent); M.A. Brown (Matthew); J-A. Zwart (John-Anker); A.G. Uitterlinden (André); S.H. Ralston (Stuart); J.P.A. Ioannidis (John); D.P. Kiel (Douglas); F. Rivadeneira Ramirez (Fernando)
textabstractBone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top
Hartanto, T A; Krafft, C E; Iosif, A M; Schweitzer, J B
Hyperactivity is a key symptom and the most observable manifestation of attention-deficit/hyperactivity disorder (ADHD). The over-activity associated with ADHD can cause specific challenges in academic settings, extracurricular activities and social relationships. Cognitive control challenges are also well established in ADHD. The current study included 44 children between the ages of 10 and 17 diagnosed with ADHD or who were typically developing (TD), all of whom had no psychiatric co-morbidity or significant learning disorders. Participants wore an actometer on their ankle while performing a flanker paradigm in order to objectively measure their rates of activity in association with cognitive control. Analyses assessed the relationship between frequency and intensity of activity to task accuracy on a trial-by-trial basis. A significant interaction effect between group and performance revealed that more intense movement was associated with better performance in the ADHD group but not in the TD group. The ADHD group demonstrated more intense activity than the TD group during correct (but not error) trials. Within-group, children with ADHD generated higher intensity movements in their correct trials compared to their error trials, whereas the TD group did not demonstrate any within-group differences. These findings suggest that excessive motoric activity associated with clinically significant ADHD symptoms may reflect compensatory efforts to modulate attention and alertness. Future research should systematically explore the relationship between motion in ADHD and how it might be used to improve cognitive performance.
Lee, Bo-Young; Shin, Dong Hyun; Cho, Seoae; Seo, Kang-Seok; Kim, Heebal
Many anthropometric measures, including body mass index (BMI), waist-to-hip ratio (WHR), and subcutaneous fat thickness, are used as indicators of nutritional status, fertility and predictors of future health outcomes. While BMI is currently the best available estimate of body adiposity, WHR and skinfold thickness at various sites (biceps, triceps, suprailiac, and subscapular) are used as indices of body fat distribution. Copy number variation (CNV) is an attractive emerging approach to the study of associations with various diseases. In this study, we investigated the dosage effect of genes in the CNV genome widely associated with fat distribution phenotypes in large cohorts. We used the Affymetrix genome-wide human SNP Array 5.0 data of 8,842 healthy unrelated adults in KARE cohorts and identified CNVs associated with BMI and fat distribution-related traits including WHR and subcutaneous skinfold thickness at suprailiac (SUP) and subscapular (SUB) sites. CNV segmentation of each chromosome was performed using Golden Helix SVS 7.0, and single regression analysis was used to identify CNVs associated with each phenotype. We found one CNV for BMI, 287 for WHR, 2,157 for SUP, and 2,102 for SUB at the 5% significance level after Holm-Bonferroni correction. Genes included in the CNV were used for the analysis of functional annotations using the Database for Annotation, Visualization and Integrated Discovery (DAVID v6.7b) tool. Functional gene classification analysis identified five significant gene clusters (metallothionein, ATP-binding proteins, ribosomal proteins, kinesin family members, and zinc finger proteins) for SUP, three (keratin-associated proteins, zinc finger proteins, keratins) for SUB, and one (protamines) for WHR. BMI was excluded from this analysis because the entire structure of no gene was identified in the CNV. Based on the analysis of genes enriched in the clusters, the fat distribution traits of KARE cohorts were related to the fat redistribution
Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L; Ntzani, Evangelia E; Oei, Ling; Albagha, Omar M E; Amin, Najaf; Kemp, John P; Koller, Daniel L; Li, Guo; Liu, Ching-Ti; Minster, Ryan L; Moayyeri, Alireza; Vandenput, Liesbeth; Willner, Dana; Xiao, Su-Mei; Yerges-Armstrong, Laura M; Zheng, Hou-Feng; Alonso, Nerea; Eriksson, Joel; Kammerer, Candace M; Kaptoge, Stephen K; Leo, Paul J; Thorleifsson, Gudmar; Wilson, Scott G; Wilson, James F; Aalto, Ville; Alen, Markku; Aragaki, Aaron K; Aspelund, Thor; Center, Jacqueline R; Dailiana, Zoe; Duggan, David J; Garcia, Melissa; Garcia-Giralt, Natàlia; Giroux, Sylvie; Hallmans, Göran; Hocking, Lynne J; Husted, Lise Bjerre; Jameson, Karen A; Khusainova, Rita; Kim, Ghi Su; Kooperberg, Charles; Koromila, Theodora; Kruk, Marcin; Laaksonen, Marika; Lacroix, Andrea Z; Lee, Seung Hun; Leung, Ping C; Lewis, Joshua R; Masi, Laura; Mencej-Bedrac, Simona; Nguyen, Tuan V; Nogues, Xavier; Patel, Millan S; Prezelj, Janez; Rose, Lynda M; Scollen, Serena; Siggeirsdottir, Kristin; Smith, Albert V; Svensson, Olle; Trompet, Stella; Trummer, Olivia; van Schoor, Natasja M; Woo, Jean; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Buckley, Brendan M; Cheng, Sulin; Christiansen, Claus; Cooper, Cyrus; Dedoussis, George; Ford, Ian; Frost, Morten; Goltzman, David; González-Macías, Jesús; Kähönen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung-Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D; Lips, Paul; Ljunggren, Östen; Lorenc, Roman S; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; Olmos, José M; Pettersson-Kymmer, Ulrika; Reid, David M; Riancho, José A; Ridker, Paul M; Rousseau, François; Slagboom, P Eline; Tang, Nelson LS; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, María T; Aulchenko, Yurii S; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gómez, Carolina; Palsson, Stefan Th; Reppe, Sjur; Rotter, Jerome I; Sigurdsson, Gunnar; van Meurs, Joyce B J; Verlaan, Dominique; Williams, Frances MK; Wood, Andrew R; Zhou, Yanhua; Gautvik, Kaare M; Pastinen, Tomi; Raychaudhuri, Soumya; Cauley, Jane A; Chasman, Daniel I; Clark, Graeme R; Cummings, Steven R; Danoy, Patrick; Dennison, Elaine M; Eastell, Richard; Eisman, John A; Gudnason, Vilmundur; Hofman, Albert; Jackson, Rebecca D; Jones, Graeme; Jukema, J Wouter; Khaw, Kay-Tee; Lehtimäki, Terho; Liu, Yongmei; Lorentzon, Mattias; McCloskey, Eugene; Mitchell, Braxton D; Nandakumar, Kannabiran; Nicholson, Geoffrey C; Oostra, Ben A; Peacock, Munro; Pols, Huibert A P; Prince, Richard L; Raitakari, Olli; Reid, Ian R; Robbins, John; Sambrook, Philip N; Sham, Pak Chung; Shuldiner, Alan R; Tylavsky, Frances A; van Duijn, Cornelia M; Wareham, Nick J; Cupples, L Adrienne; Econs, Michael J; Evans, David M; Harris, Tamara B; Kung, Annie Wai Chee; Psaty, Bruce M; Reeve, Jonathan; Spector, Timothy D; Streeten, Elizabeth A; Zillikens, M Carola; Thorsteinsdottir, Unnur; Ohlsson, Claes; Karasik, David; Richards, J Brent; Brown, Matthew A; Stefansson, Kari; Uitterlinden, André G; Ralston, Stuart H; Ioannidis, John P A; Kiel, Douglas P; Rivadeneira, Fernando
Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (PLRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. PMID:22504420
Brisbin Abra G
Full Text Available Abstract Background Human chromosomal region 8q24 contains several genes which could be functionally related to cancer, including the proto-oncogene c-MYC. However, the abundance of associations around 128 Mb on chromosome 8 could mask the appearance of a weaker, but important, association elsewhere on 8q24. Methods In this study, we completed a meta-analysis of results from nine genome-wide association studies for seven types of solid-tumor cancers (breast, prostate, pancreatic, lung, ovarian, colon, and glioma to identify additional associations that were not apparent in any individual study. Results Fifteen SNPs in the 8q24 region had meta-analysis p-values NOV and ENPP2, which have been shown to play a role in tumor development and motility. An additional region consisting of 5 markers from 128,478,000 bp - 128,524,000 (around gene POU5F1B had p-values Conclusions Further research in this area is warranted as these results demonstrate that the chromosomal region 8q24 may contain a locus that influences general cancer susceptibility between 120,576 and 120,630 kb.
Full Text Available Introduction: Risk of testicular germ cell tumors (TGCT is consistently associated with a history of cryptorchidism (CO in epidemiologic studies. Factors modifying the association may provide insights regarding etiology of TGCT and suggest a basis for individualized care of CO. To identify modifiers of the CO-TGCT association, we conducted a comprehensive, quantitative evaluation of epidemiologic data.Materials and Methods: Human studies cited in PubMed or ISI Web of Science indices through December 2011 and selected unpublished epidemiologic data were reviewed to identify 35 articles and one unpublished dataset with high-quality data on the CO-TGCT association. Association data were extracted as point and 95% confidence interval estimates of odds ratio (OR or standardized incidence ratio (SIR, or as tabulated data. Values were recorded for each study population, and for subgroups defined by features of study design, CO and TGCT. Extracted data were used to estimate summary risk ratios (sRR and evaluate heterogeneity of the CO-TGCT association between subgroups.Results: The overall meta-analysis showed that history of CO is associated with four-fold increased TGCT risk (RR=4.1(95%CI=3.6-4.7. Subgroup analyses identified five determinants of stronger association: bilateral CO, unilateral CO ipsilateral to TGCT, delayed CO treatment, TGCT diagnosed before 1970, and seminoma histology. Conclusions: Modifying factors may provide insight into TGCT etiology and suggest improved approaches to managing CO. Based on available data, cryptorchidism patients and their parents or caregivers should be made aware of elevated TGCT risk following orchidopexy, regardless of age at repair, unilateral versus bilateral nondescent, or position of undescended testes.
Ying, Qi; Ansong, Emmanuel; Diamond, Alan M; Lu, Zhaoxin; Yang, Wancai; Bie, Xiaomei
Previous studies have shown the tumor-suppressive role of selenium-binding protein 1 (SBP1), but the underlying mechanisms are unclear. In this study, we found that induction of SBP1 showed significant inhibition of colorectal cancer cell growth and metastasis in mice. We further employed isobaric tags for relative and absolute quantitation (iTRAQ) to identify proteins that were involved in SBP1-mediated anti-cancer effects in tumor tissues. We identified 132 differentially expressed proteins, among them, 53 proteins were upregulated and 79 proteins were downregulated. Importantly, many of the differentially altered proteins were associated with lipid/glucose metabolism, which were also linked to Glycolysis, MAPK, Wnt, NF-kB, NOTCH and epithelial-mesenchymal transition (EMT) signaling pathways. These results have revealed a novel mechanism that SBP1-mediated cancer inhibition is through altering lipid/glucose metabolic signaling pathways.
Pither, Jason; Botta, Amy; Maity, Chittaranjan; Ghosh, Sanjoy
In recent years, dietary polyunsaturated fatty acids (PUFA) have increased in parallel to sedentary behavior and diabetes across the world. To test any putative association between dietary PUFA and sedentary behavior or diabetes in females, we obtained country-specific, cross-sectional data on sedentary activity and diabetes prevalence from European Cardiovascular Statistics 2012. Age and gender-specific, nutritional data from each country were obtained from nutritional surveys as well. Socioeconomic (GDP), physical environment (urbanization index) and climatic confounders were accounted for each country. Upon analysis, we found a strong, positive association between sedentary lifestyle in 11-yr old girls (> = 2 hours of TV/ weekday) and dietary PUFA across 21 European countries. Further, a weak association of dietary PUFA and a strong relationship of per-capita GDP was established with elevated fasting blood glucose [(> = 7.0 mmol/L; or on medication] among 25+ year old adult females across 23 countries in Europe. In summary, we present novel ecological evidence that dietary PUFA is strongly associated with sedentary behavior among pre-teen girls and weakly associated with diabetes among adult women across Europe. In the latter group, per-capita GDP was a significant predictor for diabetes as well. Therefore, we recommend that prospective randomized controlled trials (RCTs) be implemented to evaluate if ubiquitous presence of dietary PUFA and low socioeconomic status are possible confounders when intervening to treat/prevent sedentary lifestyle or diabetes in female subjects in Western nations.
Monosomic analysis reveals duplicated chromosomal segments in maize genome. MAHESH C. YADAV1,2∗, J. K. S. ... cated chromosomal segments in maize genome. Materials and methods. Development and .... each in chromosomes 2 and 7, while 10 other pairs of du- plicate loci had one copy in chromosome 3 and the ...
Genomics analysis of genes expressed reveals differential responses to low chronic nitrogen stress in maize. ... Most induced clones were largely involved in various metabolism processes including physiological process, organelle regulation of biological process, nutrient reservoir activity, transcription regulator activity and ...
Bekele, Aschalew Z; Koike, Satoshi; Kobayashi, Yasuo
Treponema spp. are a commonly detected bacterial group in the rumen that are involved in the degradation of soluble fibers. In this study, a ruminal Treponema group-specific PCR primer targeting the 16S rRNA gene was designed and used to assess the phylogenetic diversity and diet association of this group in sheep rumen. Total DNA was extracted from rumen digesta of three sheep fed a diet based on alfalfa/orchardgrass hay or concentrate. The real-time PCR quantification indicated that the relative abundance of the Treponema group in the total rumen bacteria was as high as 1.05%, while the known species Treponema bryantii accounted for only 0.02%. Fingerprints of the Treponema community determined by 16S rDNA-targeted denaturing gradient gel electrophoresis (DGGE) analysis tended to differ among the diets. Principal component analysis of the DGGE profiles distinguished those Treponema associated with either the hay or the concentrate diets. Analysis of a Treponema 16S rRNA gene clone library showed phylogenetically distinct operational taxonomic units for a specific dietary condition, and significant (P=0.001) differences in community composition were observed among clone libraries constructed from each dietary regimen. The majority of clones (75.4%) had Treponema. These results suggest the predominance of uncultured Treponema that appear to have distinct members related to the digestion of either hay or concentrate diet. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.
Pausch, Hubert; Emmerling, Reiner; Gredler-Grandl, Birgit; Fries, Ruedi; Daetwyler, Hans D; Goddard, Michael E
Genotyping and whole-genome sequencing data have been generated for hundreds of thousands of cattle. International consortia used these data to compile imputation reference panels that facilitate the imputation of sequence variant genotypes for animals that have been genotyped using dense microarrays. Association studies with imputed sequence variant genotypes allow for the characterization of quantitative trait loci (QTL) at nucleotide resolution particularly when individuals from several breeds are included in the mapping populations. We imputed genotypes for 28 million sequence variants in 17,229 cattle of the Braunvieh, Fleckvieh and Holstein breeds in order to compile large mapping populations that provide high power to identify QTL for milk production traits. Association tests between imputed sequence variant genotypes and fat and protein percentages in milk uncovered between six and thirteen QTL (P < 1e-8) per breed. Eight of the detected QTL were significant in more than one breed. We combined the results across breeds using meta-analysis and identified a total of 25 QTL including six that were not significant in the within-breed association studies. Two missense mutations in the ABCG2 (p.Y581S, rs43702337, P = 4.3e-34) and GHR (p.F279Y, rs385640152, P = 1.6e-74) genes were the top variants at QTL on chromosomes 6 and 20. Another known causal missense mutation in the DGAT1 gene (p.A232K, rs109326954, P = 8.4e-1436) was the second top variant at a QTL on chromosome 14 but its allelic substitution effects were inconsistent across breeds. It turned out that the conflicting allelic substitution effects resulted from flaws in the imputed genotypes due to the use of a multi-breed reference population for genotype imputation. Many QTL for milk production traits segregate across breeds and across-breed meta-analysis has greater power to detect such QTL than within-breed association testing. Association testing between imputed sequence variant genotypes and
Zhang, Nan; Yang, Dongqing; Kendall, Joshua R A; Borriss, Rainer; Druzhinina, Irina S; Kubicek, Christian P; Shen, Qirong; Zhang, Ruifu
Bacillus subtilis and its sister species B. amyloliquefaciens comprise an evolutionary compact but physiologically versatile group of bacteria that includes strains isolated from diverse habitats. Many of these strains are used as plant growth-promoting rhizobacteria (PGPR) in agriculture and a plant-specialized subspecies of B. amyloliquefaciens-B. amyloliquefaciens subsp. plantarum , has recently been recognized, here we used 31 whole genomes [including two newly sequenced PGPR strains: B. amyloliquefaciens NJN-6 isolated from Musa sp. (banana) and B. subtilis HJ5 from Gossypium sp. (cotton)] to perform comparative analysis and investigate the genomic characteristics and evolution traits of both species in different niches. Phylogenomic analysis indicated that strains isolated from plant-associated (PA) habitats could be distinguished from those from non-plant-associated (nPA) niches in both species. The core genomes of PA strains are more abundant in genes relevant to intermediary metabolism and secondary metabolites biosynthesis as compared with those of nPA strains, and they also possess additional specific genes involved in utilization of plant-derived substrates and synthesis of antibiotics. A further gene gain/loss analysis indicated that only a few of these specific genes (18/192 for B. amyloliquefaciens and 53/688 for B. subtilis ) were acquired by PA strains at the initial divergence event, but most were obtained successively by different subgroups of PA stains during the evolutional process. This study demonstrated the genomic differences between PA and nPA B. amyloliquefaciens and B. subtilis from different niches and the involved evolutional traits, and has implications for screening of PGPR strains in agricultural production.
Medina-Gomez, Carolina; Kemp, John P; Dimou, Niki L; Kreiner, Eskil; Chesi, Alessandra; Zemel, Babette S; Bønnelykke, Klaus; Boer, Cindy G; Ahluwalia, Tarunveer S; Bisgaard, Hans; Evangelou, Evangelos; Heppe, Denise H M; Bonewald, Lynda F; Gorski, Jeffrey P; Ghanbari, Mohsen; Demissie, Serkalem; Duque, Gustavo; Maurano, Matthew T; Kiel, Douglas P; Hsu, Yi-Hsiang; C J van der Eerden, Bram; Ackert-Bicknell, Cheryl; Reppe, Sjur; Gautvik, Kaare M; Raastad, Truls; Karasik, David; van de Peppel, Jeroen; Jaddoe, Vincent W V; Uitterlinden, André G; Tobias, Jonathan H; Grant, Struan F A; Bagos, Pantelis G; Evans, David M; Rivadeneira, Fernando
Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.
Full Text Available The broadleaved evergreen forests of the East Asian warm temperate zone are characterised by their high biodiversity and endemism, and there is therefore a need to extend our understanding of its genetic diversity and phylogeographic patterns. Castanopsis (Fagaceae is one of the dominant tree species in the broadleaved evergreen forests of Japan. In this study we investigate the genetic diversity, genetic structure and leaf epidermal morphology of 63 natural populations of C. sieboldii and C. cuspidata, using 32 Expressed Sequence Tag associated microsatellites. The overall genetic differentiation between populations was low (GST = 0.069 in C. sieboldii and GST = 0.057 in C. cuspidata. Neighbor-joining tree and Bayesian clustering analyses revealed that the populations of C. sieboldii and C. cuspidata were genetically clearly differentiated, a result which is consistent with the morphology of their epidermal cell layers. This suggests that C. sieboldii and C. cuspidata should be treated as independent species, although intermediate morphologies are often observed, especially at sites where the two species coexist. The higher level of genetic diversity observed in the Kyushu region (for both species and the Ryukyu Islands (for C. sieboldii is consistent with the available fossil pollen data for Castanopsis-type broadleaved evergreen trees during the Last Glacial Maximum and suggests the existence of refugia for Castanopsis forests in southern Japan. Within the C. sieboldii populations, Bayesian clustering analyses detected three clusters, in the western and eastern parts of the main islands and in the Ryukyu Islands. The west-east genetic differentiation observed for this species in the main islands, a pattern which is also found in several plant and animal species inhabiting Castanopsis forests in Japan, suggests that they have been isolated from each other in the western and eastern populations for an extended period of time, and may
Full Text Available Frontotemporal Dementia (FTD is the form of neurodegenerative dementia with the highest prevalence after Alzheimer's disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72 have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.
Zhou, Lei; Wei, Ruihua; Zhao, Ping; Koh, Siew Kwan; Beuerman, Roger W; Ding, Chuanqing
Sjögren's syndrome (SS) is an autoimmune disease that results in pathological dryness of mouth and eye. The diagnosis of SS depends on both clinical evaluation and specific antibodies. The goal of this study was to use quantitative proteomics to investigate changes in tear proteins in a rabbit model of SS-associated dry eye, induced autoimmune dacryoadenitis (IAD). Proteomic analysis was performed by iTRAQ and nano LC-MS/MS on tears collected from the ocular surface, and specific proteins were verified by high resolution MRM. It was found that in the tears of IAD rabbits at 2 and 4 weeks after induction, S100 A6, S100 A9, and serum albumin were upregulated, whereas serotransferrin (TF), prolactin-inducible protein (PIP), polymeric immunoglobulin receptor (pIgR), and Ig gamma chain C region were downregulated. High resolution MRM with mTRAQ labeling verified the changes in S100 A6, TF, PIP, and pIgR. Our results indicated significant changes of tear proteins in IAD rabbits, suggesting these proteins could potentially be used as biomarkers for the diagnosis and prognosis of dry eye. Several of these proteins were also found in the tears of non-SS dry eye patients indicating a common basis of ocular surface pathology, however, pIgR appears to be unique to SS. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Heid, Iris M; Jackson, Anne U; Randall, Joshua C
adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1...... and CPEB4 (P = 1.9 × 10¿¿ to P = 1.8 × 10¿4°) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10¿³ to P = 1.2 × 10¿¹³). These findings provide evidence for multiple loci that modulate......Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR...
Wang, Y; Lupiani, B; Reddy, S M; Lamont, S J; Zhou, H
Avian influenza virus (AIV) is a type A virus of the family Orthomyxoviridae. Avian influenza virus infection can cause significant economic losses to the poultry industry, and raises a great public health threat due to potential host jump from animals to humans. To develop more effective intervention strategies to prevent and control AIV infection in poultry, it is essential to elucidate molecular mechanisms of host response to AIV infection in chickens. The objective of this study was to identify genes and signal pathways associated with resistance to AIV infection in 2 genetically distinct highly inbred chicken lines (Fayoumi, relatively resistant to AIV infection, and Leghorn, susceptible to AIV infection). Three-week-old chickens were inoculated with 10(7) EID50 of low pathogenic H5N3 AIV, and lungs and trachea were harvested 4 d postinoculation. Four cDNA libraries (1 library each for infected and noninfected Leghorn, and infected and noninfected Fayoumi) were prepared from the lung samples and sequenced by Illumina Genome Analyzer II, which yielded a total of 116 million, 75-bp single-end reads. Gene expression levels of all annotated chicken genes were analyzed using CLC Genomics Workbench. DESeq was used to identify differentially expressed transcripts between infected and noninfected birds and between genetic lines (false discovery rate change > 2). Of the expressed transcripts in a total of 17,108 annotated chicken genes in Ensembl database, 82.44 and 81.40% were identified in Leghorn and Fayoumi birds, respectively. The bioinformatics analysis suggests that the hemoglobin family genes, the functional involvements for oxygen transportation and circulation, and cell adhesion molecule signaling pathway play significant roles in disease resistance to AIV infection in chickens. Further investigation of the roles of these candidate genes and signaling pathways in the regulation of host-AIV interaction can lead new directions for the development of antiviral
Andrea D Coviello
Full Text Available Sex hormone-binding globulin (SHBG is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106, PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11, GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16, ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09, JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35, SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08, NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12, ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14, TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14, LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07, BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08, and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06. These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08, women p = 0.66, heterogeneity p = 0.003. Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion
H. Wesseling (Hendrik); P.C. Guest (Paul); C.-M. Lee (Chi-Ming); E.H.F. Wong (Erik); H. Rahmoune (Hassan); S. Bahn (Sabine)
textabstractBackground: Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1neo-/-) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative
Wesseling, Hendrik; Guest, Paul; Lee, Chi-Ming; Wong, Erik; Rahmoune, Hassan; Bahn, Sabine
textabstractBackground: Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1neo-/-) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of ...
Passos Gregorio, Sheila; Gattaz, Wagner F; Tavares, Hildeberto
the association of the NUMBL variant, our most promising finding, in an unrelated set of 684 Danish patients and controls. When the Brazilian and Danish cohorts were merged, a total of 1084 subjects, we found the allele 18 CAG of NUMBL (p=0.003, x2=8.88, OR=1.30, 95% CI 1.09-1.56) as well as the 18/18 CAG...... genotype (p=0.002, x2=9.46, OR=1.46, 95% CI 1.15-1.87) to be associated with schizophrenia. The consistency of this finding in two independent and unrelated populations reinforces the veracity of this association....
Kim, Hyo Young; Cho, Seoae; Yu, Jeongmi; Sung, Samsun; Kim, Heebal
Biochemical tests such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are useful for diagnosing patients with liver disease. In this study, we tested the association between copy number variation and the hepatic biomarkers AST and ALT based on 8,842 samples from population-based cohorts in Korea. We used Affymetrix Genome-Wide Human 5.0 arrays and identified 10,534 CNVs using HelixTree software. Of the CNVs tested using univariate linear regression, 100 CNVs were significant for AST and 16 were significant for ALT (P < 0.05). We identified 39 genes located within the CNV regions. DKK1 and HS3ST3B1 were shown to play roles in heparan sulfate biosynthesis and the Wnt signaling pathway, respectively. NAF1 and NPY1R were associated with glycoprotein processes and neuropeptide Y receptor activity based on GO categories. PTER, SOX14 and TM7SF4 were expressed in liver. DPYS and CTSC were found to be associated with dihydropyrimidinuria and Papillon-Lefevre syndrome phenotypes using OMIM. NPY5R was found to be associated with dyslipidemia using the Genetic Association Database.
Rajkumar, A.P.; Christensen, Jane H.; Mattheisen, Manuel
OBJECTIVES: Breakpoints of chromosomal abnormalities facilitate identification of novel candidate genes for psychiatric disorders. Genome-wide significant evidence supports the linkage between chromosome 17q25.3 and bipolar disorder (BD). Co-segregation of translocation t(9;17)(q33.2;q25.......3) with psychiatric disorders has been reported. We aimed to narrow down these chromosomal breakpoint regions and to investigate the associations between single nucleotide polymorphisms within these regions and BD as well as schizophrenia (SZ) in large genome-wide association study samples. METHODS: We cross......,856) data. Genetic associations between these disorders and single nucleotide polymorphisms within these breakpoint regions were analysed by BioQ, FORGE, and RegulomeDB programmes. RESULTS: Four protein-coding genes [coding for (endonuclease V (ENDOV), neuronal pentraxin I (NPTX1), ring finger protein 213...
Do, Duy Ngoc; Strathe, Anders Bjerring; Ostersen, Tage
implied porcine RFI is regulated by multiple biological mechanisms, although the metabolic processes might be the most important. Olfactory transduction pathway controlling the perception of feed via smell, insulin pathway controlling food intake might be important pathways for RFI. Furthermore, our study....... Metabolic pathway was significantly associated with both RFIs. Other biological pathways regulating phagosome, tight junctions, olfactory transduction, and insulin secretion were significantly associated with both RFI traits when relaxed threshold for cut-off p-value was used (p ≤ 0.05). These results...
Liao, H-L; Chen, Y; Bruns, T D; Peay, K G; Taylor, J W; Branco, S; Talbot, J M; Vilgalys, R
Ectomycorrhizal (EM) fungi form symbiotic associations with plant roots that regulate nutrient exchange between forest plants and soil. Environmental metagenomics approaches that employ next-generation sequencing show great promise for studying EM symbioses; however, metatranscriptomic studies have been constrained by the inherent difficulties associated with isolation and sequencing of RNA from mycorrhizae. Here we apply an optimized method for combined DNA/RNA extraction using field-collected EM fungal-pine root clusters, together with protocols for taxonomic identification of expressed ribosomal RNA, and inference of EM function based on plant and fungal metatranscriptomics. We used transcribed portions of ribosomal RNA genes to identify several transcriptionally dominant fungal taxa associated with loblolly pine including Amphinema, Russula and Piloderma spp. One taxon, Piloderma croceum, has a publically available genome that allowed us to identify patterns of gene content and transcript abundance. Over 1500 abundantly expressed Piloderma genes were detected from mycorrhizal roots, including genes for protein metabolism, cell signalling, electron transport, terpene synthesis and other extracellular activities. In contrast, Piloderma gene encoding an ammonia transporter showed highest transcript abundance in soil samples. Our methodology highlights the potential of metatranscriptomics to identify genes associated with symbiosis and ecosystem function using field-collected samples. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.
Rangewide analysis of fungal associations in the fully mycoheterotrophic Corallorhiza striata complex (Orchidaceae) reveals extreme specificity on ectomycorrhizal Tomentella (Thelephoraceae) across North America
Craig F. Barrett; John V. Freudenstein; D. Lee Taylor; Urmas. Koljalg
Fully mycoheterotrophic plants offer a fascinating system for studying phylogenetic associations and dynamics of symbiotic specificity between hosts and parasites. These plants frequently parasitize mutualistic mycorrhizal symbioses between fungi and trees. Corallorhiza striata is a fully mycoheterotrophic, North American orchid distributed from...
Stature is affected by many polymorphisms of small effect in humans but in contrast variation in dogs, even within breeds is largely due to variants in six genes. Here we use data from cattle to compare genetic architecture of stature to that in humans and dogs. We conducted a meta-analysis for stat...
Medina-Gomez, Carolina; Kemp, John P; Dimou, Niki L
Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone...
M.C. Medina-Gomez (Carolina); J.P. Kemp (John); Dimou, N.L. (Niki L.); Kreiner, E. (Eskil); A. Chesi (Alessandra); B.S. Zemel (Babette S.); K. Bønnelykke (Klaus); Boer, C.G. (Cindy G.); T.S. Ahluwalia (Tarunveer Singh); H. Bisgaard; E. Evangelou (Evangelos); D.H.M. Heppe (Denise); Bonewald, L.F. (Lynda F.); Gorski, J.P. (Jeffrey P.); M. Ghanbari (Mohsen); S. Demissie (Serkalem); Duque, G. (Gustavo); M.T. Maurano (Matthew T.); D.P. Kiel (Douglas P.); Y.-H. Hsu (Yi-Hsiang); B.C.J. van der Eerden (Bram); Ackert-Bicknell, C. (Cheryl); S. Reppe (Sjur); K.M. Gautvik (Kaare); Raastad, T. (Truls); D. Karasik (David); J. van de Peppel (Jeroen); V.W.V. Jaddoe (Vincent); A.G. Uitterlinden (André); J.H. Tobias (Jon); S.F.A. Grant (Struan); Bagos, P.G. (Pantelis G.); D.M. Evans (David); F. Rivadeneira Ramirez (Fernando)
markdownabstractBone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body
Liu, Liyan; Feng, Rennan; Guo, Fuchuan; Li, Ying; Jiao, Jundong; Sun, Changhao
Obesity is the result of a positive energy balance and often leads to difficulties in maintaining normal postprandial metabolism. The changes in postprandial metabolites after an oral glucose tolerance test (OGTT) in young obese Chinese men are unclear. In this work, the aim is to investigate the complex metabolic alterations in obesity provoked by an OGTT using targeted metabolomics. We used gas chromatography-mass spectrometry and ultra high performance liquid chromatography-triple quadrupole mass spectrometry to analyze serum fatty acids, amino acids and biogenic amines profiles from 15 control and 15 obese subjects at 0, 30, 60, 90 and 120 min during an OGTT. Metabolite profiles from 30 obese subjects as independent samples were detected in order to validate the change of metabolites. There were the decreased levels of fatty acid, amino acids and biogenic amines after OGTT in obesity. At 120 min, percent change of 20 metabolites in obesity has statistical significance when comparing with the controls. The obese parameters was positively associated with changes in arginine and histidine (Pchange in palmitic acid (PA), branched-chain amino acids (BCAAs) and phenylalanine between 1 and 120 min were positively associated with fasting insulin and HOMA-IR (all Presistance in obesity. Our findings offer new insights in the complex physiological regulation of the metabolism during an OGTT in obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Angela N Brooks
Full Text Available Although recurrent somatic mutations in the splicing factor U2AF1 (also known as U2AF35 have been identified in multiple cancer types, the effects of these mutations on the cancer transcriptome have yet to be fully elucidated. Here, we identified splicing alterations associated with U2AF1 mutations across distinct cancers using DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA. Using RNA-Seq data from 182 lung adenocarcinomas and 167 acute myeloid leukemias (AML, in which U2AF1 is somatically mutated in 3-4% of cases, we identified 131 and 369 splicing alterations, respectively, that were significantly associated with U2AF1 mutation. Of these, 30 splicing alterations were statistically significant in both lung adenocarcinoma and AML, including three genes in the Cancer Gene Census, CTNNB1, CHCHD7, and PICALM. Cell line experiments expressing U2AF1 S34F in HeLa cells and in 293T cells provide further support that these altered splicing events are caused by U2AF1 mutation. Consistent with the function of U2AF1 in 3' splice site recognition, we found that S34F/Y mutations cause preferences for CAG over UAG 3' splice site sequences. This report demonstrates consistent effects of U2AF1 mutation on splicing in distinct cancer cell types.
Medina-Gomez, Carolina; Kemp, John P; Dimou, Niki L
Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone...... mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established...... as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total...
Monti, Stefano; Chapuy, Bjoern; Takeyama, Kunihiko; Rodig, Scott J; Hao, Yansheng; Yeda, Kelly T; Inguilizian, Haig; Mermel, Craig; Currie, Treeve; Dogan, Ahmet; Kutok, Jeffery L; Beroukhim, Rameen; Neuberg, Donna; Habermann, Thomas M; Getz, Gad; Kung, Andrew L; Golub, Todd R; Shipp, Margaret A
Diffuse large B cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease with a high proliferation rate. By integrating copy number data with transcriptional profiles and performing pathway analysis in primary DLBCLs, we identified a comprehensive set of copy number alterations (CNAs) that decreased p53 activity and perturbed cell cycle regulation. Primary tumors either had multiple complementary alterations of p53 and cell cycle components or largely lacked these lesions. DLBCLs with p53 and cell cycle pathway CNAs had decreased abundance of p53 target transcripts and increased expression of E2F target genes and the Ki67 proliferation marker. CNAs of the CDKN2A-TP53-RB-E2F axis provide a structural basis for increased proliferation in DLBCL, predict outcome with current therapy, and suggest targeted treatment approaches. Copyright © 2012 Elsevier Inc. All rights reserved.
Monti, Stefano; Chapuy, Bjoern; Takeyama, Kunihiko; Rodig, Scott J; Hao, Yangsheng; Yeda, Kelly T.; Inguilizian, Haig; Mermel, Craig; Curie, Treeve; Dogan, Ahmed; Kutok, Jeffery L; Beroukim, Rameen; Neuberg, Donna; Habermann, Thomas; Getz, Gad; Kung, Andrew L; Golub, Todd R; Shipp, Margaret A
Summary Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease with a high proliferation rate. By integrating copy number data with transcriptional profiles and performing pathway analysis in primary DLBCLs, we identified a comprehensive set of copy number alterations (CNAs) that decreased p53 activity and perturbed cell cycle regulation. Primary tumors either had multiple complementary alterations of p53 and cell cycle components or largely lacked these lesions. DLBCLs with p53 and cell cycle pathway CNAs had decreased abundance of p53 target transcripts and increased expression of E2F target genes and the Ki67 proliferation marker. CNAs of the CDKN2A-TP53-RB-E2F axis provide a structural basis for increased proliferation in DLBCL, predict outcome with current therapy and suggest targeted treatment approaches. PMID:22975378
Cohen, Adam; Sato, Mariko; Aldape, Kenneth; Mason, Clinton C; Alfaro-Munoz, Kristin; Heathcock, Lindsey; South, Sarah T; Abegglen, Lisa M; Schiffman, Joshua D; Colman, Howard
Isocitrate dehydrogenase (IDH) mutation status and grade define subgroups of diffuse gliomas differing based on age, tumor location, presentation, and prognosis. While some biologic differences between IDH mutated (IDH (mut)) and wild-type (IDH (wt)) gliomas are clear, the distinct alterations associated with progression of the two subtypes to glioblastoma (GBM, Grade IV) have not been well described. We analyzed copy number alterations (CNAs) across grades (Grade II-III and GBM) in both IDH (mut) and IDH (wt) infiltrating gliomas using molecular inversion probe arrays. Ninety four patient samples were divided into four groups: Grade II-III IDH (wt) (n = 17), Grade II-III IDH (mut) (n = 28), GBM IDH (wt) (n = 25), and GBM IDH (mut) (n = 24). We validated prior observations that IDH (wt) GBM have a high frequency of chromosome 7 gain (including EGFR) and chromosome 10 loss (including PTEN) compared with IDH (mut) GBM. Hierarchical clustering of IDH (mut) gliomas demonstrated distinct CNA patterns distinguishing lower grade gliomas versus GBM. However, similar hierarchical clustering of IDH (wt) gliomas demonstrated no CNA distinction between lower grade glioma and GBM. Functional analyses showed that IDH (wt) gliomas had more chromosome gains in regions containing receptor tyrosine kinase pathways. In contrast, IDH (mut) gliomas more commonly demonstrated amplification of cyclins and cyclin dependent kinase genes. One of the most common alterations associated with transformation of lower grade to GBM IDH (mut) gliomas was the loss of chromosomal regions surrounding PTEN. IDH (mut) GBM tumors demonstrated significantly higher levels of overall CNAs compared to lower grade IDH (mut) tumors and all grades of IDH (wt) tumors, and IDH (mut) GBMs also demonstrated significant increase in incidence of chromothripsis. Taken together, these analyses demonstrate distinct molecular ontogeny between IDH (wt) and IDH (mut) gliomas. Our data also support the novel
Owiti, Judith; Grossmann, Jonas; Gehrig, Peter; Dessimoz, Christophe; Laloi, Christophe; Hansen, Maria Benn; Gruissem, Wilhelm; Vanderschuren, Hervé
The short storage life of harvested cassava roots is an important constraint that limits the full potential of cassava as a commercial food crop in developing countries. We investigated the molecular changes during physiological deterioration of cassava root after harvesting using isobaric tags for relative and absolute quantification (iTRAQ) of proteins in soluble and non-soluble fractions prepared during a 96 h post-harvest time course. Combining bioinformatic approaches to reduce information redundancy for unsequenced or partially sequenced plant species, we established a comprehensive proteome map of the cassava root and identified quantitatively regulated proteins. Up-regulation of several key proteins confirmed that physiological deterioration of cassava root after harvesting is an active process, with 67 and 170 proteins, respectively, being up-regulated early and later after harvesting. This included regulated proteins that had not previously been associated with physiological deterioration after harvesting, such as linamarase, glutamic acid-rich protein, hydroxycinnamoyl transferase, glycine-rich RNA binding protein, β-1,3-glucanase, pectin methylesterase, maturase K, dehydroascorbate reductase, allene oxide cyclase, and proteins involved in signal pathways. To confirm the regulation of these proteins, activity assays were performed for selected enzymes. Together, our results show that physiological deterioration after harvesting is a highly regulated complex process involving proteins that are potential candidates for biotechnology approaches to reduce such deterioration. © 2011 The Authors. The Plant Journal © 2011 Blackwell Publishing Ltd.
Song, Chao; Zhang, Jian; Liu, Yan; Pan, Hao; Qi, Han-Ping; Cao, Yong-Gang; Zhao, Jian-Mei; Li, Shang; Guo, Jing; Sun, Hong-Li; Li, Chun-Quan
Cardiac hypertrophy (CH) could increase cardiac after-load and lead to heart failure. Recent studies have suggested that long non-coding RNA (lncRNA) played a crucial role in the process of the cardiac hypertrophy, such as Mhrt, TERMINATOR. Some studies have further found a new interacting mechanism, competitive endogenous RNA (ceRNA), of which lncRNA could interact with micro-RNAs (miRNA) and indirectly interact with mRNAs through competing interactions. However, the mechanism of ceRNA regulated by lncRNA in the CH remained unclear. In our study, we generated a global triple network containing mRNA, miRNA and lncRNA, and extracted a CH related lncRNA-mRNA network (CHLMN) through integrating the data from starbase, miRanda database and gene expression profile. Based on the ceRNA mechanism, we analyzed the characters of CHLMN and found that 3 lncRNAs (SLC26A4-AS1, RP11-344E13.3 and MAGI1-IT1) were high related to CH. We further performed cluster module analysis and random walk with restart for the CHLMN, finally 14 lncRNAs had been discovered as the potential CH related disease genes. Our results showed that lncRNA played an important role in the CH and could shed new light to the understanding underlying mechanisms of the CH.
Tabaja, Nassif; Yuan, Zhenyu; Oswald, Franz; Kovall, Rhett A
The Notch pathway is a cell-to-cell signaling mechanism that is essential for tissue development and maintenance, and aberrant Notch signaling has been implicated in various cancers, congenital defects, and cardiovascular diseases. Notch signaling activates the expression of target genes, which are regulated by the transcription factor CSL (CBF1/RBP-J, Su(H), Lag-1). CSL interacts with both transcriptional corepressor and coactivator proteins, functioning as both a repressor and activator, respectively. Although Notch activation complexes are relatively well understood at the structural level, less is known about how CSL interacts with corepressors. Recently, a new RBP-J (mammalian CSL ortholog)-interacting protein termed RITA has been identified and shown to export RBP-J out of the nucleus, thereby leading to the down-regulation of Notch target gene expression. However, the molecular details of RBP-J/RITA interactions are unclear. Here, using a combination of biochemical/cellular, structural, and biophysical techniques, we demonstrate that endogenous RBP-J and RITA proteins interact in cells, map the binding regions necessary for RBP-J·RITA complex formation, and determine the X-ray structure of the RBP-J·RITA complex bound to DNA. To validate the structure and glean more insights into function, we tested structure-based RBP-J and RITA mutants with biochemical/cellular assays and isothermal titration calorimetry. Whereas our structural and biophysical studies demonstrate that RITA binds RBP-J similarly to the RAM (RBP-J-associated molecule) domain of Notch, our biochemical and cellular assays suggest that RITA interacts with additional regions in RBP-J. Taken together, these results provide molecular insights into the mechanism of RITA-mediated regulation of Notch signaling, contributing to our understanding of how CSL functions as a transcriptional repressor of Notch target genes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Haddon, D James; Wand, Hannah E; Jarrell, Justin A; Spiera, Robert F; Utz, Paul J; Gordon, Jessica K; Chung, Lorinda S
Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-β signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial. We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ≥ 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc. The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib. Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.gov NCT00555581 and NCT01166139.
Eloiza de Rezende
Full Text Available Leishmaniasis is an antropozoonosis caused by Leishmania parasites that affects around 12 million people in 98 different countries. The disease has different clinical forms, which depend mainly on the parasite genetics and on the immunologic status of the host. The promastigote form of the parasite is transmitted by an infected female phlebotomine sand fly, is internalized by phagocytic cells, mainly macrophages, and converts into amastigotes which replicate inside these cells. Macrophages are important cells of the immune system, capable of efficiently killing intracellular pathogens. However, Leishmania can evade these mechanisms due to expression of virulence factors. Different strains of the same Leishmania species may have different infectivity and metastatic phenotypes in vivo, and we have previously shown that analysis of amastigote proteome can give important information on parasite infectivity. Differential abundance of virulence factors probably accounts for the higher virulence of PH8 strain parasites shown in this work. In order to test this hypothesis, we have quantitatively compared the proteomes of PH8 and LV79 lesion-derived amastigotes using a label-free proteomic approach.In the present work, we have compared lesion development by L. (L. amazonensis PH8 and LV79 strains in mice, showing that they have different virulence in vivo. Viability and numbers of lesion-derived amastigotes were accordingly significantly different. Proteome profiles can discriminate parasites from the two strains and several proteins were differentially expressed.This work shows that PH8 strain is more virulent in mice, and that lesion-derived parasites from this strain are more viable and more infective in vitro. Amastigote proteome comparison identified GP63 as highly expressed in PH8 strain, and Superoxide Dismutase, Tryparedoxin Peroxidase and Heat Shock Protein 70 as more abundant in LV79 strain. The expression profile of all proteins and of the
Steele, Joshua A; Countway, Peter D; Xia, Li; Vigil, Patrick D; Beman, J Michael; Kim, Diane Y; Chow, Cheryl-Emiliane T; Sachdeva, Rohan; Jones, Adriane C; Schwalbach, Michael S; Rose, Julie M; Hewson, Ian; Patel, Anand; Sun, Fengzhu; Caron, David A; Fuhrman, Jed A
Microbes have central roles in ocean food webs and global biogeochemical processes, yet specific ecological relationships among these taxa are largely unknown. This is in part due to the dilute, microscopic nature of the planktonic microbial community, which prevents direct observation of their interactions. Here, we use a holistic (that is, microbial system-wide) approach to investigate time-dependent variations among taxa from all three domains of life in a marine microbial community. We investigated the community composition of bacteria, archaea and protists through cultivation-independent methods, along with total bacterial and viral abundance, and physico-chemical observations. Samples and observations were collected monthly over 3 years at a well-described ocean time-series site of southern California. To find associations among these organisms, we calculated time-dependent rank correlations (that is, local similarity correlations) among relative abundances of bacteria, archaea, protists, total abundance of bacteria and viruses and physico-chemical parameters. We used a network generated from these statistical correlations to visualize and identify time-dependent associations among ecologically important taxa, for example, the SAR11 cluster, stramenopiles, alveolates, cyanobacteria and ammonia-oxidizing archaea. Negative correlations, perhaps suggesting competition or predation, were also common. The analysis revealed a progression of microbial communities through time, and also a group of unknown eukaryotes that were highly correlated with dinoflagellates, indicating possible symbioses or parasitism. Possible 'keystone' species were evident. The network has statistical features similar to previously described ecological networks, and in network parlance has non-random, small world properties (that is, highly interconnected nodes). This approach provides new insights into the natural history of microbes.
Chavez, Juan D; Schweppe, Devin K; Eng, Jimmy K; Zheng, Chunxiang; Taipale, Alex; Zhang, Yiyi; Takara, Kohji; Bruce, James E
Chemoresistance is a common mode of therapy failure for many cancers. Tumours develop resistance to chemotherapeutics through a variety of mechanisms, with proteins serving pivotal roles. Changes in protein conformations and interactions affect the cellular response to environmental conditions contributing to the development of new phenotypes. The ability to understand how protein interaction networks adapt to yield new function or alter phenotype is limited by the inability to determine structural and protein interaction changes on a proteomic scale. Here, chemical crosslinking and mass spectrometry were employed to quantify changes in protein structures and interactions in multidrug-resistant human carcinoma cells. Quantitative analysis of the largest crosslinking-derived, protein interaction network comprising 1,391 crosslinked peptides allows for 'edgotype' analysis in a cell model of chemoresistance. We detect consistent changes to protein interactions and structures, including those involving cytokeratins, topoisomerase-2-alpha, and post-translationally modified histones, which correlate with a chemoresistant phenotype.
Li, Chuang; Gong, Wenbing; Zhang, Lin; Yang, Zhiquan; Nong, Wenyan; Bian, Yinbing; Kwan, Hoi-Shan; Cheung, Man-Kit; Xiao, Yang
Association mapping is a robust approach for the detection of quantitative trait loci (QTLs). Here, by genotyping 297 genome-wide molecular markers of 89 Lentinula edodes cultivars in China, the genetic diversity, population structure and genetic loci associated with 11 agronomic traits were examined. A total of 873 alleles were detected in the tested strains with a mean of 2.939 alleles per locus, and the Shannon's information index was 0.734. Population structure analysis revealed two robustly differentiated groups among the Chinese L. edodes cultivars (FST = 0.247). Using the mixed linear model, a total of 43 markers were detected to be significantly associated with four traits. The number of markers associated with traits ranged from 9 to 26, and the phenotypic variations explained by each marker varied from 12.07% to 31.32%. Apart from five previously reported markers, the remaining 38 markers were newly reported here. Twenty-one markers were identified as simultaneously linked to two to four traits, and five markers were associated with the same traits in cultivation tests performed in two consecutive years. The 43 traits-associated markers were related to 97 genes, and 24 of them were related to 10 traits-associated markers detected in both years or identified previously, 13 of which had a >2-fold expression change between the mycelium and primordium stages. Our study has provided candidate markers for marker-assisted selection (MAS) and useful clues for understanding the genetic architecture of agronomic traits in the shiitake mushroom. PMID:28261189
De Wet, Juanita; Slippers, Bernard; Preisig, Oliver; Wingfield, Brenda D; Wingfield, Michael J
Three anamorph genera of the Botryosphaeriaceae namely Diplodia, Lasiodiplodia and Dothiorella have typically dark, ovoid conidia with thick walls, and are consequently difficult to distinguish from each other. These genera are well-known pathogens of especially pine species. We generated a multiple gene genealogy to resolve the phylogenetic relationships of Botryosphaeriaceae with dark conidial anamorphs, and mapped host associations based on this phylogeny. The multiple gene genealogy separated Diplodia, Lasiodiplodia and Dothiorella and it revealed trends in the patterns of host association. The data set was expanded to include more lineages of the Botryosphaeriaceae, and included all isolates from different host species for which ITS sequence data are available. Results indicate that Diplodia species occur mainly on gymnosperms, with a few species on both gymnosperms and angiosperms. Lasiodiplodia species occur equally on both gymnosperms and angiosperms, Dothiorella species are restricted to angiosperms and Neofusicoccum species occur mainly on angiosperms with rare reports on Southern Hemisphere gymnosperms. Botryosphaeria species with Fusicoccum anamorphs occur mostly on angiosperms with rare reports on gymnosperms. Ancestral state reconstruction suggests that a putative ancestor of the Botryosphaeriaceae most likely evolved on the angiosperms. Another interesting observation was that both host generalist and specialist species were observed in all the lineages of the Botryosphaeriaceae, with little evidence of host associated co-evolution.
Ilias, Aris; Lagnel, Jacques; Kapantaidaki, Despoina E; Roditakis, Emmanouil; Tsigenopoulos, Costas S; Vontas, John; Tsagkarakou, Anastasia
Bemisia tabaci is one of the most damaging agricultural pests world-wide. Although its control is based on insecticides, B. tabaci has developed resistance against almost all classes of insecticides, including neonicotinoids. We employed an RNA-seq approach to generate genome wide expression data and identify genes associated with neonicotinoid resistance in Mediterranean (MED) B. tabaci (Q1 biotype). Twelve libraries from insecticide resistant and susceptible whitefly populations were sequenced on an Illumina Next-generation sequencing platform, and genomic sequence information of approximately 73 Gbp was generated. A reference transcriptome was built by de novo assembly and functionally annotated. A total of 146 P450s, 18 GSTs and 23 CCEs enzymes (unigenes) potentially involved in the detoxification of xenobiotics were identified, along with 78 contigs encoding putative target proteins of six different insecticide classes. Ten unigenes encoding nicotinic Acetylcholine Receptors (nAChR), the target of neoinicotinoids, were identified and phylogenetically classified. No nAChR polymorphism potentially related with the resistant phenotypes, was observed among the studied strains. DE analysis revealed that among the 550 differentially (logFC > 1) over-transcribed unigenes, 52 detoxification enzymes were over expressed including unigenes with orthologues in P450s, GSTs, CCE and UDP-glucuronosyltransferases. Eight P450 unigenes belonging to clades CYP2, CYP3 and CYP4 were highly up-regulated (logFC > 2) including CYP6CM1, a gene already known to confer imidacloprid resistance in B. tabaci. Using quantitative qPCRs, a larger screening of field MED B. tabaci from Crete with known neonicotinoid phenotype was performed to associate expression levels of P450s with resistance levels. Expression levels of five P450s, including CYP6CM1, were found associated with neonicotinoid resistance. However, a significant correlation was found only in CYP303 and CYP6CX3, with imidacloprid
Full Text Available Genome-wide association studies (GWASs discovered a number of SNPs and genes associated with Alzheimer's disease (AD. However, how these SNPs and genes influence the liability to AD is not fully understood. We deployed computational approaches to explore the function and action mechanisms of AD -related SNPs and genes identified by GWASs, including the effects of 195 GWAS lead SNPs and 338 proxy SNPs on miRNAs binding and protein phosphorylation, their RegulomeDB and 3DSNP scores, and gene ontology, pathway enrichment and protein-protein interaction network of 126 AD-associated genes. Our computational analysis identified 6 lead SNPs (rs10119, rs1048699, rs148763909, rs610932, rs6857 and rs714948 and 2 proxy SNPs (rs12539172 and rs2847655 that potentially impacted the miRNA binding. Lead SNP rs2296160 and proxy SNPs rs679620 and rs2228145 were identified as PhosSNPs potentially influencing protein phosphorylation. AD-associated genes showed enrichment of "regulation of beta-amyloid formation", "regulation of neurofibrillary tangle assembly", "leukocyte mediated immunity" and "protein-lipid complex assembly" signaling pathway. Protein-protein interaction network and functional module analyses identified highly-interconnected "hub" genes (APOE, PICALM, BIN1, ABCA7, CD2AP, CLU, CR1, MS4A4E and MS4A6A and bottleneck genes (APOE, TOMM40, NME8, PICALM, CD2AP, ZCWPW1, FAM180B, GAB2 and PTK2B that created three tight subnetworks. Our results provided the targets for further experimental assessment and further insight on AD pathophysiology.
Brooke N. Dulka
Full Text Available Acute social defeat represents a naturalistic form of conditioned fear and is an excellent model in which to investigate the biological basis of stress resilience. While there is growing interest in identifying biomarkers of stress resilience, until recently, it has not been feasible to associate levels of large numbers of neurochemicals and metabolites to stress-related phenotypes. The objective of the present study was to use an untargeted metabolomics approach to identify known and unknown neurochemicals in select brain regions that distinguish susceptible and resistant individuals in two rodent models of acute social defeat. In the first experiment, male mice were first phenotyped as resistant or susceptible. Then, mice were subjected to acute social defeat, and tissues were immediately collected from the ventromedial prefrontal cortex (vmPFC, basolateral/central amygdala (BLA/CeA, nucleus accumbens (NAc, and dorsal hippocampus (dHPC. Ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-HRMS was used for the detection of water-soluble neurochemicals. In the second experiment, male Syrian hamsters were paired in daily agonistic encounters for 2 weeks, during which they formed stable dominant-subordinate relationships. Then, 24 h after the last dominance encounter, animals were exposed to acute social defeat stress. Immediately after social defeat, tissue was collected from the vmPFC, BLA/CeA, NAc, and dHPC for analysis using UPLC-HRMS. Although no single biomarker characterized stress-related phenotypes in both species, commonalities were found. For instance, in both model systems, animals resistant to social defeat stress also show increased concentration of molecules to protect against oxidative stress in the NAc and vmPFC. Additionally, in both mice and hamsters, unidentified spectral features were preliminarily annotated as potential targets for future experiments. Overall, these findings
Full Text Available BACKGROUND: The leatherback turtle (Dermochelys coriacea has undergone a dramatic decline over the last 25 years, and this is believed to be primarily the result of mortality associated with fisheries bycatch followed by egg and nesting female harvest. Atlantic leatherback turtles undertake long migrations across ocean basins from subtropical and tropical nesting beaches to productive frontal areas. Migration between two nesting seasons can last 2 or 3 years, a time period termed the remigration interval (RI. Recent satellite transmitter data revealed that Atlantic leatherbacks follow two major dispersion patterns after nesting season, through the North Gulf Stream area or more eastward across the North Equatorial Current. However, information on the whole RI is lacking, precluding the accurate identification of feeding areas where conservation measures may need to be applied. METHODOLOGY/PRINCIPAL FINDINGS: Using stable isotopes as dietary tracers we determined the characteristics of feeding grounds of leatherback females nesting in French Guiana. During migration, 3-year RI females differed from 2-year RI females in their isotope values, implying differences in their choice of feeding habitats (offshore vs. more coastal and foraging latitude (North Atlantic vs. West African coasts, respectively. Egg-yolk and blood isotope values are correlated in nesting females, indicating that egg analysis is a useful tool for assessing isotope values in these turtles, including adults when not available. CONCLUSIONS/SIGNIFICANCE: Our results complement previous data on turtle movements during the first year following the nesting season, integrating the diet consumed during the year before nesting. We suggest that the French Guiana leatherback population segregates into two distinct isotopic groupings, and highlight the urgent need to determine the feeding habitats of the turtle in the Atlantic in order to protect this species from incidental take by
Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei
Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.
Loving, Cathleen C.; Cobern, William W.
This paper analyzes how Thomas Kuhn's writings are used by others, especially science education researchers. Previous research in citation analysis is used to frame questions related to who cites Kuhn, in what manner and why. Research questions first focus on the variety of disciplines invoking Kuhn and to what extent Structure of Scientific Revolutions (SSR) is cited. The Web of Science database provides material from 1982 for this analysis. The science education literature is analyzed using back issues from 1985 of the Journal of Research in Science Teaching and Science Education. An article analysis reveals trends in terms of what Kuhnian ideas are most frequently invoked. Results indicate a wide array of disciplines from beekeeping to law cite Kuhn - especially generic citations to SSR. The science education journal analysis reveals pervasive use of the term paradigm, although use is quite varied. The two areas of research in science education most impacted by Kuhn appear to be conceptual change theory and constructivist epistemologies. Additional uses of Kuhn are discussed. The degree to which Kuhn is invoked in ways supporting the theoretical framework of citation analysis, whether his work is misappropriated, and the impact of Kuhn are discussed.
Buschhardt, Tasja; Bahl, Martin Iain; Hansen, Tina Beck
monitored during aerobic chill-storage (4 °C and 7 °C) and temperature abuse (12 °C and 16 °C) for 96 hours, by culture-based methods and 16S rRNA gene sequencing. Bacterial genera that dominated during prolonged temperature abuse were Acinetobacter, Serratia and Pseudomonas, whereas chill-stored meat...... was dominated by Pseudomonas only. We also showed that the initial community affects subsequent changes during storage. The results suggest that principal coordinate analysis of beta diversity could be a useful tool to reveal temperature abused meat. Sequence data and culturing data revealed a strong positive......Violations of temperature regulations in the meat chain may affect meat safety. Methods are lacking to estimate whether meat has been subjected to temperature abuse. Exposure to too high temperatures may lead to systematic changes in the diverse bacterial communities of fresh meat. We investigated...
Buschhardt, Tasja; Bahl, Martin Iain; Hansen, Tina Beck
Violations of temperature regulations in the meat chain may affect meat safety. Methods are lacking to estimate whether meat has been subjected to temperature abuse. Exposure to too high temperatures may lead to systematic changes in the diverse bacterial communities of fresh meat. We investigated...... monitored during aerobic chill-storage (4 °C and 7 °C) and temperature abuse (12 °C and 16 °C) for 96 hours, by culture-based methods and 16S rRNA gene sequencing. Bacterial genera that dominated during prolonged temperature abuse were Acinetobacter, Serratia and Pseudomonas, whereas chill-stored meat...... was dominated by Pseudomonas only. We also showed that the initial community affects subsequent changes during storage. The results suggest that principal coordinate analysis of beta diversity could be a useful tool to reveal temperature abused meat. Sequence data and culturing data revealed a strong positive...
Quantitative Analysis of Dynamic Protein Interactions during Transcription Reveals a Role for Casein Kinase II in Polymerase-associated Factor (PAF) Complex Phosphorylation and Regulation of Histone H2B Monoubiquitylation.
Bedard, Lynn Glowczewski; Dronamraju, Raghuvar; Kerschner, Jenny L; Hunter, Gerald O; Axley, Elizabeth DeVlieger; Boyd, Asha K; Strahl, Brian D; Mosley, Amber L
Using affinity purification MS approaches, we have identified a novel role for casein kinase II (CKII) in the modification of the polymerase associated factor complex (PAF-C). Our data indicate that the facilitates chromatin transcription complex (FACT) interacts with CKII and may facilitate PAF complex phosphorylation. Posttranslational modification analysis of affinity-isolated PAF-C shows extensive CKII phosphorylation of all five subunits of PAF-C, although CKII subunits were not detected as interacting partners. Consistent with this, recombinant CKII or FACT-associated CKII isolated from cells can phosphorylate PAF-C in vitro, whereas no intrinsic kinase activity was detected in PAF-C samples. Significantly, PAF-C purifications combined with stable isotope labeling in cells (SILAC) quantitation for PAF-C phosphorylation from wild-type and CKII temperature-sensitive strains (cka1Δ cka2-8) showed that PAF-C phosphorylation at consensus CKII sites is significantly reduced in cka1Δ cka2-8 strains. Consistent with a role of CKII in FACT and PAF-C function, we show that decreased CKII function in vivo results in decreased levels of histone H2B lysine 123 monoubiquitylation, a modification dependent on FACT and PAF-C. Taken together, our results define a coordinated role of CKII and FACT in the regulation of RNA polymerase II transcription through chromatin via phosphorylation of PAF-C. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression.
Behan, A T
The dorsolateral prefrontal cortex (dlpfc) is strongly implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BPD) and, within this region, abnormalities in glutamatergic neurotransmission and synaptic function have been described. Proteins associated with these functions are enriched in membrane microdomains (MM). In the current study, we used two complementary proteomic methods, two-dimensional difference gel electrophoresis and one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis followed by reverse phase-liquid chromatography-tandem mass spectrometry (RP-LC-MS\\/MS) (gel separation liquid chromatography-tandem mass spectrometry (GeLC-MS\\/MS)) to assess protein expression in MM in pooled samples of dlpfc from SCZ, BPD and control cases (n=10 per group) from the Stanley Foundation Brain series. We identified 16 proteins altered in one\\/both disorders using proteomic methods. We selected three proteins with roles in synaptic function (syntaxin-binding protein 1 (STXBP1), brain abundant membrane-attached signal protein 1 (BASP1) and limbic system-associated membrane protein (LAMP)) for validation by western blotting. This revealed significantly increased expression of these proteins in SCZ (STXBP1 (24% difference; P<0.001), BASP1 (40% difference; P<0.05) and LAMP (22% difference; P<0.01)) and BPD (STXBP1 (31% difference; P<0.001), BASP1 (23% difference; P<0.01) and LAMP (20% difference; P<0.01)) in the Stanley brain series (n=20 per group). Further validation in dlpfc from the Harvard brain subseries (n=10 per group) confirmed increased protein expression in SCZ of STXBP1 (18% difference; P<0.0001), BASP1 (14% difference; P<0.0001) but not LAMP (20% difference; P=0.14). No significant differences in STXBP1, BASP1 or LAMP protein expression in BPD dlpfc were observed. This study, through proteomic assessments of MM in dlpfc and validation in two brain series, strongly implicates LAMP, STXBP1 and BASP1 in SCZ and supports
van Schijndel, Jessica E; van Loo, Karen M J; van Zweeden, Martine
Schizophrenia is a complex neurodevelopmental disorder that is thought to be induced by an interaction between predisposing genes and environmental stressors. To identify predisposing genetic factors, we performed a targeted (mostly neurodevelopmental) gene approach involving the screening of 396...... selected non-synonymous single-nucleotide polymorphisms (SNPs) in three independent Caucasian schizophrenia case-control cohorts (USA, Denmark and Norway). A meta-analysis revealed ten non-synonymous SNPs that were nominally associated with schizophrenia, nine of which have not been previously linked...... for schizophrenia....
Soto-Cerda, Braulio J; Duguid, Scott; Booker, Helen; Rowland, Gordon; Diederichsen, Axel; Cloutier, Sylvie
The extreme climate of the Canadian Prairies poses a major challenge to improve yield. Although it is possible to breed for yield per se, focusing on yield-related traits could be advantageous because of their simpler genetic architecture. The Canadian flax core collection of 390 accessions was genotyped with 464 simple sequence repeat markers, and phenotypic data for nine agronomic traits including yield, bolls per area, 1,000 seed weight, seeds per boll, start of flowering, end of flowering, plant height, plant branching, and lodging collected from up to eight environments was used for association mapping. Based on a mixed model (principal component analysis (PCA) + kinship matrix (K)), 12 significant marker-trait associations for six agronomic traits were identified. Most of the associations were stable across environments as revealed by multivariate analyses. Statistical simulation for five markers associated with 1000 seed weight indicated that the favorable alleles have additive effects. None of the modern cultivars carried the five favorable alleles and the maximum number of four observed in any accessions was mostly in breeding lines. Our results confirmed the complex genetic architecture of yield-related traits and the inherent difficulties associated with their identification while illustrating the potential for improvement through marker-assisted selection. © 2013 Her Majesty the Queen in Right of Canada. Journal of Integrative Plant Biology published by Wiley Publishing Asia Pty Ltd on behalf of Institute of Botany, Chinese Academy of Sciences.
Linda E. Kippner
Full Text Available Single-cell analysis has the potential to provide us with a host of new knowledge about biological systems, but it comes with the challenge of correctly interpreting the biological information. While emerging techniques have made it possible to measure inter-cellular variability at the transcriptome level, no consensus yet exists on the most appropriate method of data analysis of such single cell data. Methods for analysis of transcriptional data at the population level are well established but are not well suited to single cell analysis due to their dependence on population averages. In order to address this question, we have systematically tested combinations of methods for primary data analysis on single cell transcription data generated from two types of primary immune cells, neutrophils and T lymphocytes. Cells were obtained from healthy individuals, and single cell transcript expression data was obtained by a combination of single cell sorting and nanoscale quantitative real time PCR (qRT-PCR for markers of cell type, intracellular signaling, and immune functionality. Gene expression analysis was focused on hierarchical clustering to determine the existence of cellular subgroups within the populations. Nine combinations of criteria for data exclusion and normalization were tested and evaluated. Bimodality in gene expression indicated the presence of cellular subgroups which were also revealed by data clustering. We observed evidence for two clearly defined cellular subtypes in the neutrophil populations and at least two in the T lymphocyte populations. When normalizing the data by different methods, we observed varying outcomes with corresponding interpretations of the biological characteristics of the cell populations. Normalization of the data by linear standardization taking into account technical effects such as plate effects, resulted in interpretations that most closely matched biological expectations. Single cell transcription
Full Text Available Egg number (EN, egg laying rate (LR and age at first egg (AFE are important production traits related to egg production in poultry industry. To better understand the knowledge of genetic architecture of dynamic EN during the whole laying cycle and provide the precise positions of associated variants for EN, LR and AFE, laying records from 21 to 72 weeks of age were collected individually for 1,534 F2 hens produced by reciprocal crosses between White Leghorn and Dongxiang Blue-shelled chicken, and their genotypes were assayed by chicken 600 K Affymetrix high density genotyping arrays. Subsequently, pedigree and SNP-based genetic parameters were estimated and a genome-wide association study (GWAS was conducted on EN, LR and AFE. The heritability estimates were similar between pedigree and SNP-based estimates varying from 0.17 to 0.36. In the GWA analysis, we identified nine genome-wide significant loci associated with EN of the laying periods from 21 to 26 weeks, 27 to 36 weeks and 37 to 72 weeks. Analysis of GTF2A1 and CLSPN suggested that they influenced the function of ovary and uterus, and may be considered as relevant candidates. The identified SNP rs314448799 for accumulative EN from 21 to 40 weeks on chromosome 5 created phenotypic differences of 6.86 eggs between two homozygous genotypes, which could be potentially applied to the molecular breeding for EN selection. Moreover, our finding showed that LR was a moderate polygenic trait. The suggestive significant region on chromosome 16 for AFE suggested the relationship between sex maturity and immune in the current population. The present study comprehensively evaluates the role of genetic variants in the development of egg laying. The findings will be helpful to investigation of causative genes function and future marker-assisted selection and genomic selection in chickens.
Schoos, Ann-Marie M.; Chawes, Bo L.; Melen, Erik
BACKGROUND: Assessment of sensitization at a single time point during childhood provides limited clinical information. We hypothesized that sensitization develops as specific patterns with respect to age at debut, development over time, and involved allergens and that such patterns might be more...... biologically and clinically relevant. OBJECTIVE: We sought to explore latent patterns of sensitization during the first 6 years of life and investigate whether such patterns associate with the development of asthma, rhinitis, and eczema. METHODS: We investigated 398 children from the at-risk Copenhagen...... Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort with specific IgE against 13 common food and inhalant allergens at the ages of ½, 1½, 4, and 6 years. An unsupervised cluster analysis for 3-dimensional data (nonnegative sparse parallel factor analysis) was used to extract latent...
Ikegami, Keisuke; Yoshimura, Takashi
Animals utilize photoperiodic changes as a calendar to regulate seasonal reproduction. Birds have highly sophisticated photoperiodic mechanisms and functional genomics analysis in quail uncovered the signal transduction pathway regulating avian seasonal reproduction. Birds detect light with deep brain photoreceptors. Long day (LD) stimulus induces secretion of thyroid-stimulating hormone (TSH) from the pars tuberalis (PT) of the pituitary gland. PT-derived TSH locally activates thyroid hormone (TH) in the hypothalamus, which induces gonadotropin-releasing hormone (GnRH) and hence gonadotropin secretion. However, during winter, low temperatures increase serum TH for adaptive thermogenesis, which accelerates germ cell apoptosis by activating the genes involved in metamorphosis. Therefore, TH has a dual role in the regulation of seasonal reproduction. Studies using TSH receptor knockout mice confirmed the involvement of PT-derived TSH in mammalian seasonal reproduction. In addition, studies in mice revealed that the tissue-specific glycosylation of TSH diversifies its function in the circulation to avoid crosstalk. In contrast to birds and mammals, one of the molecular machineries necessary for the seasonal reproduction of fish are localized in the saccus vasculosus from the photoreceptor to the neuroendocrine output. Thus, comparative analysis is a powerful tool to uncover the universality and diversity of fundamental properties in various organisms. Copyright © 2015 Elsevier Inc. All rights reserved.
Hasene Esra Yildirir; Hatice Demirkol
The current study aimed at examining the utility of a word association test in revealing students’ cognitive structure in a specific chemistry topic through a word association test. The participants were 153 6th graders in a western Turkish city. The results revealed that the word association test serves a useful purpose in exploring the students’ cognitive structure with regard to physical and chemical change and identifying their misconceptions about this topic. Some students gave irrelevan...
Full Text Available Abstract Background In oviparous vertebrates, including fish, vitellogenesis consists of highly regulated pathways involving 17β-estradiol (E2. Previous studies focused on a relatively small number of hepatic expressed genes during vitellogenesis. This study aims to identify hepatic genes involved in vitellogenesis and regulated by E2, by using zebrafish microarray gene expression profiling, and to provide information on functional distinctive genes expressed in the liver of a vitellogenic female, using zebrafish as a model fish. Results Genes associated with vitellogenesis were revealed by the following paired t-tests (SAM comparisons: a two-month old vitellogenic (Vit2 females were compared with non-vitellogenic (NV females, showing 825 differentially expressed transcripts during early stages of vitellogenesis, b four-month old vitellogenic (Vit4 females were compared with NV females, showing 1,046 differentially expressed transcripts during vitellogenesis and c E2-treated males were compared with control males, showing 1,828 differentially expressed transcripts regulated by E2. A Venn diagram revealed 822 common transcripts in the three groups, indicating that these transcripts were involved in vitellogenesis and putatively regulated by E2. In addition, 431 transcripts were differentially expressed in Vit2 and Vit4 females but not in E2-treated males, indicating that they were putatively not up-regulated by E2. Correspondence analysis showed high similarity in expression profiles of Vit2 with Vit4 and of NV females with control males. The E2-treated males differed from the other groups. The repertoire of genes putatively regulated by E2 in vitellogenic females included genes associated with protein synthesis and reproduction. Genes associated with the immune system processes and biological adhesion, were among the genes that were putatively not regulated by E2. E2-treated males expressed a large array of transcripts that were not associated
Full Text Available Analysis of mutants and gene expression patterns provides a powerful approach for investigating genes involved in key stages of plant fiber development. In this study, lintless-fuzzless XinWX and linted-fuzzless XinFLM with a single genetic locus difference for lint were used to identify differentially expressed genes. Scanning electron microscopy showed fiber initiation in XinFLM at 0 days post anthesis (DPA. Fiber transcriptional profiling of the lines at three initiation developmental stages (-1, 0, 1 DPA was performed using an oligonucleotide microarray. Loop comparisons of the differentially expressed genes within and between the lines was carried out, and functional classification and enrichment analysis showed that gene expression patterns during fiber initiation were heavily associated with hormone metabolism, transcription factor regulation, lipid transport, and asparagine biosynthetic processes, as previously reported. Further, four members of the allene-oxide cyclase (AOC family that function in jasmonate biosynthesis were parallel up-regulation in fiber initiation, especially at -1 DPA, compared to other tissues and organs in linted-fuzzed TM-1. Real time-quantitative PCR (RT-qPCR analysis in different fiber mutant lines revealed that AOCs were up-regulated higher at -1 DPA in lintless-fuzzless than that in linted-fuzzless and linted-fuzzed materials, and transcription of the AOCs was increased under jasmonic acid (JA treatment. Expression analysis of JA biosynthesis-associated genes between XinWX and XinFLM showed that they were up-regulated during fiber initiation in the fuzzless-lintless mutant. Taken together, jasmonic acid-associated metabolism was related to cotton fiber initiation. Parallel up-regulation of AOCs expression may be important for normal fiber initiation development, while overproduction of AOCs might disrupt normal fiber development.
Schoos, Ann-Marie M; Chawes, Bo L; Melén, Erik; Bergström, Anna; Kull, Inger; Wickman, Magnus; Bønnelykke, Klaus; Bisgaard, Hans; Rasmussen, Morten A
Assessment of sensitization at a single time point during childhood provides limited clinical information. We hypothesized that sensitization develops as specific patterns with respect to age at debut, development over time, and involved allergens and that such patterns might be more biologically and clinically relevant. We sought to explore latent patterns of sensitization during the first 6 years of life and investigate whether such patterns associate with the development of asthma, rhinitis, and eczema. We investigated 398 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC 2000 ) birth cohort with specific IgE against 13 common food and inhalant allergens at the ages of ½, 1½, 4, and 6 years. An unsupervised cluster analysis for 3-dimensional data (nonnegative sparse parallel factor analysis) was used to extract latent patterns explicitly characterizing temporal development of sensitization while clustering allergens and children. Subsequently, these patterns were investigated in relation to asthma, rhinitis, and eczema. Verification was sought in an independent unselected birth cohort (BAMSE) constituting 3051 children with specific IgE against the same allergens at 4 and 8 years of age. The nonnegative sparse parallel factor analysis indicated a complex latent structure involving 7 age- and allergen-specific patterns in the COPSAC 2000 birth cohort data: (1) dog/cat/horse, (2) timothy grass/birch, (3) molds, (4) house dust mites, (5) peanut/wheat flour/mugwort, (6) peanut/soybean, and (7) egg/milk/wheat flour. Asthma was solely associated with pattern 1 (odds ratio [OR], 3.3; 95% CI, 1.5-7.2), rhinitis with patterns 1 to 4 and 6 (OR, 2.2-4.3), and eczema with patterns 1 to 3 and 5 to 7 (OR, 1.6-2.5). All 7 patterns were verified in the independent BAMSE cohort (R 2 > 0.89). This study suggests the presence of specific sensitization patterns in early childhood differentially associated with development of
Cohen Kadosh, Roi; Gevers, Wim; Notebaert, Wim
Automatic processing of irrelevant stimulus dimensions has been demonstrated in a variety of tasks. Previous studies have shown that conflict between relevant and irrelevant dimensions can be reduced when a feature of the irrelevant dimension is repeated. The specific level at which the automatic process is suppressed (e.g., perceptual repetition, response repetition), however, is less understood. In the current experiment we used the numerical Stroop paradigm, in which the processing of irrelevant numerical values of 2 digits interferes with the processing of their physical size, to pinpoint the precise level of the suppression. Using a sequential analysis, we dissociated perceptual repetition from response repetition of the relevant and irrelevant dimension. Our analyses of reaction times, error rates, and diffusion modeling revealed that the congruity effect is significantly reduced or even absent when the response sequence of the irrelevant dimension, rather than the numerical value or the physical size, is repeated. These results suggest that automatic activation of the irrelevant dimension is suppressed at the response level. The current results shed light on the level of interaction between numerical magnitude and physical size as well as the effect of variability of responses and stimuli on automatic processing. (c) 2011 APA, all rights reserved.
M?ller, Sebastian; Balaz, Miroslav; Stefanicka, Patrik; Varga, Lukas; Amri, Ez-Zoubir; Ukropec, Jozef; Wollscheid, Bernd; Wolfrum, Christian
Human brown adipose tissue (BAT) has become an attractive target to combat the current epidemical spread of obesity and its associated co-morbidities. Currently, information on its functional role is primarily derived from rodent studies. Here, we present the first comparative proteotype analysis of primary human brown adipose tissue versus adjacent white adipose tissue, which reveals significant quantitative differences in protein abundances and in turn differential functional capabilities. ...
Disasters events are perfect examples of compound events. Disaster risk lies at the intersection of several independent components such as hazard, exposure and vulnerability. Understanding the weight of each component requires extensive standardisation. Here, I show how footprints of past disastrous events were generated using GIS modelling techniques and used for extracting population and economic exposures based on distribution models. Using past event losses, it was possible to identify and quantify a wide range of socio-politico-economic drivers associated with human vulnerability. The analysis was applied to about nine thousand individual past disastrous events covering earthquakes, floods and tropical cyclones. Using a multiple regression analysis on these individual events it was possible to quantify each risk component and assess how vulnerability is influenced by various hazard intensities. The results show that hazard intensity, exposure, poverty, governance as well as other underlying factors (e.g. remoteness) can explain the magnitude of past disasters. Analysis was also performed to highlight the role of future trends in population and climate change and how this may impacts exposure to tropical cyclones in the future. GIS models combined with statistical multiple regression analysis provided a powerful methodology to identify, quantify and model disaster risk taking into account its various components. The same methodology can be applied to various types of risk at local to global scale. This method was applied and developed for the Global Risk Analysis of the Global Assessment Report on Disaster Risk Reduction (GAR). It was first applied on mortality risk in GAR 2009 and GAR 2011. New models ranging from global assets exposure and global flood hazard models were also recently developed to improve the resolution of the risk analysis and applied through CAPRA software to provide probabilistic economic risk assessments such as Average Annual Losses (AAL
Zhu, Z-Q; Tang, J-S; Cao, X-J
Ankylosing spondylitis (AS) is a chronic, inflammatory arthritis and autoimmune disease. The main symptom of AS is inflammatory spinal pain; with time, some patients develop ankylosis and spinal immobility. We aim to find cure available for ankylosing spondylitis. We used the GSE11886 series to identify potential genes that related to AS to construct a regulation network. In the network, some of TFs and target genes have been proved related with AS in previous study, such as NFKB1, STAT1, STAT4, TNFSF10, IL2RA, and IL2RB. We also found some new TFs (Franscription Factors) and target genes response to AS, such as BXDC5, and EGFR. Further analysis indicated some significant pathways are associated with AS, including antigen processing and presentation and cytokine-cytokine receptor interaction, etc.; although not significant, there was evident that they play an important role in AS progression, such as apoptosis and systemic lupus erythematosus. Therefore, it is demonstrated that transcriptome network analysis is useful in identification of the candidate genes in AS.
Integrative analysis of Salmonellosis in Israel reveals association of Salmonella enterica Serovar 9,12:l,v:- with extraintestinal infections, dissemination of endemic S. enterica Serovar Typhimurium DT104 biotypes, and severe underreporting of outbreaks.
Marzel, Alex; Desai, Prerak T; Nissan, Israel; Schorr, Yosef Ilan; Suez, Jotham; Valinsky, Lea; Reisfeld, Abraham; Agmon, Vered; Guard, Jean; McClelland, Michael; Rahav, Galia; Gal-Mor, Ohad
Salmonella enterica is the leading etiologic agent of bacterial food-borne outbreaks worldwide. This ubiquitous species contains more than 2,600 serovars that may differ in their host specificity, clinical manifestations, and epidemiology. To characterize salmonellosis epidemiology in Israel and to study the association of nontyphoidal Salmonella (NTS) serovars with invasive infections, 48,345 Salmonella cases reported and serotyped at the National Salmonella Reference Center between 1995 and 2012 were analyzed. A quasi-Poisson regression was used to identify irregular clusters of illness, and pulsed-field gel electrophoresis in conjunction with whole-genome sequencing was applied to molecularly characterize strains of interest. Three hundred twenty-nine human salmonellosis clusters were identified, representing an annual average of 23 (95% confidence interval [CI], 20 to 26) potential outbreaks. We show that the previously unsequenced S. enterica serovar 9,12:l,v:- belongs to the B clade of Salmonella enterica subspecies enterica, and we show its frequent association with extraintestinal infections, compared to other NTS serovars. Furthermore, we identified the dissemination of two prevalent Salmonella enterica serovar Typhimurium DT104 clones in Israel, which are genetically distinct from other global DT104 isolates. Accumulatively, these findings indicate a severe underreporting of Salmonella outbreaks in Israel and provide insights into the epidemiology and genomics of prevalent serovars, responsible for recurring illness. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
Tao, Yongfu; Mace, Emma S; Tai, Shuaishuai; Cruickshank, Alan; Campbell, Bradley C; Zhao, Xianrong; Van Oosterom, Erik J; Godwin, Ian D; Botella, Jose R; Jordan, David R
Seed size and seed weight are major quality attributes and important determinants of yield that have been strongly selected for during crop domestication. Limited information is available about the genetic control and genes associated with seed size and weight in sorghum. This study identified sorghum orthologs of genes with proven effects on seed size and weight in other plant species and searched for evidence of selection during domestication by utilizing resequencing data from a diversity panel. In total, 114 seed size candidate genes were identified in sorghum, 63 of which exhibited signals of purifying selection during domestication. A significant number of these genes also had domestication signatures in maize and rice, consistent with the parallel domestication of seed size in cereals. Seed size candidate genes that exhibited differentially high expression levels in seed were also found more likely to be under selection during domestication, supporting the hypothesis that modification to seed size during domestication preferentially targeted genes for intrinsic seed size rather than genes associated with physiological factors involved in the carbohydrate supply and transport. Our results provide improved understanding of the complex genetic control of seed size and weight and the impact of domestication on these genes.
Full Text Available Alzheimer's disease (AD, the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs, we identified the PINs expressed in three brain regions: the entorhinal cortex (EC, hippocampus (HIP and superior frontal gyrus (SFG. Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.
Pereira-Marques, Joana; Pinto-Ribeiro, Ines; Costa, Jose L; Carneiro, Fatima; Machado, Jose C
Objective Gastric carcinoma development is triggered by Helicobacter pylori. Chronic H. pylori infection leads to reduced acid secretion, which may allow the growth of a different gastric bacterial community. This change in the microbiome may increase aggression to the gastric mucosa and contribute to malignancy. Our aim was to evaluate the composition of the gastric microbiota in chronic gastritis and in gastric carcinoma. Design The gastric microbiota was retrospectively investigated in 54 patients with gastric carcinoma and 81 patients with chronic gastritis by 16S rRNA gene profiling, using next-generation sequencing. Differences in microbial composition of the two patient groups were assessed using linear discriminant analysis effect size. Associations between the most relevant taxa and clinical diagnosis were validated by real-time quantitative PCR. Predictive functional profiling of microbial communities was obtained with PICRUSt. Results The gastric carcinoma microbiota was characterised by reduced microbial diversity, by decreased abundance of Helicobacter and by the enrichment of other bacterial genera, mostly represented by intestinal commensals. The combination of these taxa into a microbial dysbiosis index revealed that dysbiosis has excellent capacity to discriminate between gastritis and gastric carcinoma. Analysis of the functional features of the microbiota was compatible with the presence of a nitrosating microbial community in carcinoma. The major observations were confirmed in validation cohorts from different geographic origins. Conclusions Detailed analysis of the gastric microbiota revealed for the first time that patients with gastric carcinoma exhibit a dysbiotic microbial community with genotoxic potential, which is distinct from that of patients with chronic gastritis. PMID:29102920
Full Text Available Yellowstone National Park is home to one of the only plains bison populations that have continuously existed on their present landscape since prehistoric times without evidence of domestic cattle introgression. Previous studies characterized the relatively high levels of nuclear genetic diversity in these bison, but little is known about their mitochondrial haplotype diversity. This study assessed mitochondrial genomes from 25 randomly selected Yellowstone bison and found 10 different mitochondrial haplotypes with a haplotype diversity of 0.78 (± 0.06. Spatial analysis of these mitochondrial DNA (mtDNA haplotypes did not detect geographic population subdivision (FST = -0.06, p = 0.76. However, we identified two independent and historically important lineages in Yellowstone bison by combining data from 65 bison (defined by 120 polymorphic sites from across North America representing a total of 30 different mitochondrial DNA haplotypes. Mitochondrial DNA haplotypes from one of the Yellowstone lineages represent descendants of the 22 indigenous bison remaining in central Yellowstone in 1902. The other mitochondrial DNA lineage represents descendants of the 18 females introduced from northern Montana in 1902 to supplement the indigenous bison population and develop a new breeding herd in the northern region of the park. Comparing modern and historical mitochondrial DNA diversity in Yellowstone bison helps uncover a historical context of park restoration efforts during the early 1900s, provides evidence against a hypothesized mitochondrial disease in bison, and reveals the signature of recent hybridization between American plains bison (Bison bison bison and Canadian wood bison (B. b. athabascae. Our study demonstrates how mitochondrial DNA can be applied to delineate the history of wildlife species and inform future conservation actions.
Fan, Jing; Ye, Jiangbin; Kamphorst, Jurre J.; Shlomi, Tomer; Thompson, Craig B.; Rabinowitz, Joshua D.
ATP is the dominant energy source in animals for mechanical and electrical work (for example, muscle contraction or neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defence and reductive biosynthesis. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway, with malic enzyme sometimes also important. Although the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analysed, similar analysis of NADPH metabolism has been lacking. Here we demonstrate the ability to directly track, by liquid chromatography-mass spectrometry, the passage of deuterium from labelled substrates into NADPH, and combine this approach with carbon labelling and mathematical modelling to measure NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxidative pentose phosphate pathway. Surprisingly, a nearly comparable contribution comes from serine-driven one-carbon metabolism, in which oxidation of methylene tetrahydrofolate to 10-formyl-tetrahydrofolate is coupled to reduction of NADP+ to NADPH. Moreover, tracing of mitochondrial one-carbon metabolism revealed complete oxidation of 10-formyl-tetrahydrofolate to make NADPH. As folate metabolism has not previously been considered an NADPH producer, confirmation of its functional significance was undertaken through knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) genes. Depletion of either the cytosolic or mitochondrial MTHFD isozyme resulted in decreased cellular NADPH/NADP+ and reduced/oxidized glutathione ratios (GSH/GSSG) and increased cell sensitivity to oxidative stress. Thus, although the importance of folate metabolism for proliferating cells has been long recognized and attributed to its function of producing one-carbon units for nucleic acid synthesis, another crucial function of this pathway is generating reducing power.
Carneiro, Ana M D; Airey, David C; Thompson, Brent; Zhu, Chong-Bin; Lu, Lu; Chesler, Elissa J; Erikson, Keith M; Blakely, Randy D
The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J x DBA/2J = BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.
Jain, Dharamdeep; Stark, Alyssa Y.; Niewiarowski, Peter H.; Miyoshi, Toshikazu; Dhinojwala, Ali
Lipid and protein aggregates are one of the fundamental materials of biological systems. Examples include cell membranes, insect cuticle, vertebrate epidermis, feathers, hair and adhesive structures known as ‘setae’ on gecko toes. Until recently gecko setae were assumed to be composed entirely of keratin, but analysis of footprints left behind by geckos walking on surfaces revealed that setae include various kinds of lipids. However, the arrangement and molecular-level behavior of lipids and keratin in the setae is still not known. In the present study we demonstrate, for the first time, the use of Nuclear Magnetic Resonance (NMR) spectroscopy techniques to confirm the presence of lipids and investigate their association with keratin in ‘pristine' sheds, or natural molts of the adhesive toe pad and non-adhesive regions of the skin. Analysis was also carried on the sheds after they were ‘delipidized’ to remove surface lipids. Our results show a distribution of similar lipids in both the skin and toe shed but with different dynamics at a molecular level. The present study can help us understand the gecko system both biologically and for design of synthetic adhesives, but the findings may be relevant to the characteristics of lipid-protein interactions in other biological systems. PMID:25902194
Brante P Sampey
Full Text Available Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD to "Cafeteria diets" (CAF consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity
Carneiro, Ana [Vanderbilt University; Airey, David [University of Tennessee Health Science Center, Memphis; Thompson, Brent [Vanderbilt University; Zhu, C [Vanderbilt University; Rinchik, Eugene M [ORNL; Lu, Lu [University of Tennessee Health Science Center, Memphis; Chesler, Elissa J [ORNL; Erikson, Keith [University of North Carolina; Blakely, Randy [Vanderbilt University
The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology or treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism and obsessive-compulsive disorder (OCD). Here we utilize naturally occurring polymorphisms in recombinant inbred (RI) lines to identify novel phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by two nonsynonymous coding variants (Gly39 and Lys152 (GK)). At these positions, many other mouse lines, including DBA/2J, encode Glu39 and Arg152 (ER haplotype), assignments found also in hSERT. Synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant. Heterologous expression studies confirmed a reduced SERT turnover rate for the GK variant. Experimental and in silico approaches using RI lines (C57Bl/6J X DBA/2J=BXD) identifies multiple anatomical, biochemical and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are multiple traits associated with anxiety and alcohol consumption, as well as of the control of dopamine (DA) signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates ironregulated DA phenotypes. Our studies provide a novel example of the power of coordinated in vitro, in vivo and in silico approaches using murine RI lines to elucidate and quantify the system-level impact of gene variation.
Speliotes, Elizabeth K; Willer, Cristen J; Berndt, Sonja I; Monda, Keri L; Thorleifsson, Gudmar; Jackson, Anne U; Lango Allen, Hana; Lindgren, Cecilia M; Luan, Jian'an; Mägi, Reedik; Randall, Joshua C; Vedantam, Sailaja; Winkler, Thomas W; Qi, Lu; Workalemahu, Tsegaselassie; Heid, Iris M; Steinthorsdottir, Valgerdur; Stringham, Heather M; Weedon, Michael N; Wheeler, Eleanor; Wood, Andrew R; Ferreira, Teresa; Weyant, Robert J; Segrè, Ayellet V; Estrada, Karol; Liang, Liming; Nemesh, James; Park, Ju-Hyun; Gustafsson, Stefan; Kilpeläinen, Tuomas O; Yang, Jian; Bouatia-Naji, Nabila; Esko, Tõnu; Feitosa, Mary F; Kutalik, Zoltán; Mangino, Massimo; Raychaudhuri, Soumya; Scherag, Andre; Smith, Albert Vernon; Welch, Ryan; Zhao, Jing Hua; Aben, Katja K; Absher, Devin M; Amin, Najaf; Dixon, Anna L; Fisher, Eva; Glazer, Nicole L; Goddard, Michael E; Heard-Costa, Nancy L; Hoesel, Volker; Hottenga, Jouke-Jan; Johansson, Asa; Johnson, Toby; Ketkar, Shamika; Lamina, Claudia; Li, Shengxu; Moffatt, Miriam F; Myers, Richard H; Narisu, Narisu; Perry, John R B; Peters, Marjolein J; Preuss, Michael; Ripatti, Samuli; Rivadeneira, Fernando; Sandholt, Camilla; Scott, Laura J; Timpson, Nicholas J; Tyrer, Jonathan P; van Wingerden, Sophie; Watanabe, Richard M; White, Charles C; Wiklund, Fredrik; Barlassina, Christina; Chasman, Daniel I; Cooper, Matthew N; Jansson, John-Olov; Lawrence, Robert W; Pellikka, Niina; Prokopenko, Inga; Shi, Jianxin; Thiering, Elisabeth; Alavere, Helene; Alibrandi, Maria T S; Almgren, Peter; Arnold, Alice M; Aspelund, Thor; Atwood, Larry D; Balkau, Beverley; Balmforth, Anthony J; Bennett, Amanda J; Ben-Shlomo, Yoav; Bergman, Richard N; Bergmann, Sven; Biebermann, Heike; Blakemore, Alexandra I F; Boes, Tanja; Bonnycastle, Lori L; Bornstein, Stefan R; Brown, Morris J; Buchanan, Thomas A; Busonero, Fabio; Campbell, Harry; Cappuccio, Francesco P; Cavalcanti-Proença, Christine; Chen, Yii-Der Ida; Chen, Chih-Mei; Chines, Peter S; Clarke, Robert; Coin, Lachlan; Connell, John; Day, Ian N M; den Heijer, Martin; Duan, Jubao; Ebrahim, Shah; Elliott, Paul; Elosua, Roberto; Eiriksdottir, Gudny; Erdos, Michael R; Eriksson, Johan G; Facheris, Maurizio F; Felix, Stephan B; Fischer-Posovszky, Pamela; Folsom, Aaron R; Friedrich, Nele; Freimer, Nelson B; Fu, Mao; Gaget, Stefan; Gejman, Pablo V; Geus, Eco J C; Gieger, Christian; Gjesing, Anette P; Goel, Anuj; Goyette, Philippe; Grallert, Harald; Grässler, Jürgen; Greenawalt, Danielle M; Groves, Christopher J; Gudnason, Vilmundur; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hall, Alistair S; Havulinna, Aki S; Hayward, Caroline; Heath, Andrew C; Hengstenberg, Christian; Hicks, Andrew A; Hinney, Anke; Hofman, Albert; Homuth, Georg; Hui, Jennie; Igl, Wilmar; Iribarren, Carlos; Isomaa, Bo; Jacobs, Kevin B; Jarick, Ivonne; Jewell, Elizabeth; John, Ulrich; Jørgensen, Torben; Jousilahti, Pekka; Jula, Antti; Kaakinen, Marika; Kajantie, Eero; Kaplan, Lee M; Kathiresan, Sekar; Kettunen, Johannes; Kinnunen, Leena; Knowles, Joshua W; Kolcic, Ivana; König, Inke R; Koskinen, Seppo; Kovacs, Peter; Kuusisto, Johanna; Kraft, Peter; Kvaløy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lanzani, Chiara; Launer, Lenore J; Lecoeur, Cecile; Lehtimäki, Terho; Lettre, Guillaume; Liu, Jianjun; Lokki, Marja-Liisa; Lorentzon, Mattias; Luben, Robert N; Ludwig, Barbara; Manunta, Paolo; Marek, Diana; Marre, Michel; Martin, Nicholas G; McArdle, Wendy L; McCarthy, Anne; McKnight, Barbara; Meitinger, Thomas; Melander, Olle; Meyre, David; Midthjell, Kristian; Montgomery, Grant W; Morken, Mario A; Morris, Andrew P; Mulic, Rosanda; Ngwa, Julius S; Nelis, Mari; Neville, Matt J; Nyholt, Dale R; O'Donnell, Christopher J; O'Rahilly, Stephen; Ong, Ken K; Oostra, Ben; Paré, Guillaume; Parker, Alex N; Perola, Markus; Pichler, Irene; Pietiläinen, Kirsi H; Platou, Carl G P; Polasek, Ozren; Pouta, Anneli; Rafelt, Suzanne; Raitakari, Olli; Rayner, Nigel W; Ridderstråle, Martin; Rief, Winfried; Ruokonen, Aimo; Robertson, Neil R; Rzehak, Peter; Salomaa, Veikko; Sanders, Alan R; Sandhu, Manjinder S; Sanna, Serena; Saramies, Jouko; Savolainen, Markku J; Scherag, Susann; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Silander, Kaisa; Sinisalo, Juha; Siscovick, David S; Smit, Jan H; Soranzo, Nicole; Sovio, Ulla; Stephens, Jonathan; Surakka, Ida; Swift, Amy J; Tammesoo, Mari-Liis; Tardif, Jean-Claude; Teder-Laving, Maris; Teslovich, Tanya M; Thompson, John R; Thomson, Brian; Tönjes, Anke; Tuomi, Tiinamaija; van Meurs, Joyce B J; van Ommen, Gert-Jan; Vatin, Vincent; Viikari, Jorma; Visvikis-Siest, Sophie; Vitart, Veronique; Vogel, Carla I G; Voight, Benjamin F; Waite, Lindsay L; Wallaschofski, Henri; Walters, G Bragi; Widen, Elisabeth; Wiegand, Susanna; Wild, Sarah H; Willemsen, Gonneke; Witte, Daniel R; Witteman, Jacqueline C; Xu, Jianfeng; Zhang, Qunyuan; Zgaga, Lina; Ziegler, Andreas; Zitting, Paavo; Beilby, John P; Farooqi, I Sadaf; Hebebrand, Johannes; Huikuri, Heikki V; James, Alan L; Kähönen, Mika; Levinson, Douglas F; Macciardi, Fabio; Nieminen, Markku S; Ohlsson, Claes; Palmer, Lyle J; Ridker, Paul M; Stumvoll, Michael; Beckmann, Jacques S; Boeing, Heiner; Boerwinkle, Eric; Boomsma, Dorret I; Caulfield, Mark J; Chanock, Stephen J; Collins, Francis S; Cupples, L Adrienne; Smith, George Davey; Erdmann, Jeanette; Froguel, Philippe; Grönberg, Henrik; Gyllensten, Ulf; Hall, Per; Hansen, Torben; Harris, Tamara B; Hattersley, Andrew T; Hayes, Richard B; Heinrich, Joachim; Hu, Frank B; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Kaprio, Jaakko; Karpe, Fredrik; Khaw, Kay-Tee; Kiemeney, Lambertus A; Krude, Heiko; Laakso, Markku; Lawlor, Debbie A; Metspalu, Andres; Munroe, Patricia B; Ouwehand, Willem H; Pedersen, Oluf; Penninx, Brenda W; Peters, Annette; Pramstaller, Peter P; Quertermous, Thomas; Reinehr, Thomas; Rissanen, Aila; Rudan, Igor; Samani, Nilesh J; Schwarz, Peter E H; Shuldiner, Alan R; Spector, Timothy D; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, André; Valle, Timo T; Wabitsch, Martin; Waeber, Gérard; Wareham, Nicholas J; Watkins, Hugh; Wilson, James F; Wright, Alan F; Zillikens, M Carola; Chatterjee, Nilanjan; McCarroll, Steven A; Purcell, Shaun; Schadt, Eric E; Visscher, Peter M; Assimes, Themistocles L; Borecki, Ingrid B; Deloukas, Panos; Fox, Caroline S; Groop, Leif C; Haritunians, Talin; Hunter, David J; Kaplan, Robert C; Mohlke, Karen L; O'Connell, Jeffrey R; Peltonen, Leena; Schlessinger, David; Strachan, David P; van Duijn, Cornelia M; Wichmann, H-Erich; Frayling, Timothy M; Thorsteinsdottir, Unnur; Abecasis, Gonçalo R; Barroso, Inês; Boehnke, Michael; Stefansson, Kari; North, Kari E; McCarthy, Mark I; Hirschhorn, Joel N; Ingelsson, Erik; Loos, Ruth J F
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Speliotes, Elizabeth K.; Willer, Cristen J.; Berndt, Sonja I.; Monda, Keri L.; Thorleifsson, Gudmar; Jackson, Anne U.; Allen, Hana Lango; Lindgren, Cecilia M.; Luan, Jian’an; Mägi, Reedik; Randall, Joshua C.; Vedantam, Sailaja; Winkler, Thomas W.; Qi, Lu; Workalemahu, Tsegaselassie; Heid, Iris M.; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Weedon, Michael N.; Wheeler, Eleanor; Wood, Andrew R.; Ferreira, Teresa; Weyant, Robert J.; Segré, Ayellet V.; Estrada, Karol; Liang, Liming; Nemesh, James; Park, Ju-Hyun; Gustafsson, Stefan; Kilpeläinen, Tuomas O.; Yang, Jian; Bouatia-Naji, Nabila; Esko, Tõnu; Feitosa, Mary F.; Kutalik, Zoltán; Mangino, Massimo; Raychaudhuri, Soumya; Scherag, Andre; Smith, Albert Vernon; Welch, Ryan; Zhao, Jing Hua; Aben, Katja K.; Absher, Devin M.; Amin, Najaf; Dixon, Anna L.; Fisher, Eva; Glazer, Nicole L.; Goddard, Michael E.; Heard-Costa, Nancy L.; Hoesel, Volker; Hottenga, Jouke-Jan; Johansson, Åsa; Johnson, Toby; Ketkar, Shamika; Lamina, Claudia; Li, Shengxu; Moffatt, Miriam F.; Myers, Richard H.; Narisu, Narisu; Perry, John R.B.; Peters, Marjolein J.; Preuss, Michael; Ripatti, Samuli; Rivadeneira, Fernando; Sandholt, Camilla; Scott, Laura J.; Timpson, Nicholas J.; Tyrer, Jonathan P.; van Wingerden, Sophie; Watanabe, Richard M.; White, Charles C.; Wiklund, Fredrik; Barlassina, Christina; Chasman, Daniel I.; Cooper, Matthew N.; Jansson, John-Olov; Lawrence, Robert W.; Pellikka, Niina; Prokopenko, Inga; Shi, Jianxin; Thiering, Elisabeth; Alavere, Helene; Alibrandi, Maria T. S.; Almgren, Peter; Arnold, Alice M.; Aspelund, Thor; Atwood, Larry D.; Balkau, Beverley; Balmforth, Anthony J.; Bennett, Amanda J.; Ben-Shlomo, Yoav; Bergman, Richard N.; Bergmann, Sven; Biebermann, Heike; Blakemore, Alexandra I.F.; Boes, Tanja; Bonnycastle, Lori L.; Bornstein, Stefan R.; Brown, Morris J.; Buchanan, Thomas A.; Busonero, Fabio; Campbell, Harry; Cappuccio, Francesco P.; Cavalcanti-Proença, Christine; Chen, Yii-Der Ida; Chen, Chih-Mei; Chines, Peter S.; Clarke, Robert; Coin, Lachlan; Connell, John; Day, Ian N.M.; den Heijer, Martin; Duan, Jubao; Ebrahim, Shah; Elliott, Paul; Elosua, Roberto; Eiriksdottir, Gudny; Erdos, Michael R.; Eriksson, Johan G.; Facheris, Maurizio F.; Felix, Stephan B.; Fischer-Posovszky, Pamela; Folsom, Aaron R.; Friedrich, Nele; Freimer, Nelson B.; Fu, Mao; Gaget, Stefan; Gejman, Pablo V.; Geus, Eco J.C.; Gieger, Christian; Gjesing, Anette P.; Goel, Anuj; Goyette, Philippe; Grallert, Harald; Gräßler, Jürgen; Greenawalt, Danielle M.; Groves, Christopher J.; Gudnason, Vilmundur; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hall, Alistair S.; Havulinna, Aki S.; Hayward, Caroline; Heath, Andrew C.; Hengstenberg, Christian; Hicks, Andrew A.; Hinney, Anke; Hofman, Albert; Homuth, Georg; Hui, Jennie; Igl, Wilmar; Iribarren, Carlos; Isomaa, Bo; Jacobs, Kevin B.; Jarick, Ivonne; Jewell, Elizabeth; John, Ulrich; Jørgensen, Torben; Jousilahti, Pekka; Jula, Antti; Kaakinen, Marika; Kajantie, Eero; Kaplan, Lee M.; Kathiresan, Sekar; Kettunen, Johannes; Kinnunen, Leena; Knowles, Joshua W.; Kolcic, Ivana; König, Inke R.; Koskinen, Seppo; Kovacs, Peter; Kuusisto, Johanna; Kraft, Peter; Kvaløy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lanzani, Chiara; Launer, Lenore J.; Lecoeur, Cecile; Lehtimäki, Terho; Lettre, Guillaume; Liu, Jianjun; Lokki, Marja-Liisa; Lorentzon, Mattias; Luben, Robert N.; Ludwig, Barbara; Manunta, Paolo; Marek, Diana; Marre, Michel; Martin, Nicholas G.; McArdle, Wendy L.; McCarthy, Anne; McKnight, Barbara; Meitinger, Thomas; Melander, Olle; Meyre, David; Midthjell, Kristian; Montgomery, Grant W.; Morken, Mario A.; Morris, Andrew P.; Mulic, Rosanda; Ngwa, Julius S.; Nelis, Mari; Neville, Matt J.; Nyholt, Dale R.; O’Donnell, Christopher J.; O’Rahilly, Stephen; Ong, Ken K.; Oostra, Ben; Paré, Guillaume; Parker, Alex N.; Perola, Markus; Pichler, Irene; Pietiläinen, Kirsi H.; Platou, Carl G.P.; Polasek, Ozren; Pouta, Anneli; Rafelt, Suzanne; Raitakari, Olli; Rayner, Nigel W.; Ridderstråle, Martin; Rief, Winfried; Ruokonen, Aimo; Robertson, Neil R.; Rzehak, Peter; Salomaa, Veikko; Sanders, Alan R.; Sandhu, Manjinder S.; Sanna, Serena; Saramies, Jouko; Savolainen, Markku J.; Scherag, Susann; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Silander, Kaisa; Sinisalo, Juha; Siscovick, David S.; Smit, Jan H.; Soranzo, Nicole; Sovio, Ulla; Stephens, Jonathan; Surakka, Ida; Swift, Amy J.; Tammesoo, Mari-Liis; Tardif, Jean-Claude; Teder-Laving, Maris; Teslovich, Tanya M.; Thompson, John R.; Thomson, Brian; Tönjes, Anke; Tuomi, Tiinamaija; van Meurs, Joyce B.J.; van Ommen, Gert-Jan; Vatin, Vincent; Viikari, Jorma; Visvikis-Siest, Sophie; Vitart, Veronique; Vogel, Carla I. G.; Voight, Benjamin F.; Waite, Lindsay L.; Wallaschofski, Henri; Walters, G. Bragi; Widen, Elisabeth; Wiegand, Susanna; Wild, Sarah H.; Willemsen, Gonneke; Witte, Daniel R.; Witteman, Jacqueline C.; Xu, Jianfeng; Zhang, Qunyuan; Zgaga, Lina; Ziegler, Andreas; Zitting, Paavo; Beilby, John P.; Farooqi, I. Sadaf; Hebebrand, Johannes; Huikuri, Heikki V.; James, Alan L.; Kähönen, Mika; Levinson, Douglas F.; Macciardi, Fabio; Nieminen, Markku S.; Ohlsson, Claes; Palmer, Lyle J.; Ridker, Paul M.; Stumvoll, Michael; Beckmann, Jacques S.; Boeing, Heiner; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Collins, Francis S.; Cupples, L. Adrienne; Smith, George Davey; Erdmann, Jeanette; Froguel, Philippe; Grönberg, Henrik; Gyllensten, Ulf; Hall, Per; Hansen, Torben; Harris, Tamara B.; Hattersley, Andrew T.; Hayes, Richard B.; Heinrich, Joachim; Hu, Frank B.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Kaprio, Jaakko; Karpe, Fredrik; Khaw, Kay-Tee; Kiemeney, Lambertus A.; Krude, Heiko; Laakso, Markku; Lawlor, Debbie A.; Metspalu, Andres; Munroe, Patricia B.; Ouwehand, Willem H.; Pedersen, Oluf; Penninx, Brenda W.; Peters, Annette; Pramstaller, Peter P.; Quertermous, Thomas; Reinehr, Thomas; Rissanen, Aila; Rudan, Igor; Samani, Nilesh J.; Schwarz, Peter E.H.; Shuldiner, Alan R.; Spector, Timothy D.; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, André; Valle, Timo T.; Wabitsch, Martin; Waeber, Gérard; Wareham, Nicholas J.; Watkins, Hugh; Wilson, James F.; Wright, Alan F.; Zillikens, M. Carola; Chatterjee, Nilanjan; McCarroll, Steven A.; Purcell, Shaun; Schadt, Eric E.; Visscher, Peter M.; Assimes, Themistocles L.; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Groop, Leif C.; Haritunians, Talin; Hunter, David J.; Kaplan, Robert C.; Mohlke, Karen L.; O’Connell, Jeffrey R.; Peltonen, Leena; Schlessinger, David; Strachan, David P.; van Duijn, Cornelia M.; Wichmann, H.-Erich; Frayling, Timothy M.; Thorsteinsdottir, Unnur; Abecasis, Gonçalo R.; Barroso, Inês; Boehnke, Michael; Stefansson, Kari; North, Kari E.; McCarthy, Mark I.; Hirschhorn, Joel N.; Ingelsson, Erik; Loos, Ruth J.F.
Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation. PMID:20935630
Speliotes, Elizabeth K; Willer, Cristen J; Berndt, Sonja I
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SN...
Speliotes, Elizabeth K.; Willer, Cristen J.; Berndt, Sonja I.; Monda, Keri L.; Thorleifsson, Gudmar; Jackson, Anne U.; Allen, Hana Lango; Lindgren, Cecilia M.; Luan, Jian'an; Maegi, Reedik; Randall, Joshua C.; Vedantam, Sailaja; Winkler, Thomas W.; Qi, Lu; Workalemahu, Tsegaselassie; Heid, Iris M.; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Weedon, Michael N.; Wheeler, Eleanor; Wood, Andrew R.; Ferreira, Teresa; Weyant, Robert J.; Segre, Ayellet V.; Estrada, Karol; Liang, Liming; Nemesh, James; Park, Ju-Hyun; Gustafsson, Stefan; Kilpelaenen, Tuomas O.; Yang, Jian; Bouatia-Naji, Nabila; Esko, Tonu; Feitosa, Mary F.; Kutalik, Zoltan; Mangino, Massimo; Raychaudhuri, Soumya; Scherag, Andre; Smith, Albert Vernon; Welch, Ryan; Zhao, Jing Hua; Aben, Katja K.; Absher, Devin M.; Amin, Najaf; Dixon, Anna L.; Fisher, Eva; Glazer, Nicole L.; Goddard, Michael E.; Heard-Costa, Nancy L.; Hoesel, Volker; Hottenga, Jouke-Jan; Johansson, Asa; Johnson, Toby; Ketkar, Shamika; Lamina, Claudia; Li, Shengxu; Moffatt, Miriam F.; Myers, Richard H.; Narisu, Narisu; Perry, John R. B.; Peters, Marjolein J.; Preuss, Michael; Ripatti, Samuli; Rivadeneira, Fernando; Sandholt, Camilla; Scott, Laura J.; Timpson, Nicholas J.; Tyrer, Jonathan P.; van Wingerden, Sophie; Watanabe, Richard M.; White, Charles C.; Wiklund, Fredrik; Barlassina, Christina; Chasman, Daniel I.; Cooper, Matthew N.; Jansson, John-Olov; Lawrence, Robert W.; Pellikka, Niina; Prokopenko, Inga; Shi, Jianxin; Thiering, Elisabeth; Alavere, Helene; Alibrandi, Maria T. S.; Almgren, Peter; Arnold, Alice M.; Aspelund, Thor; Atwood, Larry D.; Balkau, Beverley; Balmforth, Anthony J.; Bennett, Amanda J.; Ben-Shlomo, Yoav; Bergman, Richard N.; Bergmann, Sven; Biebermann, Heike; Blakemore, Alexandra I. F.; Boes, Tanja; Bonnycastle, Lori L.; Bornstein, Stefan R.; Brown, Morris J.; Buchanan, Thomas A.; Busonero, Fabio; Campbell, Harry; Cappuccio, Francesco P.; Cavalcanti-Proenca, Christine; Chen, Yii-Der Ida; Chen, Chih-Mei; Chines, Peter S.; Clarke, Robert; Coin, Lachlan; Connell, John; Day, Ian N. M.; den Heijer, Martin; Duan, Jubao; Ebrahim, Shah; Elliott, Paul; Elosua, Roberto; Eiriksdottir, Gudny; Erdos, Michael R.; Eriksson, Johan G.; Facheris, Maurizio F.; Felix, Stephan B.; Fischer-Posovszky, Pamela; Folsom, Aaron R.; Friedrich, Nele; Freimer, Nelson B.; Fu, Mao; Gaget, Stefan; Gejman, Pablo V.; Geus, Eco J. C.; Gieger, Christian; Gjesing, Anette P.; Goel, Anuj; Goyette, Philippe; Grallert, Harald; Graessler, Juergen; Greenawalt, Danielle M.; Groves, Christopher J.; Gudnason, Vilmundur; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hall, Alistair S.; Havulinna, Aki S.; Hayward, Caroline; Heath, Andrew C.; Hengstenberg, Christian; Hicks, Andrew A.; Hinney, Anke; Hofman, Albert; Homuth, Georg; Hui, Jennie; Igl, Wilmar; Iribarren, Carlos; Isomaa, Bo; Jacobs, Kevin B.; Jarick, Ivonne; Jewell, Elizabeth; John, Ulrich; Jorgensen, Torben; Jousilahti, Pekka; Jula, Antti; Kaakinen, Marika; Kajantie, Eero; Kaplan, Lee M.; Kathiresan, Sekar; Kettunen, Johannes; Kinnunen, Leena; Knowles, Joshua W.; Kolcic, Ivana; Koenig, Inke R.; Koskinen, Seppo; Kovacs, Peter; Kuusisto, Johanna; Kraft, Peter; Kvaloy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lanzani, Chiara; Launer, Lenore J.; Lecoeur, Cecile; Lehtimaeki, Terho; Lettre, Guillaume; Liu, Jianjun; Lokki, Marja-Liisa; Lorentzon, Mattias; Luben, Robert N.; Ludwig, Barbara; Manunta, Paolo; Marek, Diana; Marre, Michel; Martin, Nicholas G.; McArdle, Wendy L.; McCarthy, Anne; McKnight, Barbara; Meitinger, Thomas; Melander, Olle; Meyre, David; Midthjell, Kristian; Montgomery, Grant W.; Morken, Mario A.; Morris, Andrew P.; Mulic, Rosanda; Ngwa, Julius S.; Nelis, Mari; Neville, Matt J.; Nyholt, Dale R.; O'Donnell, Christopher J.; O'Rahilly, Stephen; Ong, Ken K.; Oostra, Ben; Pare, Guillaume; Parker, Alex N.; Perola, Markus; Pichler, Irene; Pietilaeinen, Kirsi H.; Platou, Carl G. P.; Polasek, Ozren; Pouta, Anneli; Rafelt, Suzanne; Raitakari, Olli; Rayner, Nigel W.; Ridderstrale, Martin; Rief, Winfried; Ruokonen, Aimo; Robertson, Neil R.; Rzehak, Peter; Salomaa, Veikko; Sanders, Alan R.; Sandhu, Manjinder S.; Sanna, Serena; Saramies, Jouko; Savolainen, Markku J.; Scherag, Susann; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Silander, Kaisa; Sinisalo, Juha; Siscovick, David S.; Smit, Jan H.; Soranzo, Nicole; Sovio, Ulla; Stephens, Jonathan; Surakka, Ida; Swift, Amy J.; Tammesoo, Mari-Liis; Tardif, Jean-Claude; Teder-Laving, Maris; Teslovich, Tanya M.; Thompson, John R.; Thomson, Brian; Toenjes, Anke; Tuomi, Tiinamaija; van Meurs, Joyce B. J.; van Ommen, Gert-Jan; Vatin, Vincent; Viikari, Jorma; Visvikis-Siest, Sophie; Vitart, Veronique; Vogel, Carla I. G.; Voight, Benjamin F.; Waite, Lindsay L.; Wallaschofski, Henri; Walters, G. Bragi; Widen, Elisabeth; Wiegand, Susanna; Wild, Sarah H.; Willemsen, Gonneke; Witte, Daniel R.; Witteman, Jacqueline C.; Xu, Jianfeng; Zhang, Qunyuan; Zgaga, Lina; Ziegler, Andreas; Zitting, Paavo; Beilby, John P.; Farooqi, I. Sadaf; Hebebrand, Johannes; Huikuri, Heikki V.; James, Alan L.; Kaehoenen, Mika; Levinson, Douglas F.; Macciardi, Fabio; Nieminen, Markku S.; Ohlsson, Claes; Palmer, Lyle J.; Ridker, Paul M.; Stumvoll, Michael; Beckmann, Jacques S.; Boeing, Heiner; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Collins, Francis S.; Cupples, L. Adrienne; Smith, George Davey; Erdmann, Jeanette; Froguel, Philippe; Greonberg, Henrik; Gyllensten, Ulf; Hall, Per; Hansen, Torben; Harris, Tamara B.; Hattersley, Andrew T.; Hayes, Richard B.; Heinrich, Joachim; Hu, Frank B.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Kaprio, Jaakko; Karpe, Fredrik; Khaw, Kay-Tee; Kiemeney, Lambertus A.; Krude, Heiko; Laakso, Markku; Lawlor, Debbie A.; Metspalu, Andres; Munroe, Patricia B.; Ouwehand, Willem H.; Pedersen, Oluf; Penninx, Brenda W.; Peters, Annette; Pramstaller, Peter P.; Quertermous, Thomas; Reinehr, Thomas; Rissanen, Aila; Rudan, Igor; Samani, Nilesh J.; Schwarz, Peter E. H.; Shuldiner, Alan R.; Spector, Timothy D.; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, Andre; Valle, Timo T.; Wabitsch, Martin; Waeber, Gerard; Wareham, Nicholas J.; Watkins, Hugh; Wilson, James F.; Wright, Alan F.; Zillikens, M. Carola; Chatterjee, Nilanjan; McCarroll, Steven A.; Purcell, Shaun; Schadt, Eric E.; Visscher, Peter M.; Assimes, Themistocles L.; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Groop, Leif C.; Haritunians, Talin; Hunter, David J.; Kaplan, Robert C.; Mohlke, Karen L.; O'Connell, Jeffrey R.; Peltonen, Leena; Schlessinger, David; Strachan, David P.; van Duijn, Cornelia M.; Wichmann, H-Erich; Frayling, Timothy M.; Thorsteinsdottir, Unnur; Abecasis, Goncalo R.; Barroso, Ines; Boehnke, Michael; Stefansson, Kari; North, Kari E.; McCarthy, Mark I.; Hirschhorn, Joel N.; Ingelsson, Erik; Loos, Ruth J. F.
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of
Pillas, Demetris; Hoggart, Clive J.; Evans, David M.; O'Reilly, Paul F.; Sipil?, Kirsi; L?hdesm?ki, Raija; Millwood, Iona Y.; Kaakinen, Marika; Netuveli, Gopalakrishnan; Blane, David; Charoen, Pimphen; Sovio, Ulla; Pouta, Anneli; Freimer, Nelson; Hartikainen, Anna-Liisa
Author Summary Genome-wide association studies have been used to identify genetic variants conferring susceptibility to diseases, intermediate phenotypes, and physiological traits such as height, hair color, and age at menarche. Here we analyze the NFBC1966 and ALSPAC birth cohorts to investigate the genetic determinants of a key developmental process: primary tooth development. The prospective nature of our studies allows us to exploit accurate measurements of age at first tooth eruption and...
Sipilä, Kirsi; Lähdesmäki, Raija; Millwood, Iona Y.; Kaakinen, Marika; Netuveli, Gopalakrishnan; Blane, David; Charoen, Pimphen; Sovio, Ulla; Pouta, Anneli; Freimer, Nelson; Hartikainen, Anna-Liisa; Laitinen, Jaana; Vaara, Sarianna; Glaser, Beate; Crawford, Peter; Timpson, Nicholas J.; Ring, Susan M.; Deng, Guohong; Zhang, Weihua; McCarthy, Mark I.; Deloukas, Panos; Peltonen, Leena
Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years. PMID:20195514
Paes, Jéssica A; Lorenzatto, Karina R; de Moraes, Sofia N; Moura, Hercules; Barr, John R; Ferreira, Henrique B
Mycoplasma hyopneumoniae and Mycoplasma flocculare cohabit the porcine respiratory tract. However, M. hyopneumoniae causes the porcine enzootic pneumonia, while M. flocculare is a commensal bacterium. Comparative analyses demonstrated high similarity between these species, which includes the sharing of all predicted virulence factors. Nevertheless, studies related to soluble secretomes of mycoplasmas were little known, although they are important for bacterial-host interactions. The aim of this study was to perform a comparative analysis between the soluble secreted proteins repertoires of the pathogenic Mycoplasma hyopneumoniae and its closely related commensal Mycoplasma flocculare. For that, bacteria were cultured in medium with reduced serum concentration and secreted proteins were identified by a LC-MS/MS proteomics approach. Altogether, 62 and 26 proteins were identified as secreted by M. hyopneumoniae and M. flocculare, respectively, being just seven proteins shared between these bacteria. In M. hyopneumoniae secretome, 15 proteins described as virulence factors were found; while four putative virulence factors were identified in M. flocculare secretome. For the first time, clear differences related to virulence were found between these species, helping to elucidate the pathogenic nature of M. hyopneumoniae to swine hosts. For the first time, the secretomes of two porcine respiratory mycoplasmas, namely the pathogenic M. hyopneumoniae and the commensal M. flocculare were compared. The presented results revealed previously unknown differences between these two genetically related species, some of which are associated to the M. hyopneumoniae ability to cause porcine enzootic pneumonia. Copyright © 2016 Elsevier B.V. All rights reserved.
Saik, Olga V; Demenkov, Pavel S; Ivanisenko, Timofey V; Bragina, Elena Yu; Freidin, Maxim B; Goncharova, Irina A; Dosenko, Victor E; Zolotareva, Olga I; Hofestaedt, Ralf; Lavrik, Inna N; Rogaev, Evgeny I; Ivanisenko, Vladimir A
Hypertension and bronchial asthma are a major issue for people's health. As of 2014, approximately one billion adults, or ~ 22% of the world population, have had hypertension. As of 2011, 235-330 million people globally have been affected by asthma and approximately 250,000-345,000 people have died each year from the disease. The development of the effective treatment therapies against these diseases is complicated by their comorbidity features. This is often a major problem in diagnosis and their treatment. Hence, in this study the bioinformatical methodology for the analysis of the comorbidity of these two diseases have been developed. As such, the search for candidate genes related to the comorbid conditions of asthma and hypertension can help in elucidating the molecular mechanisms underlying the comorbid condition of these two diseases, and can also be useful for genotyping and identifying new drug targets. Using ANDSystem, the reconstruction and analysis of gene networks associated with asthma and hypertension was carried out. The gene network of asthma included 755 genes/proteins and 62,603 interactions, while the gene network of hypertension - 713 genes/proteins and 45,479 interactions. Two hundred and five genes/proteins and 9638 interactions were shared between asthma and hypertension. An approach for ranking genes implicated in the comorbid condition of two diseases was proposed. The approach is based on nine criteria for ranking genes by their importance, including standard methods of gene prioritization (Endeavor, ToppGene) as well as original criteria that take into account the characteristics of an associative gene network and the presence of known polymorphisms in the analysed genes. According to the proposed approach, the genes IL10, TLR4, and CAT had the highest priority in the development of comorbidity of these two diseases. Additionally, it was revealed that the list of top genes is enriched with apoptotic genes and genes involved in
Larsen, Sara C; Sylvestersen, Kathrine B; Mund, Andreas
The posttranslational modification of proteins by arginine methylation is functionally important, yet the breadth of this modification is not well characterized. Using high-resolution mass spectrometry, we identified 8030 arginine methylation sites within 3300 human proteins in human embryonic...... kidney 293 cells, indicating that the occurrence of this modification is comparable to phosphorylation and ubiquitylation. A site-level conservation analysis revealed that arginine methylation sites are less evolutionarily conserved compared to arginines that were not identified as modified...... as coactivator-associated arginine methyltransferase 1 (CARM1)] or PRMT1 increased the RNA binding function of HNRNPUL1. High-content single-cell imaging additionally revealed that knocking down CARM1 promoted the nuclear accumulation of SRSF2, independent of cell cycle phase. Collectively, the presented human...
Loo, Lit-Hsin; Laksameethanasan, Danai; Tung, Yi-Ling
Protein subcellular localization is a major determinant of protein function. However, this important protein feature is often described in terms of discrete and qualitative categories of subcellular compartments, and therefore it has limited applications in quantitative protein function analyses. Here, we present Protein Localization Analysis and Search Tools (PLAST), an automated analysis framework for constructing and comparing quantitative signatures of protein subcellular localization patterns based on microscopy images. PLAST produces human-interpretable protein localization maps that quantitatively describe the similarities in the localization patterns of proteins and major subcellular compartments, without requiring manual assignment or supervised learning of these compartments. Using the budding yeast Saccharomyces cerevisiae as a model system, we show that PLAST is more accurate than existing, qualitative protein localization annotations in identifying known co-localized proteins. Furthermore, we demonstrate that PLAST can reveal protein localization-function relationships that are not obvious from these annotations. First, we identified proteins that have similar localization patterns and participate in closely-related biological processes, but do not necessarily form stable complexes with each other or localize at the same organelles. Second, we found an association between spatial and functional divergences of proteins during evolution. Surprisingly, as proteins with common ancestors evolve, they tend to develop more diverged subcellular localization patterns, but still occupy similar numbers of compartments. This suggests that divergence of protein localization might be more frequently due to the development of more specific localization patterns over ancestral compartments than the occupation of new compartments. PLAST enables systematic and quantitative analyses of protein localization-function relationships, and will be useful to elucidate protein
Brandes, E.; McNunn, G. S.; Schulte, L. A.; Bonner, I. J.; Muth, D. J.; Babcock, B. A.; Sharma, B.; Heaton, E. A.
Public agencies and private enterprises increasingly desire to achieve ecosystem service outcomes in agricultural systems, but are limited by perceived conflicts between economic and ecosystem service goals and a lack of tools enabling effective operational management. Here we use Iowa—an agriculturally homogeneous state representative of the Maize Belt—to demonstrate an economic rationale for cropland diversification at the subfield scale. We used a novel computational framework that integrates disparate but publicly available data to map ˜3.3 million unique potential management polygons (9.3 Mha) and reveal subfield opportunities to increase overall field profitability. We analyzed subfield profitability for maize/soybean fields during 2010-2013—four of the most profitable years in recent history—and projected results for 2015. While cropland operating at a loss of US 250 ha-1 or more was negligible between 2010 and 2013 at 18 000-190 000 ha (<2% of row-crop land), the extent of highly unprofitable land increased to 2.5 Mha, or 27% of row-crop land, in the 2015 projection. Aggregation of these areas to the township level revealed ‘hotspots’ for potential management change in Western, Central, and Northeast Iowa. In these least profitable areas, incorporating conservation management that breaks even (e.g., planting low-input perennials), into low-yielding portions of fields could increase overall cropland profitability by 80%. This approach is applicable to the broader region and differs substantially from the status quo of ‘top-down’ land management for conservation by harnessing private interest to align profitability with the production of ecosystem services.
Magwa, Risper Auma; Zhao, Hu; Xing, Yongzhong
Seed dormancy is an adaptive trait employed by flowering plants to avoid harsh environmental conditions for the continuity of their next generations. In cereal crops, moderate seed dormancy could help prevent pre-harvest sprouting and improve grain yield and quality. We performed a genome wide association study (GWAS) for dormancy, based on seed germination percentage (GP) in freshly harvested seeds (FHS) and after-ripened seeds (ARS) in 350 worldwide accessions that were characterized with strong population structure of indica, japonica and Aus subpopulations. The germination tests revealed that Aus and indica rice had stronger seed dormancy than japonica rice in FHS. Association analysis revealed 16 loci significantly associated with GP in FHS and 38 in ARS. Three out of the 38 loci detected in ARS were also detected in FHS and 13 of the ARS loci were detected near previously mapped dormancy QTL. In FHS, three of the association loci were located within 100 kb around previously cloned GA/IAA inactivation genes such as GA2ox3, EUI1 and GH3-2 and one near dormancy gene, Sdr4. In ARS, an association signal was detected near ABA signaling gene ABI5. No association peaks were commonly detected among the sub-populations in FHS and only one association peak was detected in both indica and japonica populations in ARS. Sdr4 and GA2OX3 haplotype analysis showed that Aus and indica II (IndII) varieties had stronger dormancy alleles whereas indica I (IndI) and japonica had weak or non-dormancy alleles. The association study and haplotype analysis together, indicate an involvement of independent genes and alleles contributing towards regulation and natural variation of seed dormancy among the rice sub-populations.
c Indian Academy of Sciences. RESEARCH NOTE. A genetic analysis of segregation ... 2College of Life Science, Northeast Forest University, Harbin 150040, People's Republic of China. [Cai J., Zhang X., Wang B., Yan M., Qi Y. and Kong L. ... elite agronomic traits (Zhang et al. 2011). However, there is still no report about ...
Kevin J. McGuire; Christian E. Torgersen; Gene E. Likens; Donald C. Buso; Winsor H. Lowe; Scott W. Bailey
By coupling synoptic data from a basin-wide assessment of streamwater chemistry with network-based geostatistical analysis, we show that spatial processes differentially affect biogeochemical condition and pattern across a headwater stream network. We analyzed a high-resolution dataset consisting of 664 water samples collected every 100 m throughout 32 tributaries in...
Noar, Roslyn D; Daub, Margaret E
genes with higher expression in infected leaf tissue, suggesting that they may play a role in pathogenicity. For two other scaffolds, no transcripts were detected in either condition, and PCR assays support the hypothesis that at least one of these scaffolds corresponds to a dispensable chromosome that is not required for survival or pathogenicity. Our study revealed major changes in the transcriptome of Mycosphaerella fijiensis, when associating with its host compared to during saprophytic growth in medium. This analysis identified putative pathogenicity genes and also provides support for the existence of dispensable chromosomes in this fungus.
Ray, Ann; Kinch, Lisa N; de Souza Santos, Marcela; Grishin, Nick V; Orth, Kim; Salomon, Dor
Members of the genus Vibrio include many pathogens of humans and marine animals that share genetic information via horizontal gene transfer. Hence, the Vibrio pan-genome carries the potential to establish new pathogenic strains by sharing virulence determinants, many of which have yet to be characterized. Here, we investigated the virulence properties of Vibrio proteolyticus, a Gram-negative marine bacterium previously identified as part of the Vibrio consortium isolated from diseased corals. We found that V. proteolyticus causes actin cytoskeleton rearrangements followed by cell lysis in HeLa cells in a contact-independent manner. In search of the responsible virulence factor involved, we determined the V. proteolyticus secretome. This proteomics approach revealed various putative virulence factors, including active type VI secretion systems and effectors with virulence toxin domains; however, these type VI secretion systems were not responsible for the observed cytotoxic effects. Further examination of the V. proteolyticus secretome led us to hypothesize and subsequently demonstrate that a secreted hemolysin, belonging to a previously uncharacterized clan of the leukocidin superfamily, was the toxin responsible for the V. proteolyticus-mediated cytotoxicity in both HeLa cells and macrophages. Clearly, there remains an armory of yet-to-be-discovered virulence factors in the Vibrio pan-genome that will undoubtedly provide a wealth of knowledge on how a pathogen can manipulate host cells. The pan-genome of the genus Vibrio is a potential reservoir of unidentified toxins that can provide insight into how members of this genus have successfully risen as emerging pathogens worldwide. We focused on Vibrio proteolyticus, a marine bacterium that was previously implicated in virulence toward marine animals, and characterized its interaction with eukaryotic cells. We found that this bacterium causes actin cytoskeleton rearrangements and leads to cell death. Using a
Ebhardt, H Alexander; Tsang, Herbert H; Dai, Denny C; Liu, Yifeng; Bostan, Babak; Fahlman, Richard P
Recent advances in DNA-sequencing technology have made it possible to obtain large datasets of small RNA sequences. Here we demonstrate that not all non-perfectly matched small RNA sequences are simple technological sequencing errors, but many hold valuable biological information. Analysis of three small RNA datasets originating from Oryza sativa and Arabidopsis thaliana small RNA-sequencing projects demonstrates that many single nucleotide substitution errors overlap when aligning homologous non-identical small RNA sequences. Investigating the sites and identities of substitution errors reveal that many potentially originate as a result of post-transcriptional modifications or RNA editing. Modifications include N1-methyl modified purine nucleotides in tRNA, potential deamination or base substitutions in micro RNAs, 3' micro RNA uridine extensions and 5' micro RNA deletions. Additionally, further analysis of large sequencing datasets reveal that the combined effects of 5' deletions and 3' uridine extensions can alter the specificity by which micro RNAs associate with different Argonaute proteins. Hence, we demonstrate that not all sequencing errors in small RNA datasets are technical artifacts, but that these actually often reveal valuable biological insights to the sites of post-transcriptional RNA modifications.
Mouton, Stijn; Willems, Maxime; Back, Patricia; Braeckman, Bart; Borgonie, Gaetan
Abstract Free-living flatworms ("Turbellaria") are appropriate model organisms to gain better insight into the role of stem cells in ageing and rejuvenation. Ageing research in flatworms is, however, still scarce. This is partly due to culture difficulties and the lack of a complete set of demographic data, including parameters such as median lifespan and age-specific mortality rate. In this paper, we report on the first flatworm survival analysis. We used the species Macrostomum lignano, whi...
Full Text Available Members of the genus Vibrio include many pathogens of humans and marine animals that share genetic information via horizontal gene transfer. Hence, the Vibrio pan-genome carries the potential to establish new pathogenic strains by sharing virulence determinants, many of which have yet to be characterized. Here, we investigated the virulence properties of Vibrio proteolyticus, a Gram-negative marine bacterium previously identified as part of the Vibrio consortium isolated from diseased corals. We found that V. proteolyticus causes actin cytoskeleton rearrangements followed by cell lysis in HeLa cells in a contact-independent manner. In search of the responsible virulence factor involved, we determined the V. proteolyticus secretome. This proteomics approach revealed various putative virulence factors, including active type VI secretion systems and effectors with virulence toxin domains; however, these type VI secretion systems were not responsible for the observed cytotoxic effects. Further examination of the V. proteolyticus secretome led us to hypothesize and subsequently demonstrate that a secreted hemolysin, belonging to a previously uncharacterized clan of the leukocidin superfamily, was the toxin responsible for the V. proteolyticus-mediated cytotoxicity in both HeLa cells and macrophages. Clearly, there remains an armory of yet-to-be-discovered virulence factors in the Vibrio pan-genome that will undoubtedly provide a wealth of knowledge on how a pathogen can manipulate host cells.
Hua, Qingzhu; Zhou, Qianjun; Gan, Susheng; Wu, Jingyu; Chen, Canbin; Li, Jiaqiang; Ye, Yaoxiong; Zhao, Jietang; Hu, Guibing; Qin, Yonghua
Red dragon fruit or red pitaya ( Hylocereus polyrhizus ) is the only edible fruit that contains betalains. The color of betalains ranges from red and violet to yellow in plants. Betalains may also serve as an important component of health-promoting and disease-preventing functional food. Currently, the biosynthetic and regulatory pathways for betalain production remain to be fully deciphered. In this study, isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analyses were used to reveal the molecular mechanism of betalain biosynthesis in H. polyrhizus fruits at white and red pulp stages, respectively. A total of 1946 proteins were identified as the differentially expressed between the two samples, and 936 of them were significantly highly expressed at the red pulp stage of H. polyrhizus . RNA-seq and iTRAQ analyses showed that some transcripts and proteins were positively correlated; they belonged to "phenylpropanoid biosynthesis", "tyrosine metabolism", "flavonoid biosynthesis", "ascorbate and aldarate metabolism", "betalains biosynthesis" and "anthocyanin biosynthesis". In betalains biosynthesis pathway, several proteins/enzymes such as polyphenol oxidase, CYP76AD3 and 4,5-dihydroxy-phenylalanine (DOPA) dioxygenase extradiol-like protein were identified. The present study provides a new insight into the molecular mechanism of the betalain biosynthesis at the posttranscriptional level.
Full Text Available Red dragon fruit or red pitaya (Hylocereus polyrhizus is the only edible fruit that contains betalains. The color of betalains ranges from red and violet to yellow in plants. Betalains may also serve as an important component of health-promoting and disease-preventing functional food. Currently, the biosynthetic and regulatory pathways for betalain production remain to be fully deciphered. In this study, isobaric tags for relative and absolute quantitation (iTRAQ-based proteomic analyses were used to reveal the molecular mechanism of betalain biosynthesis in H. polyrhizus fruits at white and red pulp stages, respectively. A total of 1946 proteins were identified as the differentially expressed between the two samples, and 936 of them were significantly highly expressed at the red pulp stage of H. polyrhizus. RNA-seq and iTRAQ analyses showed that some transcripts and proteins were positively correlated; they belonged to “phenylpropanoid biosynthesis”, “tyrosine metabolism”, “flavonoid biosynthesis”, “ascorbate and aldarate metabolism”, “betalains biosynthesis” and “anthocyanin biosynthesis”. In betalains biosynthesis pathway, several proteins/enzymes such as polyphenol oxidase, CYP76AD3 and 4,5-dihydroxy-phenylalanine (DOPA dioxygenase extradiol-like protein were identified. The present study provides a new insight into the molecular mechanism of the betalain biosynthesis at the posttranscriptional level.
Full Text Available BACKGROUND: Retinal detachment often leads to a severe and permanent loss of vision and its therapeutic management remains to this day exclusively surgical. We have used surgical specimens to perform a differential analysis of the transcriptome of human retinal tissues following detachment in order to identify new potential pharmacological targets that could be used in combination with surgery to further improve final outcome. METHODOLOGY/PRINCIPAL FINDINGS: Statistical analysis reveals major involvement of the immune response in the disease. Interestingly, using a novel approach relying on coordinated expression, the interindividual variation was monitored to unravel a second crucial aspect of the pathological process: the death of photoreceptor cells. Within the genes identified, the expression of the major histocompatibility complex I gene HLA-C enables diagnosis of the disease, while PKD2L1 and SLCO4A1 -which are both down-regulated- act synergistically to provide an estimate of the duration of the retinal detachment process. Our analysis thus reveals the two complementary cellular and molecular aspects linked to retinal detachment: an immune response and the degeneration of photoreceptor cells. We also reveal that the human specimens have a higher clinical value as compared to artificial models that point to IL6 and oxidative stress, not implicated in the surgical specimens studied here. CONCLUSIONS/SIGNIFICANCE: This systematic analysis confirmed the occurrence of both neurodegeneration and inflammation during retinal detachment, and further identifies precisely the modification of expression of the different genes implicated in these two phenomena. Our data henceforth give a new insight into the disease process and provide a rationale for therapeutic strategies aimed at limiting inflammation and photoreceptor damage associated with retinal detachment and, in turn, improving visual prognosis after retinal surgery.
Warren, Wesley C; Hillier, LaDeana W; Marshall Graves, Jennifer A; Birney, Ewan; Ponting, Chris P; Grützner, Frank; Belov, Katherine; Miller, Webb; Clarke, Laura; Chinwalla, Asif T; Yang, Shiaw-Pyng; Heger, Andreas; Locke, Devin P; Miethke, Pat; Waters, Paul D; Veyrunes, Frédéric; Fulton, Lucinda; Fulton, Bob; Graves, Tina; Wallis, John; Puente, Xose S; López-Otín, Carlos; Ordóñez, Gonzalo R; Eichler, Evan E; Chen, Lin; Cheng, Ze; Deakin, Janine E; Alsop, Amber; Thompson, Katherine; Kirby, Patrick; Papenfuss, Anthony T; Wakefield, Matthew J; Olender, Tsviya; Lancet, Doron; Huttley, Gavin A; Smit, Arian F A; Pask, Andrew; Temple-Smith, Peter; Batzer, Mark A; Walker, Jerilyn A; Konkel, Miriam K; Harris, Robert S; Whittington, Camilla M; Wong, Emily S W; Gemmell, Neil J; Buschiazzo, Emmanuel; Vargas Jentzsch, Iris M; Merkel, Angelika; Schmitz, Juergen; Zemann, Anja; Churakov, Gennady; Kriegs, Jan Ole; Brosius, Juergen; Murchison, Elizabeth P; Sachidanandam, Ravi; Smith, Carly; Hannon, Gregory J; Tsend-Ayush, Enkhjargal; McMillan, Daniel; Attenborough, Rosalind; Rens, Willem; Ferguson-Smith, Malcolm; Lefèvre, Christophe M; Sharp, Julie A; Nicholas, Kevin R; Ray, David A; Kube, Michael; Reinhardt, Richard; Pringle, Thomas H; Taylor, James; Jones, Russell C; Nixon, Brett; Dacheux, Jean-Louis; Niwa, Hitoshi; Sekita, Yoko; Huang, Xiaoqiu; Stark, Alexander; Kheradpour, Pouya; Kellis, Manolis; Flicek, Paul; Chen, Yuan; Webber, Caleb; Hardison, Ross; Nelson, Joanne; Hallsworth-Pepin, Kym; Delehaunty, Kim; Markovic, Chris; Minx, Pat; Feng, Yucheng; Kremitzki, Colin; Mitreva, Makedonka; Glasscock, Jarret; Wylie, Todd; Wohldmann, Patricia; Thiru, Prathapan; Nhan, Michael N; Pohl, Craig S; Smith, Scott M; Hou, Shunfeng; Nefedov, Mikhail; de Jong, Pieter J; Renfree, Marilyn B; Mardis, Elaine R; Wilson, Richard K
We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation.
Warren, Wesley C.; Hillier, LaDeana W.; Marshall Graves, Jennifer A.; Birney, Ewan; Ponting, Chris P.; Grützner, Frank; Belov, Katherine; Miller, Webb; Clarke, Laura; Chinwalla, Asif T.; Yang, Shiaw-Pyng; Heger, Andreas; Locke, Devin P.; Miethke, Pat; Waters, Paul D.; Veyrunes, Frédéric; Fulton, Lucinda; Fulton, Bob; Graves, Tina; Wallis, John; Puente, Xose S.; López-Otín, Carlos; Ordóñez, Gonzalo R.; Eichler, Evan E.; Chen, Lin; Cheng, Ze; Deakin, Janine E.; Alsop, Amber; Thompson, Katherine; Kirby, Patrick; Papenfuss, Anthony T.; Wakefield, Matthew J.; Olender, Tsviya; Lancet, Doron; Huttley, Gavin A.; Smit, Arian F. A.; Pask, Andrew; Temple-Smith, Peter; Batzer, Mark A.; Walker, Jerilyn A.; Konkel, Miriam K.; Harris, Robert S.; Whittington, Camilla M.; Wong, Emily S. W.; Gemmell, Neil J.; Buschiazzo, Emmanuel; Vargas Jentzsch, Iris M.; Merkel, Angelika; Schmitz, Juergen; Zemann, Anja; Churakov, Gennady; Kriegs, Jan Ole; Brosius, Juergen; Murchison, Elizabeth P.; Sachidanandam, Ravi; Smith, Carly; Hannon, Gregory J.; Tsend-Ayush, Enkhjargal; McMillan, Daniel; Attenborough, Rosalind; Rens, Willem; Ferguson-Smith, Malcolm; Lefèvre, Christophe M.; Sharp, Julie A.; Nicholas, Kevin R.; Ray, David A.; Kube, Michael; Reinhardt, Richard; Pringle, Thomas H.; Taylor, James; Jones, Russell C.; Nixon, Brett; Dacheux, Jean-Louis; Niwa, Hitoshi; Sekita, Yoko; Huang, Xiaoqiu; Stark, Alexander; Kheradpour, Pouya; Kellis, Manolis; Flicek, Paul; Chen, Yuan; Webber, Caleb; Hardison, Ross; Nelson, Joanne; Hallsworth-Pepin, Kym; Delehaunty, Kim; Markovic, Chris; Minx, Pat; Feng, Yucheng; Kremitzki, Colin; Mitreva, Makedonka; Glasscock, Jarret; Wylie, Todd; Wohldmann, Patricia; Thiru, Prathapan; Nhan, Michael N.; Pohl, Craig S.; Smith, Scott M.; Hou, Shunfeng; Renfree, Marilyn B.; Mardis, Elaine R.; Wilson, Richard K.
We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation. PMID:18464734
Kjærsgård, Inger Vibeke Holst; Nørrelykke, M.R.; Jessen, Flemming
Multivariate data analysis has been combined with proteomics to enhance the recovery of information from 2-DE of cod muscle proteins during different storage conditions. Proteins were extracted according to 11 different storage conditions and samples were resolved by 2-DE. Data generated by 2-DE...... was subjected to principal component analysis (PCA) and discriminant partial least squares regression (DPLSR). Applying PCA to 2-DE data revealed the samples to form groups according to frozen storage time, whereas differences due to different storage temperatures or chilled storage in modified atmosphere...... light chain 1, 2 and 3, triose-phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, aldolase A and two ?-actin fragments, and a nuclease diphosphate kinase B fragment to change in concentration, during frozen storage. Application of proteomics, multivariate data analysis and MS/MS to analyse...
Sheng, Yue; Zhao, Wei; Song, Ying; Li, Zhigang; Luo, Majing; Lei, Quan; Cheng, Hanhua; Zhou, Rongjia
A variety of mechanisms are engaged in sex determination in vertebrates. The teleost fish swamp eel undergoes sex reversal naturally and is an ideal model for vertebrate sexual development. However, the importance of proteome-wide scanning for gonad reversal was not previously determined. We report a 2-D electrophoresis analysis of three gonad types of proteomes during sex reversal. MS/MS analysis revealed a group of differentially expressed proteins during ovary to ovotestis to testis transformation. Cbx3 is up-regulated during gonad reversal and is likely to have a role in spermatogenesis. Rab37 is down-regulated during the reversal and is mainly associated with oogenesis. Both Cbx3 and Rab37 are linked up in a protein network. These datasets in gonadal proteomes provide a new resource for further studies in gonadal development.
Alvarez-Pérez, Sergio; de Vega, Clara; Herrera, Carlos M
The genetic and evolutionary relationships among floral nectar-dwelling Pseudomonas 'sensu stricto' isolates associated to South African and Mediterranean plants were investigated by multilocus sequence analysis (MLSA) of four core housekeeping genes (rrs, gyrB, rpoB and rpoD). A total of 35 different sequence types were found for the 38 nectar bacterial isolates characterised. Phylogenetic analyses resulted in the identification of three main clades [nectar groups (NGs) 1, 2 and 3] of nectar pseudomonads, which were closely related to five intrageneric groups: Pseudomonas oryzihabitans (NG 1); P. fluorescens, P. lutea and P. syringae (NG 2); and P. rhizosphaerae (NG 3). Linkage disequilibrium analysis pointed to a mostly clonal population structure, even when the analysis was restricted to isolates from the same floristic region or belonging to the same NG. Nevertheless, signatures of recombination were observed for NG 3, which exclusively included isolates retrieved from the floral nectar of insect-pollinated Mediterranean plants. In contrast, the other two NGs comprised both South African and Mediterranean isolates. Analyses relating diversification to floristic region and pollinator type revealed that there has been more unique evolution of the nectar pseudomonads within the Mediterranean region than would be expected by chance. This is the first work analysing the sequence of multiple loci to reveal geno- and ecotypes of nectar bacteria.
David P Hall
Full Text Available Acute mountain sickness (AMS is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS, we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 292 subjects during 1110 subject-days at altitudes between 3650 m and 5200 m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Mean Spearman correlation 0.25. These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes.
Hoenigsberg H. F.
Full Text Available The above refer to experiments present a new method which permits the study of philogenesis in the genus Drosophila. There are several types of results: a close kinship among the various geographical races of D. melanogaster in the neo-tropics coincides with their spectrophotometric similarities; b the interspecific differences are also identified with the photometric analysis; c finally there are optical density affinities among the various species which belong to the same taxonomic groups. Acknowledgment. The authors want to express their gratitude to Professor Everet of the physico-chemical laboratory of the National University for the use of his Beckman DU spectrophotometer and for his generous advice. This research is supported by the American Agricultural Research Service grant F. G. Co 107. For technical assistance we are indebted to Miss B. I. Cortés and to Mr. L. Castro.
McGuire, Kevin J.; Torgersen, Christian E.; Likens, Gene E.; Buso, Donald C.; Lowe, Winsor H.; Bailey, Scott W.
By coupling synoptic data from a basin-wide assessment of streamwater chemistry with network-based geostatistical analysis, we show that spatial processes differentially affect biogeochemical condition and pattern across a headwater stream network. We analyzed a high-resolution dataset consisting of 664 water samples collected every 100 m throughout 32 tributaries in an entire fifth-order stream network. These samples were analyzed for an exhaustive suite of chemical constituents. The fine grain and broad extent of this study design allowed us to quantify spatial patterns over a range of scales by using empirical semivariograms that explicitly incorporated network topology. Here, we show that spatial structure, as determined by the characteristic shape of the semivariograms, differed both among chemical constituents and by spatial relationship (flow-connected, flow-unconnected, or Euclidean). Spatial structure was apparent at either a single scale or at multiple nested scales, suggesting separate processes operating simultaneously within the stream network and surrounding terrestrial landscape. Expected patterns of spatial dependence for flow-connected relationships (e.g., increasing homogeneity with downstream distance) occurred for some chemical constituents (e.g., dissolved organic carbon, sulfate, and aluminum) but not for others (e.g., nitrate, sodium). By comparing semivariograms for the different chemical constituents and spatial relationships, we were able to separate effects on streamwater chemistry of (i) fine-scale versus broad-scale processes and (ii) in-stream processes versus landscape controls. These findings provide insight on the hierarchical scaling of local, longitudinal, and landscape processes that drive biogeochemical patterns in stream networks.
Braeckman Bart P
Full Text Available Abstract Free-living flatworms ("Turbellaria" are appropriate model organisms to gain better insight into the role of stem cells in ageing and rejuvenation. Ageing research in flatworms is, however, still scarce. This is partly due to culture difficulties and the lack of a complete set of demographic data, including parameters such as median lifespan and age-specific mortality rate. In this paper, we report on the first flatworm survival analysis. We used the species Macrostomum lignano, which is an emerging model for studying the reciprocal influence between stem cells, ageing and rejuvenation. This species has a median lifespan of 205 ± 13 days (average ± standard deviation [SD] and a 90th percentile lifespan of 373 ± 32 days. The maximum lifespan, however, is more than 745 days, and the average survival curve is characterised by a long tail because a small number of individuals lives twice as long as 90% of the population. Similar to earlier observations in a wide range of animals, in M. lignano the age-specific mortality rate increases exponentially, but levels off at the oldest ages. To compare the senescence of M. lignano with that of other ageing models, we determined the mortality rate doubling time, which is 0.20 ± 0.02 years. As a result, we can conclude that M. lignano shows gradual senescence at a rate similar to the vertebrate ageing models Rattus norvegicus and Mus musculus. We argue that M. lignano is a suitable model for ageing and rejuvenation research, and especially for the role of stem cells in these processes, due to its accessible stem cell system and regeneration capacity, and the possibility of combining stem cell studies with demographic analyses.
Mouton, Stijn; Willems, Maxime; Back, Patricia; Braeckman, Bart P; Borgonie, Gaetan
Free-living flatworms ("Turbellaria") are appropriate model organisms to gain better insight into the role of stem cells in ageing and rejuvenation. Ageing research in flatworms is, however, still scarce. This is partly due to culture difficulties and the lack of a complete set of demographic data, including parameters such as median lifespan and age-specific mortality rate. In this paper, we report on the first flatworm survival analysis. We used the species Macrostomum lignano, which is an emerging model for studying the reciprocal influence between stem cells, ageing and rejuvenation. This species has a median lifespan of 205 +/- 13 days (average +/- standard deviation [SD]) and a 90th percentile lifespan of 373 +/- 32 days. The maximum lifespan, however, is more than 745 days, and the average survival curve is characterised by a long tail because a small number of individuals lives twice as long as 90% of the population. Similar to earlier observations in a wide range of animals, in M. lignano the age-specific mortality rate increases exponentially, but levels off at the oldest ages. To compare the senescence of M. lignano with that of other ageing models, we determined the mortality rate doubling time, which is 0.20 +/- 0.02 years. As a result, we can conclude that M. lignano shows gradual senescence at a rate similar to the vertebrate ageing models Rattus norvegicus and Mus musculus. We argue that M. lignano is a suitable model for ageing and rejuvenation research, and especially for the role of stem cells in these processes, due to its accessible stem cell system and regeneration capacity, and the possibility of combining stem cell studies with demographic analyses.
Landmark-Høyvik, Hege; Dumeaux, Vanessa; Nebdal, Daniel; Lund, Eiliv; Tost, Jörg; Kamatani, Yoichiro; Renault, Victor; Børresen-Dale, Anne-Lise; Kristensen, Vessela; Edvardsen, Hege
We investigated the effect of genetic variation on gene expression in blood from a cohort of BC survivors. Further, we investigated the associations that were specific for BC survivors by performing identical analyses for a group of healthy women and comparing the results. eQTL analysis was performed for 288 BC survivors (full data set). Further, using a subset of the data, eQTL analyses were performed on 288 BC survivors and on 81 healthy women separately and results were compared. A large number of associations were observed for the BC survivors, and the expression of human leukocyte antigen genes was found associated with SNPs in 100 genes. The comparison analyses with healthy women revealed associations occurring specifically in BC survivors, and the genes showed enrichment for immune system processes. The results suggest that the immune system has a different constitution in BC survivors compared to healthy women. © 2013 Elsevier Inc. All rights reserved.
Zhang Yu; Shao Jun; Krausert, Christopher R.; Zhang Sai; Jiang, Jack J.
Research highlights: → Low-dimensional human glottal area data. → Evidence of chaos in human laryngeal activity from high-speed digital imaging. → Traditional perturbation analysis should be cautiously applied to aperiodic high speed image signals. → Nonlinear dynamic analysis may be helpful for understanding disordered behaviors in pathological laryngeal systems. - Abstract: Laryngeal pathology is usually associated with irregular dynamics of laryngeal activity. High-speed imaging facilitates direct observation and measurement of vocal fold vibrations. However, chaotic dynamic characteristics of aperiodic high-speed image data have not yet been investigated in previous studies. In this paper, we will apply nonlinear dynamic analysis and traditional perturbation methods to quantify high-speed image data from normal subjects and patients with various laryngeal pathologies including vocal fold nodules, polyps, bleeding, and polypoid degeneration. The results reveal the low-dimensional dynamic characteristics of human glottal area data. In comparison to periodic glottal area series from a normal subject, aperiodic glottal area series from pathological subjects show complex reconstructed phase space, fractal dimension, and positive Lyapunov exponents. The estimated positive Lyapunov exponents provide the direct evidence of chaos in pathological human vocal folds from high-speed digital imaging. Furthermore, significant differences between the normal and pathological groups are investigated for nonlinear dynamic and perturbation analyses. Jitter in the pathological group is significantly higher than in the normal group, but shimmer does not show such a difference. This finding suggests that the traditional perturbation analysis should be cautiously applied to high speed image signals. However, the correlation dimension and the maximal Lyapunov exponent reveal a statistically significant difference between normal and pathological groups. Nonlinear dynamic
Yildirir, Hasene Esra; Demirkol, Hatice
The current study aimed at examining the utility of a word association test in revealing students' cognitive structure in a specific chemistry topic through a word association test. The participants were 153 6th graders in a western Turkish city. The results revealed that the word association test serves a useful purpose in exploring the students'…
Li, Yanwei; Zhou, Xin; Feng, Gui; Hu, Haoyuan; Niu, Liming; Hebert, Paul D N; Huang, Dawei
Although the genus Sycophila has broad host preferences, some species are specifically associated with figs as nonpollinator wasps. Because of their sexual dimorphism, morphological plasticity, cryptic mating behaviour and poorly known biology, species identifications are often uncertain. It is particularly difficult to match conspecific females and males. In this study, we employed two molecular markers, mitochondrial COI and nuclear ITS2, to identify Sycophila from six Chinese fig species. Morphological studies revealed 25 female and male morphs, while sequence results for both genes were consistent in supporting the presence of 15 species, of which 13 were host specialists and two used dual hosts. A single species of Sycophila was respectively found on four fig species, but six species were isolated from Ficus benjamina and a same number was reared from Ficus microcarpa. Sequence results revealed three male morphs in one species and detected two species that were overlooked by morphological analysis. © 2009 Blackwell Publishing Ltd.
Scleractinian reef corals have recently been acknowledged as the most numerous host group found in association with hydroids belonging to the Zanclea genus. However, knowledge of the molecular phylogenetic relationships among Zanclea species associated with scleractinians is just beginning. This study, using the nuclear 28S rDNA region and the fast-evolving mitochondrial 16S rRNA and COI genes, provides the most comprehensive phylogenetic reconstruction of the genus Zanclea with a particular focus on the genetic diversity among Zanclea specimens associated with 13 scleractinian genera. The monophyly of Zanclea associated with scleractinians was strongly supported in all nuclear and mitochondrial phylogenetic reconstructions. Furthermore, a combined mitochondrial 16S and COI phylogenetic tree revealed a multitude of hidden molecular lineages within this group (Clades I, II, III, V, VI, VII, and VIII), suggesting the existence of both host-generalist and genus-specific lineages of Zanclea associated with scleractinians. In addition to Z. gallii living in association with the genus Acropora, we discovered four well-supported lineages (Clades I, II, III, and VII), each one forming a strict association with a single scleractinian genus, including sequences of Zanclea associated with Montipora from two geographically separated areas (Maldives and Taiwan). Two host-generalist Zanclea lineages were also observed, and one of them was formed by Zanclea specimens symbiotic with seven scleractinian genera (Clade VIII). We also found that the COI gene allows the recognition of separated hidden lineages in agreement with the commonly recommended mitochondrial 16S as a DNA barcoding gene for Hydrozoa and shows reasonable potential for phylogenetic and evolutionary analyses in the genus Zanclea. Finally, as no DNA sequences are available for the majority of the nominal Zanclea species known, we note that they will be necessary to elucidate the diversity of the Zanclea
Full Text Available Scleractinian reef corals have recently been acknowledged as the most numerous host group found in association with hydroids belonging to the Zanclea genus. However, knowledge of the molecular phylogenetic relationships among Zanclea species associated with scleractinians is just beginning. This study, using the nuclear 28S rDNA region and the fast-evolving mitochondrial 16S rRNA and COI genes, provides the most comprehensive phylogenetic reconstruction of the genus Zanclea with a particular focus on the genetic diversity among Zanclea specimens associated with 13 scleractinian genera. The monophyly of Zanclea associated with scleractinians was strongly supported in all nuclear and mitochondrial phylogenetic reconstructions. Furthermore, a combined mitochondrial 16S and COI phylogenetic tree revealed a multitude of hidden molecular lineages within this group (Clades I, II, III, V, VI, VII, and VIII, suggesting the existence of both host-generalist and genus-specific lineages of Zanclea associated with scleractinians. In addition to Z. gallii living in association with the genus Acropora, we discovered four well-supported lineages (Clades I, II, III, and VII, each one forming a strict association with a single scleractinian genus, including sequences of Zanclea associated with Montipora from two geographically separated areas (Maldives and Taiwan. Two host-generalist Zanclea lineages were also observed, and one of them was formed by Zanclea specimens symbiotic with seven scleractinian genera (Clade VIII. We also found that the COI gene allows the recognition of separated hidden lineages in agreement with the commonly recommended mitochondrial 16S as a DNA barcoding gene for Hydrozoa and shows reasonable potential for phylogenetic and evolutionary analyses in the genus Zanclea. Finally, as no DNA sequences are available for the majority of the nominal Zanclea species known, we note that they will be necessary to elucidate the diversity of the
Nambeesan, Savithri U; Mandel, Jennifer R; Bowers, John E; Marek, Laura F; Ebert, Daniel; Corbi, Jonathan; Rieseberg, Loren H; Knapp, Steven J; Burke, John M
Shoot branching is an important determinant of plant architecture and influences various aspects of growth and development. Selection on branching has also played an important role in the domestication of crop plants, including sunflower (Helianthus annuus L.). Here, we describe an investigation of the genetic basis of variation in branching in sunflower via association mapping in a diverse collection of cultivated sunflower lines. Detailed phenotypic analyses revealed extensive variation in the extent and type of branching within the focal population. After correcting for population structure and kinship, association analyses were performed using a genome-wide collection of SNPs to identify genomic regions that influence a variety of branching-related traits. This work resulted in the identification of multiple previously unidentified genomic regions that contribute to variation in branching. Genomic regions that were associated with apical and mid-apical branching were generally distinct from those associated with basal and mid-basal branching. Homologs of known branching genes from other study systems (i.e., Arabidopsis, rice, pea, and petunia) were also identified from the draft assembly of the sunflower genome and their map positions were compared to those of associations identified herein. Numerous candidate branching genes were found to map in close proximity to significant branching associations. In sunflower, variation in branching is genetically complex and overall branching patterns (i.e., apical vs. basal) were found to be influenced by distinct genomic regions. Moreover, numerous candidate branching genes mapped in close proximity to significant branching associations. Although the sunflower genome exhibits localized islands of elevated linkage disequilibrium (LD), these non-random associations are known to decay rapidly elsewhere. The subset of candidate genes that co-localized with significant associations in regions of low LD represents the most
Börlin, Marine; Venet, Pauline; Claisse, Olivier; Salin, Franck
ABSTRACT Three wine estates (designated A, B, and C) were sampled in Sauternes, a typical appellation of the Bordeaux wine area producing sweet white wine. From those wine estates, 551 yeast strains were collected between 2012 and 2014, added to 102 older strains from 1992 to 2011 from wine estate C. All the strains were analyzed through 15 microsatellite markers, resulting in 503 unique Saccharomyces cerevisiae genotypes, revealing high genetic diversity and a low presence of commercial yeast starters. Population analysis performed using Fst genetic distance or ancestry profiles revealed that the two closest wine estates, B and C, which have juxtaposed vineyard plots and common seasonal staff, share more related isolates with each other than with wine estate A, indicating exchange between estates. The characterization of isolates collected 23 years ago at wine estate C in relation to recent isolates obtained at wine estate B revealed the long-term persistence of isolates. Last, during the 2014 harvest period, a temporal succession of ancestral subpopulations related to the different batches associated with the selective picking of noble rotted grapes was highlighted. IMPORTANCE High genetic diversity of S. cerevisiae isolates from spontaneous fermentation on wine estates in the Sauternes appellation of Bordeaux was revealed. Only 7% of all Sauternes strains were considered genetically related to specific commercial strains. The long-term persistence (over 20 years) of S. cerevisiae profiles on a given wine estate is highlighted. PMID:26969698
An, Kang; Fang, Liurong; Luo, Rui; Wang, Dang; Xie, Lilan; Yang, Jing; Chen, Huanchun; Xiao, Shaobo
Transmissible gastroenteritis virus (TGEV), a porcine enteropathogenic coronavirus, causes lethal watery diarrhea and severe dehydration in piglets. In this study, liquid chromatography-tandem mass spectrometry coupled to isobaric tags for relative and absolute quantification labeling was used to quantitatively identify differentially expressed cellular proteins after TGEV infection in PK-15 cells. In total, 162 differentially expressed cellular proteins were identified, including 60 upregulated proteins and 102 downregulated proteins. These differentially expressed proteins were involved in the cell cycle, cellular growth and proliferation, the innate immune response, etc. Interestingly, many upregulated proteins were associated with interferon signaling, especially signal transducer and activator of transcription 1 (STAT1) and interferon-stimulated genes (ISGs). Immunoblotting and real-time quantitative reverse transcription polymerase chain reaction demonstrated that TGEV infection induces STAT1 phosphorylation and nuclear translocation, as well as ISG expression. This study for the first time reveals that TGEV induces interferon signaling from the point of proteomic analysis.
Jennifer L Anderson
Full Text Available Within vertebrates, major sex determining genes can differ among taxa and even within species. In zebrafish (Danio rerio, neither heteromorphic sex chromosomes nor single sex determination genes of large effect, like Sry in mammals, have yet been identified. Furthermore, environmental factors can influence zebrafish sex determination. Although progress has been made in understanding zebrafish gonad differentiation (e.g. the influence of germ cells on gonad fate, the primary genetic basis of zebrafish sex determination remains poorly understood. To identify genetic loci associated with sex, we analyzed F(2 offspring of reciprocal crosses between Oregon *AB and Nadia (NA wild-type zebrafish stocks. Genome-wide linkage analysis, using more than 5,000 sequence-based polymorphic restriction site associated (RAD-tag markers and population genomic analysis of more than 30,000 single nucleotide polymorphisms in our *ABxNA crosses revealed a sex-associated locus on the end of the long arm of chr-4 for both cross families, and an additional locus in the middle of chr-3 in one cross family. Additional sequencing showed that two SNPs in dmrt1 previously suggested to be functional candidates for sex determination in a cross of ABxIndia wild-type zebrafish, are not associated with sex in our AB fish. Our data show that sex determination in zebrafish is polygenic and that different genes may influence sex determination in different strains or that different genes become more important under different environmental conditions. The association of the end of chr-4 with sex is remarkable because, unique in the karyotype, this chromosome arm shares features with known sex chromosomes: it is highly heterochromatic, repetitive, late replicating, and has reduced recombination. Our results reveal that chr-4 has functional and structural properties expected of a sex chromosome.
Lecroq, Beatrice; Gooday, Andrew John; Cedhagen, Tomas
morphological features. To examine their taxonomic position at the molecular level, we analysed the SSU rDNA sequences of two species, Normanina conferta and Septuma ocotillo, obtained either with specific foraminiferal or universal eukaryotic primers. Many different sequences resulted from this investigation...... but none of them could clearly be attributed to komokiaceans. Although our study failed to confirm univocally that Komokiacea are foraminiferans, it revealed a huge eukaryotic richness associated with these organisms, comparable with the richness in the overall surrounding sediment. These observations...
Rosa, Pedro J; Morais, Diogo; Gamito, Pedro; Oliveira, Jorge; Saraiva, Tomaz
Immersive virtual reality is thought to be advantageous by leading to higher levels of presence. However, and despite users getting actively involved in immersive three-dimensional virtual environments that incorporate sound and motion, there are individual factors, such as age, video game knowledge, and the predisposition to immersion, that may be associated with the quality of virtual reality experience. Moreover, one particular concern for users engaged in immersive virtual reality environments (VREs) is the possibility of side effects, such as cybersickness. The literature suggests that at least 60% of virtual reality users report having felt symptoms of cybersickness, which reduces the quality of the virtual reality experience. The aim of this study was thus to profile the right user to be involved in a VRE through head-mounted display. To examine which user characteristics are associated with the most effective virtual reality experience (lower cybersickness), a multiple correspondence analysis combined with cluster analysis technique was performed. Results revealed three distinct profiles, showing that the PC gamer profile is more associated with higher levels of virtual reality effectiveness, that is, higher predisposition to be immersed and reduced cybersickness symptoms in the VRE than console gamer and nongamer. These findings can be a useful orientation in clinical practice and future research as they help identify which users are more predisposed to benefit from immersive VREs.
Jaiswal Dinesh Kumar
Full Text Available Abstract Background Compartmentalization is a unique feature of eukaryotes that helps in maintaining cellular homeostasis not only in intra- and inter-organellar context, but also between the cells and the external environment. Plant cells are highly compartmentalized with a complex metabolic network governing various cellular events. The membranes are the most important constituents in such compartmentalization, and membrane-associated proteins play diverse roles in many cellular processes besides being part of integral component of many signaling cascades. Results To obtain valuable insight into the dynamic repertoire of membrane proteins, we have developed a proteome reference map of a grain legume, chickpea, using two-dimensional gel electrophoresis. MALDI-TOF/TOF and LC-ESI-MS/MS analysis led to the identification of 91 proteins involved in a variety of cellular functions viz., bioenergy, stress-responsive and signal transduction, metabolism, protein synthesis and degradation, among others. Significantly, 70% of the identified proteins are putative integral membrane proteins, possessing transmembrane domains. Conclusions The proteomic analysis revealed many resident integral membrane proteins as well as membrane-associated proteins including those not reported earlier. To our knowledge, this is the first report of membrane proteome from aerial tissues of a crop plant. The findings may provide a better understanding of the biochemical machinery of the plant membranes at the molecular level that might help in functional genomics studies of different developmental pathways and stress-responses.
Raluca G. Mateescu
Full Text Available Improvements in eating satisfaction will benefit consumers and should increase beef demand which is of interest to the beef industry. Tenderness, juiciness, and flavor are major determinants of the palatability of beef and are often used to reflect eating satisfaction. Carcass qualities are used as indicator traits for meat quality, with higher quality grade carcasses expected to relate to more tender and palatable meat. However, meat quality is a complex concept determined by many component traits making interpretation of genome-wide association studies (GWAS on any one component challenging to interpret. Recent approaches combining traditional GWAS with gene network interactions theory could be more efficient in dissecting the genetic architecture of complex traits. Phenotypic measures of 23 traits reflecting carcass characteristics, components of meat quality, along with mineral and peptide concentrations were used along with Illumina 54k bovine SNP genotypes to derive an annotated gene network associated with meat quality in 2,110 Angus beef cattle. The efficient mixed model association (EMMAX approach in combination with a genomic relationship matrix was used to directly estimate the associations between 54k SNP genotypes and each of the 23 component traits. Genomic correlated regions were identified by partial correlations which were further used along with an information theory algorithm to derive gene network clusters. Correlated SNP across 23 component traits were subjected to network scoring and visualization software to identify significant SNP. Significant pathways implicated in the meat quality complex through GO term enrichment analysis included angiogenesis, inflammation, transmembrane transporter activity, and receptor activity. These results suggest that network analysis using partial correlations and annotation of significant SNP can reveal the genetic architecture of complex traits and provide novel information regarding
Full Text Available Chronic kidney disease (CKD is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR, the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
Full Text Available Circulating lipid ratios are considered predictors of cardiovascular risks and metabolic syndrome, which cause coronary heart diseases. One constitutional type of Korean medicine prone to weight accumulation, the Tae-Eum type, predisposes the consumers to metabolic syndrome, hypertension, diabetes mellitus, etc. Here, we aimed to identify genetic variants for lipid ratios using a genome-wide association study (GWAS and followed replication analysis in Koreans and constitutional subgroups. GWASs in 5,292 individuals of the Korean Genome and Epidemiology Study and replication analyses in 2,567 subjects of the Korea medicine Data Center were performed to identify genetic variants associated with triglyceride (TG to HDL cholesterol (HDLC, LDL cholesterol (LDLC to HDLC, and non-HDLC to HDLC ratios. For subgroup analysis, a computer-based constitution analysis tool was used to categorize the constitutional types of the subjects. In the discovery stage, seven variants in four loci, three variants in three loci, and two variants in one locus were associated with the ratios of log-transformed TG:HDLC (log[TG]:HDLC, LDLC:HDLC, and non-HDLC:HDLC, respectively. The associations of the GWAS variants with lipid ratios were replicated in the validation stage: for the log[TG]:HDLC ratio, rs6589566 near APOA5 and rs4244457 and rs6586891 near LPL; for the LDLC:HDLC ratio, rs4420638 near APOC1 and rs17445774 near C2orf47; and for the non-HDLC:HDLC ratio, rs6589566 near APOA5. Five of these six variants are known to be associated with TG, LDLC, and/or HDLC, but rs17445774 was newly identified to be involved in lipid level changes in this study. Constitutional subgroup analysis revealed effects of variants associated with log[TG]:HDLC and non-HDLC:HDLC ratios in both the Tae-Eum and non-Tae-Eum types, whereas the effect of the LDLC:HDLC ratio-associated variants remained only in the Tae-Eum type. In conclusion, we identified three log[TG]:HDLC ratio-associated
Kim, Taehyeung; Park, Ah Yeon; Baek, Younghwa; Cha, Seongwon
Circulating lipid ratios are considered predictors of cardiovascular risks and metabolic syndrome, which cause coronary heart diseases. One constitutional type of Korean medicine prone to weight accumulation, the Tae-Eum type, predisposes the consumers to metabolic syndrome, hypertension, diabetes mellitus, etc. Here, we aimed to identify genetic variants for lipid ratios using a genome-wide association study (GWAS) and followed replication analysis in Koreans and constitutional subgroups. GWASs in 5,292 individuals of the Korean Genome and Epidemiology Study and replication analyses in 2,567 subjects of the Korea medicine Data Center were performed to identify genetic variants associated with triglyceride (TG) to HDL cholesterol (HDLC), LDL cholesterol (LDLC) to HDLC, and non-HDLC to HDLC ratios. For subgroup analysis, a computer-based constitution analysis tool was used to categorize the constitutional types of the subjects. In the discovery stage, seven variants in four loci, three variants in three loci, and two variants in one locus were associated with the ratios of log-transformed TG:HDLC (log[TG]:HDLC), LDLC:HDLC, and non-HDLC:HDLC, respectively. The associations of the GWAS variants with lipid ratios were replicated in the validation stage: for the log[TG]:HDLC ratio, rs6589566 near APOA5 and rs4244457 and rs6586891 near LPL; for the LDLC:HDLC ratio, rs4420638 near APOC1 and rs17445774 near C2orf47; and for the non-HDLC:HDLC ratio, rs6589566 near APOA5. Five of these six variants are known to be associated with TG, LDLC, and/or HDLC, but rs17445774 was newly identified to be involved in lipid level changes in this study. Constitutional subgroup analysis revealed effects of variants associated with log[TG]:HDLC and non-HDLC:HDLC ratios in both the Tae-Eum and non-Tae-Eum types, whereas the effect of the LDLC:HDLC ratio-associated variants remained only in the Tae-Eum type. In conclusion, we identified three log[TG]:HDLC ratio-associated variants, two LDLC
Full Text Available Abstract Background Although mitochondrial dysfunction is consistently manifested in patients with Type 2 Diabetes mellitus (T2DM, the association of mitochondrial DNA (mtDNA sequence variants with T2DM varies among populations. These differences might stem from differing environmental influences among populations. However, other potentially important considerations emanate from the very nature of mitochondrial genetics, namely the notable high degree of partitioning in the distribution of human mtDNA variants among populations, as well as the interaction of mtDNA and nuclear DNA-encoded factors working in concert to govern mitochondrial function. We hypothesized that association of mtDNA genetic variants with T2DM could be revealed while controlling for the effect of additional inherited factors, reflected in family history information. Methods To test this hypothesis we set out to investigate whether mtDNA genetic variants will be differentially associated with T2DM depending on the diabetes status of the parents. To this end, association of mtDNA genetic backgrounds (haplogroups with T2DM was assessed in 1055 Jewish patients with and without T2DM parents ('DP' and 'HP', respectively. Results Haplogroup J1 was found to be 2.4 fold under-represented in the 'HP' patients (p = 0.0035. These results are consistent with a previous observation made in Finnish T2DM patients. Moreover, assessing the haplogroup distribution in 'DP' versus 'HP' patients having diabetic siblings revealed that haplogroup J1 was virtually absent in the 'HP' group. Conclusion These results imply the involvement of inherited factors, which modulate the susceptibility of haplogroup J1 to T2DM.
Zhao, Dayong; Shen, Feng; Zeng, Jin; Huang, Rui; Yu, Zhongbo; Wu, Qinglong L
Association network approaches have recently been proposed as a means for exploring the associations between bacterial communities. In the present study, high-throughput sequencing was employed to investigate the seasonal variations in the composition of bacterioplankton communities in six eutrophic urban lakes of Nanjing City, China. Over 150,000 16S rRNA sequences were derived from 52 water samples, and correlation-based network analyses were conducted. Our results demonstrated that the architecture of the co-occurrence networks varied in different seasons. Cyanobacteria played various roles in the ecological networks during different seasons. Co-occurrence patterns revealed that members of Cyanobacteria shared a very similar niche and they had weak positive correlations with other phyla in summer. To explore the effect of environmental factors on species-species co-occurrence networks and to determine the most influential environmental factors, the original positive network was simplified by module partitioning and by calculating module eigengenes. Module eigengene analysis indicated that temperature only affected some Cyanobacteria; the rest were mainly affected by nitrogen associated factors throughout the year. Cyanobacteria were dominant in summer which may result from strong co-occurrence patterns and suitable living conditions. Overall, this study has improved our understanding of the roles of Cyanobacteria and other bacterioplankton in ecological networks. Copyright Â© 2016 Elsevier B.V. All rights reserved.
Xu, Chao; Zhang, Ji-Gang; Lin, Dongdong; Zhang, Lan; Shen, Hui; Deng, Hong-Wen
Integrating diverse genomics data can provide a global view of the complex biological processes related to the human complex diseases. Although substantial efforts have been made to integrate different omics data, there are at least three challenges for multi-omics integration methods: (i) How to simultaneously consider the effects of various genomic factors, since these factors jointly influence the phenotypes; (ii) How to effectively incorporate the information from publicly accessible databases and omics datasets to fully capture the interactions among (epi)genomic factors from diverse omics data; and (iii) Until present, the combination of more than two omics datasets has been poorly explored. Current integration approaches are not sufficient to address all of these challenges together. We proposed a novel integrative analysis framework by incorporating sparse model, multivariate analysis, Gaussian graphical model, and network analysis to address these three challenges simultaneously. Based on this strategy, we performed a systemic analysis for glioblastoma multiforme (GBM) integrating genome-wide gene expression, DNA methylation, and miRNA expression data. We identified three regulatory modules of genomic factors associated with GBM survival time and revealed a global regulatory pattern for GBM by combining the three modules, with respect to the common regulatory factors. Our method can not only identify disease-associated dysregulated genomic factors from different omics, but more importantly, it can incorporate the information from publicly accessible databases and omics datasets to infer a comprehensive interaction map of all these dysregulated genomic factors. Our work represents an innovative approach to enhance our understanding of molecular genomic mechanisms underlying human complex diseases. Copyright © 2017 Xu et al.
Li, Bing; Yang, Ying; Ma, Liping; Ju, Feng; Guo, Feng; Tiedje, James M; Zhang, Tong
A metagenomic approach and network analysis was used to investigate the wide-spectrum profiles of antibiotic resistance genes (ARGs) and their co-occurrence patterns in 50 samples from 10 typical environments. In total, 260 ARG subtypes belonging to 18 ARG types were detected with an abundance range of 5.4 × 10(-6)-2.2 × 10(-1) copy of ARG per copy of 16S-rRNA gene. The trend of the total ARG abundances in environments matched well with the levels of anthropogenic impacts on these environments. From the less impacted environments to the seriously impacted environments, the total ARG abundances increased up to three orders of magnitude, that is, from 3.2 × 10(-3) to 3.1 × 10(0) copy of ARG per copy of 16S-rRNA gene. The abundant ARGs were associated with aminoglycoside, bacitracin, β-lactam, chloramphenicol, macrolide-lincosamide-streptogramin, quinolone, sulphonamide and tetracycline, in agreement with the antibiotics extensively used in human medicine or veterinary medicine/promoters. The widespread occurrences and abundance variation trend of vancomycin resistance genes in different environments might imply the spread of vancomycin resistance genes because of the selective pressure resulting from vancomycin use. The simultaneous enrichment of 12 ARG types in adult chicken faeces suggests the coselection of multiple ARGs in this production system. Non-metric multidimensional scaling analysis revealed that samples belonging to the same environment generally possessed similar ARG compositions. Based on the co-occurrence pattern revealed by network analysis, tetM and aminoglycoside resistance protein, the hubs of the ARG network, are proposed to be indicators to quantitatively estimate the abundance of 23 other co-occurring ARG subtypes by power functions.
Bajanca, Fernanda; Gonzalez-Perez, Vinicio; Gillespie, Sean J; Beley, Cyriaque; Garcia, Luis; Theveneau, Eric; Sear, Richard P; Hughes, Simon M
Dystrophin forms an essential link between sarcolemma and cytoskeleton, perturbation of which causes muscular dystrophy. We analysed Dystrophin binding dynamics in vivo for the first time. Within maturing fibres of host zebrafish embryos, our analysis reveals a pool of diffusible Dystrophin and complexes bound at the fibre membrane. Combining modelling, an improved FRAP methodology and direct semi-quantitative analysis of bleaching suggests the existence of two membrane-bound Dystrophin populations with widely differing bound lifetimes: a stable, tightly bound pool, and a dynamic bound pool with high turnover rate that exchanges with the cytoplasmic pool. The three populations were found consistently in human and zebrafish Dystrophins overexpressed in wild-type or dmd(ta222a/ta222a) zebrafish embryos, which lack Dystrophin, and in Gt(dmd-Citrine)(ct90a) that express endogenously-driven tagged zebrafish Dystrophin. These results lead to a new model for Dystrophin membrane association in developing muscle, and highlight our methodology as a valuable strategy for in vivo analysis of complex protein dynamics.
Miller, Frederick W.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy; Isenberg, David A.; Chinoy, Hector; Ollier, William E. R.; O’Hanlon, Terrance P.; Peng, Bo; Lee, Annette; Lamb, Janine A.; Chen, Wei; Amos, Christopher I.; Gregersen, Peter K.
Objective To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. PMID:23983088
Gokhale, Priyanka; Mania-Pramanik, Jayanti; Sonawani, Archana; Idicula-Thomas, Susan; Kerkar, Shilpa; Tongaonkar, Hemant; Chaudhari, Hemangi; Warke, Himangi; Salvi, Vinita
We studied the relationship between human leukocyte antigen (HLA) class I alleles and cervical cancer among Indian women. Seventy-five cervical cancer cases were compared with 175 noncancer controls. Cervical biopsy tissue specimen from cancer cases and cervical swab specimen from controls were collected for HPV detection and typing. Blood was taken for HLA typing by PCR-SSOP method. The impact of HLA class I alleles on cervical cancer risk was evaluated using StatCalc program (Epi Info version 6.0.4. CDC Atlanta, GA, USA), and confirmed with Bonferroni correction. Results revealed HLA-B*37, HLA-B*58 were associated significantly with increased risk while HLA-B*40 with decreased risk for cervical cancer. At high-resolution analysis after Bonferroni correction, HLA-B*37:01 allele was associated with increased risk, whereas HLA-B*40:06 was with decreased risk for cervical cancer. HLA-B*37:01 and HLA-B*40:06 belong to the same superfamily of HLA-B44. In silico analysis revealed different binding affinities of HLA-B*37:01 and HLA-B*40:06 for the epitopes predicted for E6 and L1 proteins of HPV16. The higher binding affinity of epitopes to B*40:06, as revealed by docking studies, supports the hypothesis that this allele is able to present the antigenic peptides more efficiently than B*37:01 and thereby can protect the carriers from the risk of cervical cancer. Thus, there is a clear indication that HLA plays an important role in the development of cervical cancer in HPV-infected women. Identification of these factors in high-risk HPV-infected women may help in reducing the cervical cancer burden in India.
Henning, Heiko; Petrunkina, Anna M; Harrison, Robin A P; Waberski, Dagmar
Storage of liquid-preserved boar spermatozoa is associated with a loss of fertilising ability of the preserved spermatozoa, which standard semen parameters barely reflect. Monitoring responses to molecular effectors of sperm function (e.g. bicarbonate) has proven to be a more sensitive approach to investigating storage effects. Bicarbonate not only initiates capacitation in spermatozoa, but also induces motility activation. This occurs at ejaculation, but also happens throughout passage through the oviduct. In the present study we tested whether the specific response of boar sperm subpopulations to bicarbonate, as assessed by motility activation, is altered with the duration of storage in vitro. Three ejaculates from each of seven boars were diluted in Beltsville thawing solution and stored at 17°C. Only minor changes in the parameters of diluted semen were revealed over a period of 72h storage. For assessment of bicarbonate responses, subsamples of diluted spermatozoa were centrifuged through a discontinuous Percoll gradient after 12, 24 and 72h storage. Subsequently, spermatozoa were incubated in two Ca2+-free variants of Tyrode's medium either without (TyrControl) or with (TyrBic) 15mM bicarbonate, and computer-aided sperm analysis motility measurements were made. Cluster analysis of imaging data from motile spermatozoa revealed the presence of five major sperm subpopulations with distinct motility characteristics, differing between TyrBic and TyrControl at any given time (Pfunction in both media, bicarbonate induced an increase in a 'fast linear' cohort of spermatozoa in TyrBic regardless of storage (66.4% at 12h and 63.9% at 72h). These results imply a binary pattern in response of sperm motility function descriptors to storage: although the quantitative descriptor (percentage of motile spermatozoa) declines in washed semen samples, the qualitative descriptor (percentage of spermatozoa stimulated into fast linear motion by bicarbonate) is sustained
Francy L. García-Arias
Full Text Available Association mapping has been proposed as an efficient approach to assist plant breeding programs to investigate the genetic basis of agronomic traits. In this study, we evaluated 18 traits related to yield, (FWP, NF, FWI, and FWII, fruit size-shape (FP, FA, MW, WMH, MH, HMW, DI, FSI, FSII, OVO, OBO, and fruit quality (FIR, CF, and SST, in a diverse collection of 100 accessions of Physalis peruviana including wild, landraces, and anther culture derived lines. We identified seven accessions with suitable traits: fruit weight per plant (FWP > 7,000 g/plant and cracked fruits (CF < 4%, to be used as parents in cape gooseberry breeding program. In addition, the accessions were also characterized using Genotyping By Sequencing (GBS. We discovered 27,982 and 36,142 informative SNP markers based on the alignment against the two cape gooseberry references transcriptomes. Besides, 30,344 SNPs were identified based on alignment to the tomato reference genome. Genetic structure analysis showed that the population could be divided into two or three sub-groups, corresponding to landraces-anther culture and wild accessions for K = 2 and wild, landraces, and anther culture plants for K = 3. Association analysis was carried out using a Mixed Linear Model (MLM and 34 SNP markers were significantly associated. These results reveal the basis of the genetic control of important agronomic traits and may facilitate marker-based breeding in P. peruviana.
García-Arias, Francy L; Osorio-Guarín, Jaime A; Núñez Zarantes, Victor M
Association mapping has been proposed as an efficient approach to assist plant breeding programs to investigate the genetic basis of agronomic traits. In this study, we evaluated 18 traits related to yield, (FWP, NF, FWI, and FWII), fruit size-shape (FP, FA, MW, WMH, MH, HMW, DI, FSI, FSII, OVO, OBO), and fruit quality (FIR, CF, and SST), in a diverse collection of 100 accessions of Physalis peruviana including wild, landraces, and anther culture derived lines. We identified seven accessions with suitable traits: fruit weight per plant (FWP) > 7,000 g/plant and cracked fruits (CF) cape gooseberry breeding program. In addition, the accessions were also characterized using Genotyping By Sequencing (GBS). We discovered 27,982 and 36,142 informative SNP markers based on the alignment against the two cape gooseberry references transcriptomes. Besides, 30,344 SNPs were identified based on alignment to the tomato reference genome. Genetic structure analysis showed that the population could be divided into two or three sub-groups, corresponding to landraces-anther culture and wild accessions for K = 2 and wild, landraces, and anther culture plants for K = 3. Association analysis was carried out using a Mixed Linear Model (MLM) and 34 SNP markers were significantly associated. These results reveal the basis of the genetic control of important agronomic traits and may facilitate marker-based breeding in P. peruviana .
Full Text Available Characterizing the genetic determinants of complex diseases can be further augmented by incorporating knowledge of underlying structure or classifications of the genome, such as newly developed mappings of protein-coding genes, epigenetic marks, enhancer elements and non-coding RNAs.We apply a simple class-level testing framework, termed Genetic Class Association Testing (GenCAT, to identify protein-coding gene association with 14 cardiometabolic (CMD related traits across 6 publicly available genome wide association (GWA meta-analysis data resources. GenCAT uses SNP-level meta-analysis test statistics across all SNPs within a class of elements, as well as the size of the class and its unique correlation structure, to determine if the class is statistically meaningful. The novelty of findings is evaluated through investigation of regional signals. A subset of findings are validated using recently updated, larger meta-analysis resources. A simulation study is presented to characterize overall performance with respect to power, control of family-wise error and computational efficiency. All analysis is performed using the GenCAT package, R version 3.2.1.We demonstrate that class-level testing complements the common first stage minP approach that involves individual SNP-level testing followed by post-hoc ascribing of statistically significant SNPs to genes and loci. GenCAT suggests 54 protein-coding genes at 41 distinct loci for the 13 CMD traits investigated in the discovery analysis, that are beyond the discoveries of minP alone. An additional application to biological pathways demonstrates flexibility in defining genetic classes.We conclude that it would be prudent to include class-level testing as standard practice in GWA analysis. GenCAT, for example, can be used as a simple, complementary and efficient strategy for class-level testing that leverages existing data resources, requires only summary level data in the form of test statistics, and
Full Text Available Harmony is a fundamental attribute of music. Close connections exist between music and mathematics since both pursue harmony and unity. In music, the consonance of notes played simultaneously partly determines our perception of harmony; associates with aesthetic responses; and influences the emotion expression. The consonance could be considered as a window to understand and analyze harmony. Here for the first time we used a 1/f fluctuation analysis to investigate whether the consonance fluctuation structure in music with a wide range of composers and genres followed the scale free pattern that has been found for pitch, melody, rhythm, human body movements, brain activity, natural images and geographical features. We then used a network graph approach to investigate which composers were the most influential both within and across genres. Our results showed that patterns of consonance in music did follow scale-free characteristics, suggesting that this feature is a universally evolved one in both music and the living world. Furthermore, our network analysis revealed that Bach's harmony patterns were having the most influence on those used by other composers, followed closely by Mozart.
Wu, Dan; Kendrick, Keith M; Levitin, Daniel J; Li, Chaoyi; Yao, Dezhong
Harmony is a fundamental attribute of music. Close connections exist between music and mathematics since both pursue harmony and unity. In music, the consonance of notes played simultaneously partly determines our perception of harmony; associates with aesthetic responses; and influences the emotion expression. The consonance could be considered as a window to understand and analyze harmony. Here for the first time we used a 1/f fluctuation analysis to investigate whether the consonance fluctuation structure in music with a wide range of composers and genres followed the scale free pattern that has been found for pitch, melody, rhythm, human body movements, brain activity, natural images and geographical features. We then used a network graph approach to investigate which composers were the most influential both within and across genres. Our results showed that patterns of consonance in music did follow scale-free characteristics, suggesting that this feature is a universally evolved one in both music and the living world. Furthermore, our network analysis revealed that Bach's harmony patterns were having the most influence on those used by other composers, followed closely by Mozart.
Full Text Available Cocoon and silk yields are the most important characteristics of sericulture. However, few studies have examined the genes that modulate these features. Further studies of these genes will be useful for improving the products of sericulture. JingSong (JS and Lan10 (L10 are two strains having significantly different cocoon and silk yields. In the current study, RNA-Seq and quantitative polymerase chain reaction (qPCR were performed on both strains in order to determine divergence of the silk gland, which controls silk biosynthesis in silkworms. Compared with L10, JS had 1375 differentially expressed genes (DEGs; 738 up-regulated genes and 673 down-regulated genes. Nine enriched gene ontology (GO terms were identified by GO enrichment analysis based on these DEGs. KEGG enrichment analysis results showed that the DEGs were enriched in three pathways, which were mainly associated with the processing and biosynthesis of proteins. The representative genes in the enrichment pathways and ten significant DEGs were further verified by qPCR, the results of which were consistent with the RNA-Seq data. Our study has revealed differences in silk glands between the two silkworm strains and provides a perspective for understanding the molecular mechanisms determining silk yield.
Campobello, Daniela; Hare, James F; Sarà, Maurizio
In social species, fitness consequences are associated with both individual and social phenotypes. Social selection analysis has quantified the contribution of conspecific social traits to individual fitness. There has been no attempt, however, to apply a social selection approach to quantify the fitness implications of heterospecific social phenotypes. Here, we propose a novel social selection based approach integrating the role of all social interactions at the community level. We extended multilevel selection analysis by including a term accounting for the group phenotype of heterospecifics. We analyzed nest activity as a model social trait common to two species, the lesser kestrel (Falco naumanni) and jackdaw (Corvus monedula), nesting in either single- or mixed-species colonies. By recording reproductive outcome as a measure of relative fitness, our results reveal an asymmetric system wherein only jackdaw breeding performance was affected by the activity phenotypes of both conspecific and heterospecific neighbors. Our model incorporating heterospecific social phenotypes is applicable to animal communities where interacting species share a common social trait, thus allowing an assessment of the selection pressure imposed by interspecific interactions in nature. Finally, we discuss the potential role of ecological limitations accounting for random or preferential assortments among interspecific social phenotypes, and the implications of such processes to community evolution. © 2015 The Author(s).
Li, Juan; Qin, Sheng; Yu, Huanjun; Zhang, Jing; Liu, Na; Yu, Ye; Hou, Chengxiang; Li, Muwang
Cocoon and silk yields are the most important characteristics of sericulture. However, few studies have examined the genes that modulate these features. Further studies of these genes will be useful for improving the products of sericulture. JingSong (JS) and Lan10 (L10) are two strains having significantly different cocoon and silk yields. In the current study, RNA-Seq and quantitative polymerase chain reaction (qPCR) were performed on both strains in order to determine divergence of the silk gland, which controls silk biosynthesis in silkworms. Compared with L10, JS had 1375 differentially expressed genes (DEGs; 738 up-regulated genes and 673 down-regulated genes). Nine enriched gene ontology (GO) terms were identified by GO enrichment analysis based on these DEGs. KEGG enrichment analysis results showed that the DEGs were enriched in three pathways, which were mainly associated with the processing and biosynthesis of proteins. The representative genes in the enrichment pathways and ten significant DEGs were further verified by qPCR, the results of which were consistent with the RNA-Seq data. Our study has revealed differences in silk glands between the two silkworm strains and provides a perspective for understanding the molecular mechanisms determining silk yield.
Full Text Available Microcystis bloom, a cyanobacterial mass occurrence often found in eutrophicated water bodies, is one of the most serious threats to freshwater ecosystems worldwide. In nature, Microcystis forms aggregates or colonies that contain heterotrophic bacteria. The Microcystis-bacteria colonies were persistent even when they were maintained in lab culture for a long period. The relationship between Microcystis and the associated bacteria was investigated by a metagenomic approach in this study. We developed a visualization-guided method of binning for genome assembly after total colony DNA sequencing. We found that the method was effective in grouping sequences and it did not require reference genome sequence. Individual genomes of the colony bacteria were obtained and they provided valuable insights into microbial community structures. Analysis of metabolic pathways based on these genomes revealed that while all heterotrophic bacteria were dependent upon Microcystis for carbon and energy, Vitamin B12 biosynthesis, which is required for growth by Microcystis, was accomplished in a cooperative fashion among the bacteria. Our analysis also suggests that individual bacteria in the colony community contributed a complete pathway for degradation of benzoate, which is inhibitory to the cyanobacterial growth, and its ecological implication for Microcystis bloom is discussed.
Chen, Yu-Han; Yeh, Ting-Feng; Chu, Fang-Hua; Hsu, Fu-Lan; Chang, Shang-Tzen
Ferruginol has antifungal activity against wood-rot fungi (basidiomycetes). However, specific research on the antifungal mechanisms of ferruginol is scarce. Two-dimensional gel electrophoresis and fluorescent image analysis were employed to evaluate the differential protein expression of wood-rot fungus Trametes versicolor treated with or without ferruginol. Results from protein identification of tryptic peptides via liquid chromatography–electrospray ionization tandem mass spectrometry (LC–ESI-MS/MS) analyses revealed 17 protein assignments with differential expression. Downregulation of cytoskeleton β-tubulin 3 indicates that ferruginol has potential to be used as a microtubule-disrupting agent. Downregulation of major facilitator superfamily (MFS)–multiple drug resistance (MDR) transporter and peroxiredoxin TSA1 were observed, suggesting reduction in self-defensive capabilities of T. versicolor. In addition, the proteins involved in polypeptide sorting and DNA repair were also downregulated, while heat shock proteins and autophagy-related protein 7 were upregulated. These observations reveal that such cellular dysfunction and damage caused by ferruginol lead to growth inhibition and autophagic cell death of fungi.
Vecsey, Christopher G; Peixoto, Lucia; Choi, Jennifer H K; Wimmer, Mathieu; Jaganath, Devan; Hernandez, Pepe J; Blackwell, Jennifer; Meda, Karuna; Park, Alan J; Hannenhalli, Sridhar; Abel, Ted
Sleep deprivation is a common problem of considerable health and economic impact in today's society. Sleep loss is associated with deleterious effects on cognitive functions such as memory and has a high comorbidity with many neurodegenerative and neuropsychiatric disorders. Therefore, it is crucial to understand the molecular basis of the effect of sleep deprivation in the brain. In this study, we combined genome-wide and traditional molecular biological approaches to determine the cellular and molecular impacts of sleep deprivation in the mouse hippocampus, a brain area crucial for many forms of memory. Microarray analysis examining the effects of 5 h of sleep deprivation on gene expression in the mouse hippocampus found 533 genes with altered expression. Bioinformatic analysis revealed that a prominent effect of sleep deprivation was to downregulate translation, potentially mediated through components of the insulin signaling pathway such as the mammalian target of rapamycin (mTOR), a key regulator of protein synthesis. Consistent with this analysis, sleep deprivation reduced levels of total and phosphorylated mTOR, and levels returned to baseline after 2.5 h of recovery sleep. Our findings represent the first genome-wide analysis of the effects of sleep deprivation on the mouse hippocampus, and they suggest that the detrimental effects of sleep deprivation may be mediated by reductions in protein synthesis via downregulation of mTOR. Because protein synthesis and mTOR activation are required for long-term memory formation, our study improves our understanding of the molecular mechanisms underlying the memory impairments induced by sleep deprivation.
Mitchell R Lucas
Full Text Available Highly specific seed market classes for cowpea and other grain legumes exists because grain is most commonly cooked and consumed whole. Size, shape, color, and texture are critical features of these market classes and breeders target development of cultivars for market acceptance. Resistance to biotic and abiotic stresses that are absent from elite breeding material are often introgressed through crosses to landraces or wild relatives. When crosses are made between parents with different grain quality characteristics, recovery of progeny with acceptable or enhanced grain quality is problematic. Thus genetic markers for grain quality traits can help in pyramiding genes needed for specific market classes. Allelic variation dictating the inheritance of seed size can be tagged and used to assist the selection of large-seeded lines. In this work we applied SNP genotyping and knowledge of legume synteny to characterize regions of the cowpea genome associated with seed size. These marker-trait associations will enable breeders to use marker based selection approaches to increase the frequency of progeny with large seed. For ~800 samples derived from eight bi-parental populations, QTL analysis was used to identify markers linked to ten trait determinants. In addition, the population structure of 171 samples from the USDA core collection was identified and incorporated into a genome-wide association study which supported more than half of the trait-associated regions important in the bi-parental populations. Seven of the total ten QTL were supported based on synteny to seed size associated regions identified in the related legume soybean. In addition to delivering markers linked to major trait determinants in the context of modern breeding, we provide an analysis of the diversity of the USDA core collection of cowpea to identify genepools, migrants, admixture, and duplicates.
Lucas, Mitchell R; Huynh, Bao-Lam; da Silva Vinholes, Patricia; Cisse, Ndiaga; Drabo, Issa; Ehlers, Jeffrey D; Roberts, Philip A; Close, Timothy J
Highly specific seed market classes for cowpea and other grain legumes exist because grain is most commonly cooked and consumed whole. Size, shape, color, and texture are critical features of these market classes and breeders target development of cultivars for market acceptance. Resistance to biotic and abiotic stresses that are absent from elite breeding material are often introgressed through crosses to landraces or wild relatives. When crosses are made between parents with different grain quality characteristics, recovery of progeny with acceptable or enhanced grain quality is problematic. Thus genetic markers for grain quality traits can help in pyramiding genes needed for specific market classes. Allelic variation dictating the inheritance of seed size can be tagged and used to assist the selection of large seeded lines. In this work we applied 1,536-plex SNP genotyping and knowledge of legume synteny to characterize regions of the cowpea genome associated with seed size. These marker-trait associations will enable breeders to use marker-based selection approaches to increase the frequency of progeny with large seed. For 804 individuals derived from eight bi-parental populations, QTL analysis was used to identify markers linked to 10 trait determinants. In addition, the population structure of 171 samples from the USDA core collection was identified and incorporated into a genome-wide association study which supported more than half of the trait-associated regions important in the bi-parental populations. Seven of the total 10 QTLs were supported based on synteny to seed size associated regions identified in the related legume soybean. In addition to delivering markers linked to major trait determinants in the context of modern breeding, we provide an analysis of the diversity of the USDA core collection of cowpea to identify genepools, migrants, admixture, and duplicates.
Full Text Available Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans.To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure.The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry.Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM2.5 exposure (p<0.05. The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [β(95% CI = -0.013(-0.022 ≈ -0.004; p = 0.005], docosapentaenoic acid n3 [β(95% CI = -0.010(-0.018 ≈ -0.002; p = 0.017], and docosapentaenoic acid n6 [β(95% CI = -0.007(-0.013 ≈ -0.001; p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (p Study-2011 = 0.025; p Study-2012 = 0.021; p Combined = 0.009. The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders.High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders.
John Stephen Malamon
Full Text Available Late-onset Alzheimer’s disease (LOAD and age are significantly correlated such that one-third of Americans beyond 85 years of age are afflicted. We have designed and implemented a pilot study that combines systems biology approaches with traditional next-generation sequencing (NGS analysis techniques to identify relevant regulatory pathways, infer functional relationships and confirm the dysregulation of these biological pathways in LOAD. Our study design is a most comprehensive systems approach combining co-expression network modeling derived from RNA-seq data, rigorous quality control (QC standards, functional ontology, and expression quantitative trait loci (eQTL derived from whole exome (WES single nucleotide variant (SNV genotype data. Our initial results reveal several statistically significant, biologically relevant genes involved in sphingolipid metabolism. To validate these findings, we performed a gene set enrichment analysis (GSEA. The GSEA revealed the sphingolipid metabolism pathway and regulation of autophagy in association with LOAD cases. In the execution of this study, we have successfully tested an integrative approach to identify both novel and known LOAD drivers in order to develop a broader and more detailed picture of the highly complex transcriptional and regulatory landscape of age-related dementia.
Full Text Available Plant cell wall formation is a complex, coordinated and developmentally regulated process. Cellulose is the most dominant constituent of plant cell walls. Because of its paracrystalline structure, cellulose is the main determinant of mechanical strength of plant tissues. As the most abundant polysaccharide on earth, it is also the focus of cellulosic biofuel industry. To reduce culm lodging in wheat and for improved ethanol production, delineation of the variation for stem cellulose content could prove useful. We present results on the analysis of the stem cellulose content of 288 diverse wheat accessions and its genome-wide association study (GWAS. Cellulose concentration ranged from 35 to 52% (w/w. Cellulose content was normally distributed in the accessions around a mean and median of 45% (w/w. Genome-wide marker-trait association study using 21,073 SNPs helped identify nine SNPs that were associated (p < 1E-05 with cellulose content. Four strongly associated (p < 8.17E-05 SNP markers were linked to wheat unigenes, which included β-tubulin, Auxin-induced protein 5NG4, and a putative transmembrane protein of unknown function. These genes may be directly or indirectly involved in the formation of cellulose in wheat culms. GWAS results from this study have the potential for genetic manipulation of cellulose content in bread wheat and other small grain cereals to enhance culm strength and improve biofuel production.
Halim, Adnan; Carlsson, Michael C; Mathiesen, Caroline Benedicte K
characterization by bottom-up analysis. In addition, top-down mass spectrometry is utilized for targeted analysis of individual proteins, revealing hitherto unknown PTMs of HDM allergens. We demonstrate the presence of lysine-linked polyhexose glycans and asparagine-linked N-acetylhexosamine glycans on HDM...
Stevens, Ann M; Smith, Ann C; Marbach-Ad, Gili; Balcom, Sarah A; Buchner, John; Daniel, Sandra L; DeStefano, Jeffrey J; El-Sayed, Najib M; Frauwirth, Kenneth; Lee, Vincent T; McIver, Kevin S; Melville, Stephen B; Mosser, David M; Popham, David L; Scharf, Birgit E; Schubot, Florian D; Seyler, Richard W; Shields, Patricia Ann; Song, Wenxia; Stein, Daniel C; Stewart, Richard C; Thompson, Katerina V; Yang, Zhaomin; Yarwood, Stephanie A
Misconceptions, also known as alternate conceptions, about key concepts often hinder the ability of students to learn new knowledge. Concept inventories (CIs) are designed to assess students' understanding of key concepts, especially those prone to misconceptions. Two-tiered CIs include prompts that ask students to explain the logic behind their answer choice. Such two-tiered CIs afford an opportunity for faculty to explore the student thinking behind the common misconceptions represented by their choice of a distractor. In this study, we specifically sought to probe the misconceptions that students hold prior to beginning an introductory microbiology course (i.e., preconceptions). Faculty-learning communities at two research-intensive universities used the validated Host-Pathogen Interaction Concept Inventory (HPI-CI) to reveal student preconceptions. Our method of deep analysis involved communal review and discussion of students' explanations for their CI answer choice. This approach provided insight valuable for curriculum development. Here the process is illustrated using one question from the HPI-CI related to the important topic of antibiotic resistance. The frequencies with which students chose particular multiple-choice responses for this question were highly correlated between institutions, implying common underlying misconceptions. Examination of student explanations using our analysis approach, coupled with group discussions within and between institutions, revealed patterns in student thinking to the participating faculty. Similar application of a two-tiered concept inventory by general microbiology instructors, either individually or in groups, at other institutions will allow them to better understand student thinking related to key concepts in their curriculum.
Li, Yuanyuan; Wang, Ran; Qiao, Nan; Peng, Guangdun; Zhang, Ke; Tang, Ke; Han, Jing-Dong J; Jing, Naihe
Proper neural commitment is essential for ensuring the appropriate development of the human brain and for preventing neurodevelopmental diseases such as autism spectrum disorders, schizophrenia, and intellectual disorders. However, the molecular mechanisms underlying the neural commitment in humans remain elusive. Here, we report the establishment of a neural differentiation system based on human embryonic stem cells (hESCs) and on comprehensive RNA sequencing analysis of transcriptome dynamics during early hESC differentiation. Using weighted gene co-expression network analysis, we reveal that the hESC neurodevelopmental trajectory has five stages: pluripotency (day 0); differentiation initiation (days 2, 4, and 6); neural commitment (days 8-10); neural progenitor cell proliferation (days 12, 14, and 16); and neuronal differentiation (days 18, 20, and 22). These stages were characterized by unique module genes, which may recapitulate the early human cortical development. Moreover, a comparison of our RNA-sequencing data with several other transcriptome profiling datasets from mice and humans indicated that Module 3 associated with the day 8-10 stage is a critical window of fate switch from the pluripotency to the neural lineage. Interestingly, at this stage, no key extrinsic signals were activated. In contrast, using CRISPR/Cas9-mediated gene knockouts, we also found that intrinsic hub transcription factors, including the schizophrenia-associated SIX3 gene and septo-optic dysplasia-related HESX1 gene, are required to program hESC neural determination. Our results improve the understanding of the mechanism of neural commitment in the human brain and may help elucidate the etiology of human mental disorders and advance therapies for managing these conditions. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Full Text Available Dilated cardiomyopathy (DCM is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS to assess the contribution of missense variants to sporadic DCM.116,855 single nucleotide variants (SNVs were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01. The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01 demonstrated significant association for TTN variants only (P = 0.0085. All candidate genes but one (SLC39A8 exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033 or common (n = 36, P = 0.019 variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here.We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.
Arif Hasan Khan Robin
Full Text Available Glucosinolates are the biochemical compounds that provide defense to plants against pathogens and herbivores. In this study, the relative expression level of 48 glucosinolate biosynthesis genes was explored in four morphologically-different cabbage inbred lines by qPCR analysis. The content of aliphatic and indolic glucosinolate molecules present in those cabbage lines was also estimated by HPLC analysis. The possible association between glucosinolate accumulation and related gene expression level was explored by principal component analysis (PCA. The genotype-dependent variation in the relative expression level of different aliphatic and indolic glucosinolate biosynthesis genes is the novel result of this study. A total of eight different types of glucosinolates, including five aliphatic and three indolic glucosinolates, was detected in four cabbage lines. Three inbred lines BN3383, BN4059 and BN4072 had no glucoraphanin, sinigrin and gluconapin detected, but the inbred line BN3273 had these three aliphatic glucosinolate compounds. PCA revealed that a higher expression level of ST5b genes and lower expression of GSL-OH was associated with the accumulation of these three aliphatic glucosinolate compounds. PCA further revealed that comparatively higher accumulation of neoglucobrassicin in the inbred line, BN4072, was associated with a high level of expression of MYB34 (Bol017062 and CYP81F1 genes. The Dof1 and IQD1 genes probably trans-activated the genes related to biosynthesis of glucoerucin and methoxyglucobrassicin for their comparatively higher accumulation in the BN4059 and BN4072 lines compared to the other two lines, BN3273 and BN3383. A comparatively higher progoitrin level in BN3273 was probably associated with the higher expression level of the GSL-OH gene. The cabbage inbred line BN3383 accounted for the significantly higher relative expression level for the 12 genes out of 48, but this line had comparatively lower total
Tang Vivian W
Full Text Available Abstract Background Zonula occludens, also known as the tight junction, is a specialized cell-cell interaction characterized by membrane "kisses" between epithelial cells. A cytoplasmic plaque of ~100 nm corresponding to a meshwork of densely packed proteins underlies the tight junction membrane domain. Due to its enormous size and difficulties in obtaining a biochemically pure fraction, the molecular composition of the tight junction remains largely unknown. Results A novel biochemical purification protocol has been developed to isolate tight junction protein complexes from cultured human epithelial cells. After identification of proteins by mass spectroscopy and fingerprint analysis, candidate proteins are scored and assessed individually. A simple algorithm has been devised to incorporate transmembrane domains and protein modification sites for scoring membrane proteins. Using this new scoring system, a total of 912 proteins have been identified. These 912 hits are analyzed using a bioinformatics approach to bin the hits in 4 categories: configuration, molecular function, cellular function, and specialized process. Prominent clusters of proteins related to the cytoskeleton, cell adhesion, and vesicular traffic have been identified. Weaker clusters of proteins associated with cell growth, cell migration, translation, and transcription are also found. However, the strongest clusters belong to synaptic proteins and signaling molecules. Localization studies of key components of synaptic transmission have confirmed the presence of both presynaptic and postsynaptic proteins at the tight junction domain. To correlate proteomics data with structure, the tight junction has been examined using electron microscopy. This has revealed many novel structures including end-on cytoskeletal attachments, vesicles fusing/budding at the tight junction membrane domain, secreted substances encased between the tight junction kisses, endocytosis of tight junction
Jackson, Andrew P; Otto, Thomas D; Aslett, Martin; Armstrong, Stuart D; Bringaud, Frederic; Schlacht, Alexander; Hartley, Catherine; Sanders, Mandy; Wastling, Jonathan M; Dacks, Joel B; Acosta-Serrano, Alvaro; Field, Mark C; Ginger, Michael L; Berriman, Matthew
The evolution of parasitism is a recurrent event in the history of life and a core problem in evolutionary biology. Trypanosomatids are important parasites and include the human pathogens Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp., which in humans cause African trypanosomiasis, Chagas disease, and leishmaniasis, respectively. Genome comparison between trypanosomatids reveals that these parasites have evolved specialized cell-surface protein families, overlaid on a well-conserved cell template. Understanding how these features evolved and which ones are specifically associated with parasitism requires comparison with related non-parasites. We have produced genome sequences for Bodo saltans, the closest known non-parasitic relative of trypanosomatids, and a second bodonid, Trypanoplasma borreli. Here we show how genomic reduction and innovation contributed to the character of trypanosomatid genomes. We show that gene loss has "streamlined" trypanosomatid genomes, particularly with respect to macromolecular degradation and ion transport, but consistent with a widespread loss of functional redundancy, while adaptive radiations of gene families involved in membrane function provide the principal innovations in trypanosomatid evolution. Gene gain and loss continued during trypanosomatid diversification, resulting in the asymmetric assortment of ancestral characters such as peptidases between Trypanosoma and Leishmania, genomic differences that were subsequently amplified by lineage-specific innovations after divergence. Finally, we show how species-specific, cell-surface gene families (DGF-1 and PSA) with no apparent structural similarity are independent derivations of a common ancestral form, which we call "bodonin." This new evidence defines the parasitic innovations of trypanosomatid genomes, revealing how a free-living phagotroph became adapted to exploiting hostile host environments. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All
Voora, Deepak; Cyr, Derek; Lucas, Joseph; Chi, Jen-Tsan; Dungan, Jennifer; McCaffrey, Timothy A; Katz, Richard; Newby, L Kristin; Kraus, William E; Becker, Richard C; Ortel, Thomas L; Ginsburg, Geoffrey S
The aim of this study was to develop ribonucleic acid (RNA) profiles that could serve as novel biomarkers for the response to aspirin. Aspirin reduces death and myocardial infarction (MI), suggesting that aspirin interacts with biological pathways that may underlie these events. Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healthy volunteers (HV2) (n = 53) and outpatient cardiology patients (OPC) (n = 25). Platelet function was assessed using the platelet function score (PFS) in HV1 and HV2 and the VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) in OPC. Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for associations with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death or MI in 2 patient cohorts (n = 587 total) from RNA samples collected at cardiac catheterization. A set of 60 coexpressed genes named the "aspirin response signature" (ARS) was associated with PFS in HV1 (r = -0.31, p = 0.03), HV2 (r = -0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for the 17 ARS genes were identified in the platelet proteome, of which 6 were associated with PFS. The ARS was associated with death or MI in both patient cohorts (odds ratio: 1.2 [p = 0.01]; hazard ratio: 1.5 [p = 0.001]), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31% to 37%, p ≤ 0.0002) was improved by including the ARS or 1 of its genes, ITGA2B. RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI. Copyright © 2013 American College of Cardiology Foundation. Published by
Xi, W-D; Liu, Y-J; Sun, X-B; Shan, J; Yi, L; Zhang, T-T
RNA-seq data of colon adenocarcinoma (COAD) were analyzed with bioinformatics tools to discover critical genes in the disease. Relevant small molecule drugs, transcription factors (TFs) and microRNAs (miRNAs) were also investigated. RNA-seq data of COAD were downloaded from The Cancer Genome Atlas (TCGA). Differential analysis was performed with package edgeR. False positive discovery (FDR) 1 were set as the cut-offs to screen out differentially expressed genes (DEGs). Gene coexpression network was constructed with package Ebcoexpress. GO enrichment analysis was performed for the DEGs in the gene coexpression network with DAVID. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was also performed for the genes with KOBASS 2.0. Modules were identified with MCODE of Cytoscape. Relevant small molecules drugs were predicted by Connectivity map. Relevant miRNAs and TFs were searched by WebGestalt. A total of 457 DEGs, including 255 up-regulated and 202 down-regulated genes, were identified from 437 COAD and 39 control samples. A gene coexpression network was constructed containing 40 DEGs and 101 edges. The genes were mainly associated with collagen fibril organization, extracellular matrix organization and translation. Two modules were identified from the gene coexpression network, which were implicated in muscle contraction and extracellular matrix organization, respectively. Several critical genes were disclosed, such as MYH11, COL5A2 and ribosomal proteins. Nine relevant small molecule drugs were identified, such as scriptaid and STOCK1N-35874. Accordingly, a total of 17 TFs and 10 miRNAs related to COAD were acquired, such as ETS2, NFAT, AP4, miR-124A, MiR-9, miR-96 and let-7. Several critical genes and relevant drugs, TFs and miRNAs were revealed in COAD. These findings could advance the understanding of the disease and benefit therapy development.
Full Text Available A stringent control of homeostasis is critical for functional maintenance and survival of neurons. In the mammalian retina, the basic motif leucine zipper transcription factor NRL determines rod versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. Here, we report an integrated analysis of NRL-centered gene regulatory network by coupling chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq data from Illumina and ABI platforms with global expression profiling and in vivo knockdown studies. We identified approximately 300 direct NRL target genes. Of these, 22 NRL targets are associated with human retinal dystrophies, whereas 95 mapped to regions of as yet uncloned retinal disease loci. In silico analysis of NRL ChIP-Seq peak sequences revealed an enrichment of distinct sets of transcription factor binding sites. Specifically, we discovered that genes involved in photoreceptor function include binding sites for both NRL and homeodomain protein CRX. Evaluation of 26 ChIP-Seq regions validated their enhancer functions in reporter assays. In vivo knockdown of 16 NRL target genes resulted in death or abnormal morphology of rod photoreceptors, suggesting their importance in maintaining retinal function. We also identified histone demethylase Kdm5b as a novel secondary node in NRL transcriptional hierarchy. Exon array analysis of flow-sorted photoreceptors in which Kdm5b was knocked down by shRNA indicated its role in regulating rod-expressed genes. Our studies identify candidate genes for retinal dystrophies, define cis-regulatory module(s for photoreceptor-expressed genes and provide a framework for decoding transcriptional regulatory networks that dictate rod homeostasis.
Full Text Available Efforts to unravel the mechanisms underlying taste sensation (gustation have largely focused on rodents. Here we present the first comprehensive characterization of gene expression in primate taste buds. Our findings reveal unique new insights into the biology of taste buds. We generated a taste bud gene expression database using laser capture microdissection (LCM procured fungiform (FG and circumvallate (CV taste buds from primates. We also used LCM to collect the top and bottom portions of CV taste buds. Affymetrix genome wide arrays were used to analyze gene expression in all samples. Known taste receptors are preferentially expressed in the top portion of taste buds. Genes associated with the cell cycle and stem cells are preferentially expressed in the bottom portion of taste buds, suggesting that precursor cells are located there. Several chemokines including CXCL14 and CXCL8 are among the highest expressed genes in taste buds, indicating that immune system related processes are active in taste buds. Several genes expressed specifically in endocrine glands including growth hormone releasing hormone and its receptor are also strongly expressed in taste buds, suggesting a link between metabolism and taste. Cell type-specific expression of transcription factors and signaling molecules involved in cell fate, including KIT, reveals the taste bud as an active site of cell regeneration, differentiation, and development. IKBKAP, a gene mutated in familial dysautonomia, a disease that results in loss of taste buds, is expressed in taste cells that communicate with afferent nerve fibers via synaptic transmission. This database highlights the power of LCM coupled with transcriptional profiling to dissect the molecular composition of normal tissues, represents the most comprehensive molecular analysis of primate taste buds to date, and provides a foundation for further studies in diverse aspects of taste biology.
Gould, A L; Dunlap, P V
Discrepancies between potential and observed dispersal distances of reef fish indicate the need for a better understanding of the influence of larval behaviour on recruitment and dispersal. Population genetic studies can provide insight on the degree to which populations are connected, and the development of restriction site-associated sequencing (RAD-Seq) methods has made such studies of nonmodel organisms more accessible. We applied double-digest RAD-Seq methods to test for population differentiation in the coral reef-dwelling cardinalfish, Siphamia tubifer, which based on behavioural studies, have the potential to use navigational cues to return to natal reefs. Analysis of 11,836 SNPs from fish collected at coral reefs in Okinawa, Japan, from eleven locations over 3 years reveals little genetic differentiation between groups of S. tubifer at spatial scales from 2 to 140 km and between years at one location: pairwise F ST values were between 0.0116 and 0.0214. These results suggest that the Kuroshio Current largely influences larval dispersal in the region, and in contrast to expectations based on studies of other cardinalfishes, there is no evidence of population structure for S. tubifer at the spatial scales examined. However, analyses of outlier loci putatively under selection reveal patterns of temporal differentiation that indicate high population turnover and variable larval supply from divergent source populations between years. These findings highlight the need for more studies of fishes across various geographic regions that also examine temporal patterns of genetic differentiation to better understand the potential connections between early life-history traits and connectivity of reef fish populations. © 2017 John Wiley & Sons Ltd.
Yang, M-R; Zhang, Y; Wu, X-X; Chen, W
RNA-seq data of hepatocellular carcinoma (HCC) was analyzed to identify critical genes related to the pathogenesis and prognosis. Three RNA-seq datasets of HCC (GSE69164, GSE63863 and GSE55758) were downloaded from Gene Expression Omnibus (GEO), while another dataset including 54 HCC cases with survival time was obtained from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were identified by significant analysis of microarrays (SAM) method using package samr of R. As followed, we constructed a protein-protein interaction (PPI) network based on the information in Human Protein Reference Database (HPRD). Modules in the PPI network were identified with MCODE method using plugin clusterViz of CytoScape. Gene Ontology (GO) enrichment analysis and pathway enrichment analysis were performed with DAVID. The difference in survival curves was analyzed with Kaplan-Meier (K-M) method using package survival. A total of 2572 DEGs were identified in the 3 datasets from GEO (GSE69164, GSE63863 and GSE55758). The PPI network was constructed including 660 nodes and 1008 edges, and 4 modules were disclosed in the network. Module A (containing 244 DEGs) was found to related to HCC closely, which genes were involved in transcription factor binding, protein metabolism as well as regulation of apoptosis. Nine hub genes were identified in the module A, including PRKCA, YWHAZ, KRT18, NDRG1, HSPA1A, HSP90AA1, HSF1, IKGKB and UBE21. The network provides the protein-protein interaction of these critical genes, which were implicated in the pathogenesis of HCC. Survival analysis showed that there is a significant difference between two groups classified by the genes in module A. Further Univariate Cox regression analysis showed that 72 genes were associated with survival time significantly, such as NPM1, PRKDC, SPARC, HMGA1, COL1A1 and COL1A2. Nine critical genes related to the pathogenesis and 72 potential prognostic markers were revealed in HCC by the network and module
Pinney John W
Full Text Available Abstract Background The neprilysin (M13 family of endopeptidases are zinc-metalloenzymes, the majority of which are type II integral membrane proteins. The best characterised of this family is neprilysin, which has important roles in inactivating signalling peptides involved in modulating neuronal activity, blood pressure and the immune system. Other family members include the endothelin converting enzymes (ECE-1 and ECE-2, which are responsible for the final step in the synthesis of potent vasoconstrictor endothelins. The ECEs, as well as neprilysin, are considered valuable therapeutic targets for treating cardiovascular disease. Other members of the M13 family have not been functionally characterised, but are also likely to have biological roles regulating peptide signalling. The recent sequencing of animal genomes has greatly increased the number of M13 family members in protein databases, information which can be used to reveal evolutionary relationships and to gain insight into conserved biological roles. Results The phylogenetic analysis successfully resolved vertebrate M13 peptidases into seven classes, one of which appears to be specific to mammals, and insect genes into five functional classes and a series of expansions, which may include inactive peptidases. Nematode genes primarily resolved into groups containing no other taxa, bar the two nematode genes associated with Drosophila DmeNEP1 and DmeNEP4. This analysis reconstructed only one relationship between chordate and invertebrate clusters, that of the ECE sub-group and the DmeNEP3 related genes. Analysis of amino acid utilisation in the active site of M13 peptidases reveals a basis for their biochemical properties. A relatively invariant S1' subsite gives the majority of M13 peptidases their strong preference for hydrophobic residues in P1' position. The greater variation in the S2' subsite may be instrumental in determining the specificity of M13 peptidases for their substrates
Liu, Feng; Sun, Fei; Xia, Jun Hong; Li, Jian; Fu, Gui Hong; Lin, Grace; Tu, Rong Jian; Wan, Zi Yi; Quek, Delia; Yue, Gen Hua
Growth is an important trait in animal breeding. However, the genetic effects underpinning fish growth variability are still poorly understood. QTL mapping and analysis of candidate genes are effective methods to address this issue. We conducted a genome-wide QTL analysis for growth in tilapia. A total of 10, 7 and 8 significant QTLs were identified for body weight, total length and standard length at 140 dph, respectively. The majority of these QTLs were sex-specific. One major QTL for growth traits was identified in the sex-determining locus in LG1, explaining 71.7%, 67.2% and 64.9% of the phenotypic variation (PV) of body weight, total length and standard length, respectively. In addition, a candidate gene GHR2 in a QTL was significantly associated with body weight, explaining 13.1% of PV. Real-time qPCR revealed that different genotypes at the GHR2 locus influenced the IGF-1 expression level. The markers located in the major QTL for growth traits could be used in marker-assisted selection of tilapia. The associations between GHR2 variants and growth traits suggest that the GHR2 gene should be an important gene that explains the difference in growth among tilapia species. PMID:25435025
Caroline S Fox
Full Text Available Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT, visceral adipose tissue (VAT, VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09, previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08. Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08, but not men (p = 0.75. Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006 but not men (p = 0.24 for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]. Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI; associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a
Hopkins, John B; Whittington, Jesse; Clevenger, Anthony P; Sawaya, Michael A; St Clair, Colleen Cassady
Human-wildlife conflict is a leading cause of adult mortality for large carnivores worldwide. Train collision is the primary cause of mortality for threatened grizzly bears (Ursus arctos) in Banff National Park. We investigated the use of stable isotope analysis as a tool for identifying bears that use the railway in Banff. Rail-associated bears had higher δ(15)N and δ(34)S values than bears sampled away from the rail, but similar δ(13)C values. Because elevated δ(15)N values are indicative of higher animal protein consumption, rail-associated bears likely preyed on ungulates that foraged along the rail or scavenged on train-killed animals. The higher δ(34)S values in bear hair could have resulted from bears consuming sulfur pellets spilled on the rail or through the uptake of sulfur in the plants bears or animals consumed. Similar δ(13)C values suggest that the two types of bears had generally similar plant-based diets. Results from this study suggest that stable isotopes analysis could be used as a non-invasive, affordable, and efficient technique to identify and monitor bears that forage on the railway in Banff and potentially other transportation corridors worldwide.
Fabyano Fonseca e Silva
Full Text Available ABSTRACT: Genome association analyses have been successful in identifying quantitative trait loci (QTLs for pig body weights measured at a single age. However, when considering the whole weight trajectories over time in the context of genome association analyses, it is important to look at the markers that affect growth curve parameters. The easiest way to consider them is via the two-step method, in which the growth curve parameters and marker effects are estimated separately, thereby resulting in a reduction of the statistical power and the precision of estimates. One efficient solution is to adopt nonlinear mixed models (NMM, which enables a joint modeling of the individual growth curves and marker effects. Our aim was to propose a genome association analysis for growth curves in pigs based on NMM as well as to compare it with the traditional two-step method. In addition, we also aimed to identify the nearest candidate genes related to significant SNP (single nucleotide polymorphism markers. The NMM presented a higher number of significant SNPs for adult weight (A and maturity rate (K, and provided a direct way to test SNP significance simultaneously for both the A and K parameters. Furthermore, all significant SNPs from the two-step method were also reported in the NMM analysis. The ontology of the three candidate genes (SH3BGRL2, MAPK14, and MYL9 derived from significant SNPs (simultaneously affecting A and K allows us to make inferences with regards to their contribution to the pig growth process in the population studied.
Völksch, Beate; Thon, Susanne; Jacobsen, Ilse D; Gube, Matthias
Pantoea species are ubiquitous in nature and occasionally associated with infections caused by contaminated clinical material. Hence, Pantoea agglomerans is considered as an opportunistic pathogen of humans. Since species of the genus Pantoea and closely related species of other Enterobacteriaceae genera are phenotypically very similar, many clinical isolates are misassigned into P. agglomerans based on the use of quick commercial-offered biochemical tests. Our objective was to find markers enabling discrimination between clinical and plant isolates and to assess their virulence potential. We characterized 27 Pantoea strains, including 8 P. agglomerans isolates of clinical, and 11 of plant origin by biochemical tests and genotyping, including analysis of 16S rDNA and gapA gene sequences, and pattern polymorphisms of ITS- and ERIC/REP-DNA. All data showed that no discrete evolution occurred between plant-associated and clinical P. agglomerans isolates. Based on the typing results, five clinical- and five plant-associated P. agglomerans strains representing the majority of clades were tested on a model plant and in embryonated eggs. On soybean plants P. agglomerans strains independent of their origin could develop stable epiphytic populations. Surprisingly, in the embryonated egg model there was no difference of virulence between clinical and vegetable P. agglomerans isolates. However, these strains were significantly less virulent than a phytopathogenic P. ananatis isolate. We suggest that, independent of their origin, all P. agglomerans strains might possess indistinguishable virulence potential.
Batts, W.N.; Falk, K.; Winton, J.R.
Viruses with the morphological and biochemical characteristics of the family Paramyxoviridae (paramyxoviruses) have been isolated from adult salmon returning to rivers along the Pacific coast of North America since 1982. These Pacific salmon paramyxoviruses (PSPV), which have mainly been isolated from Chinook salmon Oncorhynchus tshawytscha, grow slowly in established fish cell lines and have not been associated with disease. Genetic analysis of a 505-base-pair region of the polymerase gene from 47 PsPV isolates produced 17 nucleotide sequence types that could be grouped into two major sublineages, designated A and B. The two independently co-circulating sublineages differed by 12.1-13.9% at the nucleotide level but by only 1.2% at the amino acid level. Isolates of PSPV from adult Pacific salmon returning to rivers from Alaska to California over a 25-year period showed little evidence of geographic or temporal grouping. Phylogenetic analyses revealed that these paramyxoviruses of Pacific salmon were most closely related to the Atlantic salmon paramyxovirus (ASPV) from Norway, having a maximum nucleotide diversity of 26.1 % and an amino acid diversity of 19.0%. When compared with homologous sequences of other paramyxoviruses, PSPV and ASPV were sufficiently distinct to suggest that they are not clearly members of any of the established genera in the family Paramyxoviridae. in the course of this study, a polymerase chain reaction assay was developed that can be used for confirmatory identification of PSPV. ?? Copyright by the American Fisheries Society 2008.
Lin, Yuan-Pin; Duann, Jeng-Ren; Feng, Wenfeng; Chen, Jyh-Horng; Jung, Tzyy-Ping
Music conveys emotion by manipulating musical structures, particularly musical mode- and tempo-impact. The neural correlates of musical mode and tempo perception revealed by electroencephalography (EEG) have not been adequately addressed in the literature. This study used independent component analysis (ICA) to systematically assess spatio-spectral EEG dynamics associated with the changes of musical mode and tempo. Empirical results showed that music with major mode augmented delta-band activity over the right sensorimotor cortex, suppressed theta activity over the superior parietal cortex, and moderately suppressed beta activity over the medial frontal cortex, compared to minor-mode music, whereas fast-tempo music engaged significant alpha suppression over the right sensorimotor cortex. The resultant EEG brain sources were comparable with previous studies obtained by other neuroimaging modalities, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). In conjunction with advanced dry and mobile EEG technology, the EEG results might facilitate the translation from laboratory-oriented research to real-life applications for music therapy, training and entertainment in naturalistic environments.
Pezzoli, Patrizia; Antfolk, Jan; Santtila, Pekka
Comorbidity challenges the notion of mental disorders as discrete categories. An increasing body of literature shows that symptoms cut across traditional diagnostic boundaries and interact in shaping the latent structure of psychopathology. Using exploratory and confirmatory factor analysis, we reveal the latent sources of covariation among nine measures of psychopathological functioning in a population-based sample of 13024 Finnish twins and their siblings. By implementing unidimensional, multidimensional, second-order, and bifactor models, we illustrate the relationships between observed variables, specific, and general latent factors. We also provide the first investigation to date of measurement invariance of the bifactor model of psychopathology across gender and age groups. Our main result is the identification of a distinct "Body" factor, alongside the previously identified Internalizing and Externalizing factors. We also report relevant cross-disorder associations, especially between body-related psychopathology and trait anger, as well as substantial sex and age differences in observed and latent means. The findings expand the meta-structure of psychopathology, with implications for empirical and clinical practice, and demonstrate shared mechanisms underlying attitudes towards nutrition, self-image, sexuality and anger, with gender- and age-specific features.
Myintzu Hlaing, Mya; Wood, Bayden; McNaughton, Don; Ying, DanYan; Augustin, Mary Ann
Dehydration of bacterial cells elicits cellular stress responses in bacteria. Microencapsulation has been used to protect cells against the environmental stress. In this study, Confocal Raman Spectroscopy was used to examine DNA changes in the chemical composition of non-encapsulated and microencapsulated Lactobacillus rhamnosus GG and the reversibility of these changes upon freeze drying and rehydration. The viability of cells upon freeze drying was also enumerated using culture methods and membrane integrity was measured using BacLight Live/Dead staining. Raman analyses show changes in the spectral features associated with various biochemical compounds, which are interpreted as the result of detrimental freeze drying effects on the bacterial cells. Specifically, analyses based on Principal Components Analysis (PCA) of Raman spectra, confirm that microencapsulation protects cells from environmental stress. The results also reveal a B- to A-like DNA conformation change in dormant cells that provided insights into the extent of reversibility of this transition upon rehydration. The extent of this reversibility is less in non-encapsulated than in microencapsulated cells. These findings indicate the potential application of Raman spectroscopy in rapid sensing of microbial dehydration stress responses. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Johnson, Brant R.; Hymes, Jeffrey; Sanozky-Dawes, Rosemary; Henriksen, Emily DeCrescenzo
The Lactobacillus acidophilus homology group comprises Gram-positive species that include L. acidophilus, L. helveticus, L. crispatus, L. amylovorus, L. gallinarum, L. delbrueckii subsp. bulgaricus, L. gasseri, and L. johnsonii. While these bacteria are closely related, they have varied ecological lifestyles as dairy and food fermenters, allochthonous probiotics, or autochthonous commensals of the host gastrointestinal tract. Bacterial cell surface components play a critical role in the molecular dialogue between bacteria and interaction signaling with the intestinal mucosa. Notably, the L. acidophilus complex is distinguished in two clades by the presence or absence of S-layers, which are semiporous crystalline arrays of self-assembling proteinaceous subunits found as the outermost layer of the bacterial cell wall. In this study, S-layer-associated proteins (SLAPs) in the exoproteomes of various S-layer-forming Lactobacillus species were proteomically identified, genomically compared, and transcriptionally analyzed. Four gene regions encoding six putative SLAPs were conserved in the S-layer-forming Lactobacillus species but not identified in the extracts of the closely related progenitor, L. delbrueckii subsp. bulgaricus, which does not produce an S-layer. Therefore, the presence or absence of an S-layer has a clear impact on the exoproteomic composition of Lactobacillus species. This proteomic complexity and differences in the cell surface properties between S-layer- and non-S-layer-forming lactobacilli reveal the potential for SLAPs to mediate intimate probiotic interactions and signaling with the host intestinal mucosa. PMID:26475115
Díaz-Gimeno, Patricia; Ruiz-Alonso, Maria; Sebastian-Leon, Patricia; Pellicer, Antonio; Valbuena, Diana; Simón, Carlos
To refine the endometrial window of implantation (WOI) transcriptomic signature by defining new subsignatures associated to live birth and biochemical pregnancy. Retrospective cohort study. University-affiliated in vitro fertilization clinic and reproductive genetics laboratory. Healthy fertile oocyte donors (n = 79) and patients with infertility diagnosed by Endometrial Receptivity Analysis (n = 771). None. WOI transcriptomic signatures associated with specific reproductive outcomes. The retrospective cohort study was designed to perform a prediction model based on transcriptomic clusters for endometrial classification (training set, n = 529). The clinical follow-up set in the expected WOI (n = 321) was tested with the transcriptomic predictor to detect WOI variability and the pregnancy outcomes associated with these subsignatures (n = 228). The endometrial receptivity signature was redefined into four WOI transcriptomic profiles. This stratification identified an optimal endometrial receptivity (RR) signature resulting in an ongoing pregnancy rate (OPR) of 80% in terms of live birth, as well as a late receptive-stage (LR) signature with a potential high risk of 50% biochemical pregnancy. Abnormal down-regulation of the cell cycle was the main dysregulated function among the 22 genes associated with biochemical pregnancy. The major differences between the WOI transcriptomic stratification were in the OPR and biochemical pregnancy rate. The OPR ranged from 76.9% and 80% in the late prereceptive (LPR) and RR signatures, respectively, versus 33.3% in the LR. The biochemical pregnancy rate was 7.7% and 6.6% in LPR and RR, respectively, but 50% in LR, which highlights the relevance of endometrial status in the progression of embryonic implantation. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Weingarten, Rebecca A; Johnson, Ryan C; Conlan, Sean; Ramsburg, Amanda M; Dekker, John P; Lau, Anna F; Khil, Pavel; Odom, Robin T; Deming, Clay; Park, Morgan; Thomas, Pamela J; Henderson, David K; Palmore, Tara N; Segre, Julia A; Frank, Karen M
The hospital environment is a potential reservoir of bacteria with plasmids conferring carbapenem resistance. Our Hospital Epidemiology Service routinely performs extensive sampling of high-touch surfaces, sinks, and other locations in the hospital. Over a 2-year period, additional sampling was conducted at a broader range of locations, including housekeeping closets, wastewater from hospital internal pipes, and external manholes. We compared these data with previously collected information from 5 years of patient clinical and surveillance isolates. Whole-genome sequencing and analysis of 108 isolates provided comprehensive characterization of bla KPC / bla NDM -positive isolates, enabling an in-depth genetic comparison. Strikingly, despite a very low prevalence of patient infections with bla KPC -positive organisms, all samples from the intensive care unit pipe wastewater and external manholes contained carbapenemase-producing organisms (CPOs), suggesting a vast, resilient reservoir. We observed a diverse set of species and plasmids, and we noted species and susceptibility profile differences between environmental and patient populations of CPOs. However, there were plasmid backbones common to both populations, highlighting a potential environmental reservoir of mobile elements that may contribute to the spread of resistance genes. Clear associations between patient and environmental isolates were uncommon based on sequence analysis and epidemiology, suggesting reasonable infection control compliance at our institution. Nonetheless, a probable nosocomial transmission of Leclercia sp. from the housekeeping environment to a patient was detected by this extensive surveillance. These data and analyses further our understanding of CPOs in the hospital environment and are broadly relevant to the design of infection control strategies in many infrastructure settings. IMPORTANCE Carbapenemase-producing organisms (CPOs) are a global concern because of the morbidity and
Full Text Available Wheat seed development is an important physiological process of seed maturation and directly affects wheat yield and quality. In this study, we performed dynamic transcriptome microarray analysis of an elite Chinese bread wheat cultivar (Jimai 20 during grain development using the GeneChip Wheat Genome Array. Grain morphology and scanning electron microscope observations showed that the period of 11–15 days post-anthesis (DPA was a key stage for the synthesis and accumulation of seed starch. Genome-wide transcriptional profiling and significance analysis of microarrays revealed that the period from 11 to 15 DPA was more important than the 15–20 DPA stage for the synthesis and accumulation of nutritive reserves. Series test of cluster analysis of differential genes revealed five statistically significant gene expression profiles. Gene ontology annotation and enrichment analysis gave further information about differentially expressed genes, and MapMan analysis revealed expression changes within functional groups during seed development. Metabolic pathway network analysis showed that major and minor metabolic pathways regulate one another to ensure regular seed development and nutritive reserve accumulation. We performed gene co-expression network analysis to identify genes that play vital roles in seed development and identified several key genes involved in important metabolic pathways. The transcriptional expression of eight key genes involved in starch and protein synthesis and stress defense was further validated by qRT-PCR. Our results provide new insight into the molecular mechanisms of wheat seed development and the determinants of yield and quality.
Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive fatal multisystemic neurodegenerative disorder caused by preferential degeneration of upper and lower motor neurons. To further delineate the genetic architecture of the disease, we used comprehensive panel sequencing in a cohort of 80 German ALS patients. The panel covered 39 confirmed ALS genes and candidate genes, as well as 238 genes associated with other entities of the neurodegenerative disease spectrum. In addition, we performed repeat length analysis for C9orf72. Our aim was to (1 identify potentially disease-causing variants, to (2 assess a proposed model of polygenic inheritance in ALS and to (3 connect ALS with other neurodegenerative entities.We identified 79 rare potentially pathogenic variants in 27 ALS associated genes in familial and sporadic cases. Five patients had pathogenic C9orf72 repeat expansions, a further four patients harbored intermediate length repeat expansions. Our findings demonstrate that a genetic background of the disease can actually be found in a large proportion of seemingly sporadic cases and that it is not limited to putative most frequently affected genes such as C9orf72 or SOD1. Assessing the polygenic nature of ALS, we identified 15 patients carrying at least two rare potentially pathogenic variants in ALS associated genes including pathogenic or intermediate C9orf72 repeat expansions. Multiple variants might influence severity or duration of disease or could account for intrafamilial phenotypic variability or reduced penetrance. However, we could not observe a correlation with age of onset in this study. We further detected potentially pathogenic variants in other neurodegeneration associated genes in 12 patients, supporting the hypothesis of common pathways in neurodegenerative diseases and linking ALS to other entities of the neurodegenerative spectrum. Most interestingly we found variants in GBE1 and SPG7 which might represent differential diagnoses
Full Text Available Abstract Background Understanding the evolution of cultivated barley is important for two reasons. First, the evolutionary relationships between different landraces might provide information on the spread and subsequent development of barley cultivation, including the adaptation of the crop to new environments and its response to human selection. Second, evolutionary information would enable landraces with similar traits but different genetic backgrounds to be identified, providing alternative strategies for the introduction of these traits into modern germplasm. Results The evolutionary relationships between 651 barley landraces were inferred from the genotypes for 24 microsatellites. The landraces could be divided into nine populations, each with a different geographical distribution. Comparisons with ear row number, caryopsis structure, seasonal growth habit and flowering time revealed a degree of association between population structure and phenotype, and analysis of climate variables indicated that the landraces are adapted, at least to some extent, to their environment. Human selection and/or environmental adaptation may therefore have played a role in the origin and/or maintenance of one or more of the barley landrace populations. There was also evidence that at least some of the population structure derived from geographical partitioning set up during the initial spread of barley cultivation into Europe, or reflected the later introduction of novel varieties. In particular, three closely-related populations were made up almost entirely of plants with the daylength nonresponsive version of the photoperiod response gene PPD-H1, conferring adaptation to the long annual growth season of northern Europe. These three populations probably originated in the eastern Fertile Crescent and entered Europe after the initial spread of agriculture. Conclusions The discovery of population structure, combined with knowledge of associated phenotypes and
Veeramah, Krishna R; Rott, Andreas; Groß, Melanie; van Dorp, Lucy; López, Saioa; Kirsanow, Karola; Sell, Christian; Blöcher, Jens; Wegmann, Daniel; Link, Vivian; Hofmanová, Zuzana; Peters, Joris; Trautmann, Bernd; Gairhos, Anja; Haberstroh, Jochen; Päffgen, Bernd; Hellenthal, Garrett; Haas-Gebhard, Brigitte; Harbeck, Michaela; Burger, Joachim
Modern European genetic structure demonstrates strong correlations with geography, while genetic analysis of prehistoric humans has indicated at least two major waves of immigration from outside the continent during periods of cultural change. However, population-level genome data that could shed light on the demographic processes occurring during the intervening periods have been absent. Therefore, we generated genomic data from 41 individuals dating mostly to the late 5th/early 6th century AD from present-day Bavaria in southern Germany, including 11 whole genomes (mean depth 5.56×). In addition we developed a capture array to sequence neutral regions spanning a total of 5 Mb and 486 functional polymorphic sites to high depth (mean 72×) in all individuals. Our data indicate that while men generally had ancestry that closely resembles modern northern and central Europeans, women exhibit a very high genetic heterogeneity; this includes signals of genetic ancestry ranging from western Europe to East Asia. Particularly striking are women with artificial skull deformations; the analysis of their collective genetic ancestry suggests an origin in southeastern Europe. In addition, functional variants indicate that they also differed in visible characteristics. This example of female-biased migration indicates that complex demographic processes during the Early Medieval period may have contributed in an unexpected way to shape the modern European genetic landscape. Examination of the panel of functional loci also revealed that many alleles associated with recent positive selection were already at modern-like frequencies in European populations ∼1,500 years ago. Copyright © 2018 the Author(s). Published by PNAS.
Haider, Muhammad S; Kurjogi, Mahantesh M; Khalil-Ur-Rehman, M; Fiaz, Muhammad; Pervaiz, Tariq; Jiu, Songtao; Haifeng, Jia; Chen, Wang; Fang, Jinggui
Drought is a ubiquitous abiotic factor that severely impedes growth and development of horticulture crops. The challenge postured by global climate change is the evolution of drought-tolerant cultivars that could cope with concurrent stress. Hence, in this study, biochemical, physiological and transcriptome analysis were investigated in drought-treated grapevine leaves. The results revealed that photosynthetic activity and reducing sugars were significantly diminished which were positively correlated with low stomatal conductance and CO 2 exchange in drought-stressed leaves. Further, the activities of superoxide dismutase, peroxidase, and catalase were significantly actuated in the drought-responsive grapevine leaves. Similarly, the levels of abscisic acid and jasmonic acid were also significantly increased in the drought-stressed leaves. In transcriptome analysis, 12,451 differentially-expressed genes (DEGs) were annotated, out of which 8021 DEGs were up-regulated and 4430 DEGs were down-regulated in response to drought stress. In addition, the genes encoding pathogen-associated molecular pattern (PAMP) triggered immunity (PTI), including calcium signals, protein phosphatase 2C, calcineurin B-like proteins, MAPKs, and phosphorylation (FLS2 and MEKK1) cascades were up-regulated in response to drought stress. Several genes related to plant-pathogen interaction pathway (RPM1, PBS1, RPS5, RIN4, MIN7, PR1, and WRKYs) were also found up-regulated in response to drought stress. Overall the results of present study showed the dynamic interaction of DEG in grapevine physiology which provides the premise for selection of defense-related genes against drought stress for subsequent grapevine breeding programs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Duncan, Laramie; Yilmaz, Zeynep; Gaspar, Helena; Walters, Raymond; Goldstein, Jackie; Anttila, Verneri; Bulik-Sullivan, Brendan; Ripke, Stephan; Thornton, Laura; Hinney, Anke; Daly, Mark; Sullivan, Patrick F; Zeggini, Eleftheria; Breen, Gerome; Bulik, Cynthia M
The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h 2 SNP ]), partitioned heritability, and genetic correlations (r g ) between anorexia nervosa and 159 other phenotypes. Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h 2 SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.
Full Text Available Rice (Oryza sativa L. is the only cereal crop that possesses the ability to germinate under flooded or other oxygen-deficient conditions. Rapid elongation of the coleoptile is a perfect response to flooding during germination, with coleoptile length differing among various rice varieties. Despite multiple studies have uncovered valuable information concerning this trait by focusing on the physiological metabolism of oxygen stress, the underlying genetic mechanism still remains unknown. In the present study, we screened coleoptile lengths of 432 indica varieties germinated in two environments (normal and flooded and found more variation existing in flooded coleoptile length (FCL rather than in normal coleoptile length (NCL. With the phenotypic data of NCL, FCL and FTI (flooding tolerance index, a genome-wide association study was performed by using 5291 single nucleotide polymorphism (SNP markers. We detected 2, 11, and 9 significant SNPs under a mixed linear mode for NCL, FCL, and FTI, respectively. Of these SNPs, five were shared by FCL and FTI. Haplotype and phenotype effect analysis on the highest ranking locus indicated one of the two haplotypes contributed to coleoptile elongation remarkably. To better understand the controlling gene of this locus, reported expression profile data was applied. We focused on LOC_Os06g03520, a candidate gene which was highly induced by anoxia (∼507 fold. Sequence analysis in 51 varieties demonstrated Hap.2 associated perfectly with flooding tolerance. Further studies on this gene may help explore the molecular mechanism of rice flooding tolerance during germination. We believe our discoveries may conduce to isolating major genes and aid the improvement of flooding tolerance in modern breeding programs.
Yue Sheng; Wei Zhao; Ying Song; Zhigang Li; Majing Luo; Quan Lei; Hanhua Cheng; Rongjia Zhou
A variety of mechanisms are engaged in sex determination in vertebrates. The teleost fish swamp eel undergoes sex reversal naturally and is an ideal model for vertebrate sexual development. However, the importance of proteome-wide scanning for gonad reversal was not previously determined. We report a 2-D electrophoresis analysis of three gonad types of proteomes during sex reversal. MS/MS analysis revealed a group of differentially expressed proteins during ovary to ovotestis to testis transf...
Stern, Adi; Mick, Eran; Tirosh, Itay; Sagy, Or; Sorek, Rotem
The bacterial community in the human gut has crucial health roles both in metabolic functions and in protection against pathogens. Phages, which are known to significantly affect microbial community composition in many ecological niches, have the potential to impact the gut microbiota, yet thorough characterization of this relationship remains elusive. We have reconstructed the content of the CRISPR bacterial immune system in the human gut microbiomes of 124 European individuals and used it to identify a catalog of 991 phages targeted by CRISPR across all individuals. Our results show that 78% of these phages are shared among two or more individuals. Moreover, a significant fraction of phages found in our study are shown to exist in fecal samples previously derived from American and Japanese individuals, identifying a common reservoir of phages frequently associated with the human gut microbiome. We further inferred the bacterial hosts for more than 130 such phages, enabling a detailed analysis of phage–bacteria interactions across the 124 individuals by correlating patterns of phage abundance with bacterial abundance and resistance. A subset of phages demonstrated preferred association with host genomes as lysogenized prophages, with highly increased abundance in specific individuals. Overall, our results imply that phage–bacterial attack–resistance interactions occur within the human gut microbiome, possibly affecting microbiota composition and human health. Our finding of global sharing of gut phages is surprising in light of the extreme genetic diversity of phages found in other ecological niches. PMID:22732228
Neave, Matthew J.
Endozoicomonas bacteria are globally distributed and often abundantly associated with diverse marine hosts including reef-building corals, yet their function remains unknown. In this study we generated novel Endozoicomonas genomes from single cells and metagenomes obtained directly from the corals Stylophora pistillata, Pocillopora verrucosa, and Acropora humilis. We then compared these culture-independent genomes to existing genomes of bacterial isolates acquired from a sponge, sea slug, and coral to examine the functional landscape of this enigmatic genus. Sequencing and analysis of single cells and metagenomes resulted in four novel genomes with 60–76% and 81–90% genome completeness, respectively. These data also confirmed that Endozoicomonas genomes are large and are not streamlined for an obligate endosymbiotic lifestyle, implying that they have free-living stages. All genomes show an enrichment of genes associated with carbon sugar transport and utilization and protein secretion, potentially indicating that Endozoicomonas contribute to the cycling of carbohydrates and the provision of proteins to their respective hosts. Importantly, besides these commonalities, the genomes showed evidence for differential functional specificity and diversification, including genes for the production of amino acids. Given this metabolic diversity of Endozoicomonas we propose that different genotypes play disparate roles and have diversified in concert with their hosts.
Kevin Barnett; Carol Miller; Tyron J. Venn
A goal of fire management in wilderness is to allow fire to play its natural ecological role without intervention. Unfortunately, most unplanned ignitions in wilderness are suppressed, in part because of the risk they might pose to values outside of the wilderness. We capitalize on recent advances in fire risk analysis to demonstrate a risk-based approach for revealing...
Ashoori, Maryam; Burns, Catherine M.; d'Entremont, Barbara; Momtahan, Kathryn
Cognitive work analysis (CWA) as an analytical approach for examining complex sociotechnical systems has shown success in modelling the work of single operators. The CWA approach incorporates social and team interactions, but a more explicit analysis of team aspects can reveal more information for systems design. In this paper, Team CWA is explored to understand teamwork within a birthing unit at a hospital. Team CWA models are derived from theories and models of teamworkand leverage the existing CWA approaches to analyse team interactions. Team CWA is explained and contrasted with prior approaches to CWA. Team CWA does not replace CWA, but supplements traditional CWA to more easily reveal team information. As a result, Team CWA may be a useful approach to enhance CWA in complex environments where effective teamwork is required. Practitioner Summary: This paper looks at ways of analysing cognitive work in healthcare teams. Team Cognitive Work Analysis, when used to supplement traditional Cognitive Work Analysis, revealed more team information than traditional Cognitive Work Analysis. Team Cognitive Work Analysis should be considered when studying teams PMID:24837514
Ashoori, Maryam; Burns, Catherine M; d'Entremont, Barbara; Momtahan, Kathryn
Cognitive work analysis (CWA) as an analytical approach for examining complex sociotechnical systems has shown success in modelling the work of single operators. The CWA approach incorporates social and team interactions, but a more explicit analysis of team aspects can reveal more information for systems design. In this paper, Team CWA is explored to understand teamwork within a birthing unit at a hospital. Team CWA models are derived from theories and models of teamwork and leverage the existing CWA approaches to analyse team interactions. Team CWA is explained and contrasted with prior approaches to CWA. Team CWA does not replace CWA, but supplements traditional CWA to more easily reveal team information. As a result, Team CWA may be a useful approach to enhance CWA in complex environments where effective teamwork is required. This paper looks at ways of analysing cognitive work in healthcare teams. Team Cognitive Work Analysis, when used to supplement traditional Cognitive Work Analysis, revealed more team information than traditional Cognitive Work Analysis. Team Cognitive Work Analysis should be considered when studying teams.
Maroofian, Reza; Riemersma, Moniek; Jae, Lucas T; Zhianabed, Narges; Willemsen, Marjolein H; Wissink-Lindhout, Willemijn M; Willemsen, Michèl A; de Brouwer, Arjan P M; Mehrjardi, Mohammad Yahya Vahidi; Ashrafi, Mahmoud Reza; Kusters, Benno; Kleefstra, Tjitske; Jamshidi, Yalda; Nasseri, Mojila; Pfundt, Rolph; Brummelkamp, Thijn R; Abbaszadegan, Mohammad Reza; Lefeber, Dirk J; van Bokhoven, Hans
The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2. The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes. In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.
Cobb, K. M.; Orland, I. J.; Carolin, S.; Adkins, J. F.; Valley, J. W.; Jersild, A.; LeGrande, A. N.; Colose, C.
The Toba super-eruption occurred in close association with an abrupt climate transition from Greenland Interstadial (GI-) 20 to Greenland Stadial (GS-) 20, roughly 74 thousand years ago. However, recent attempts to characterize either the regional or global climate response to Toba have been limited by a lack of age control, geographic proximity, and/or convincing marker of the major eruption in most high-resolution paleoclimate archives. Here, we use a suite of micro-scale analytical techniques to evaluate the oxygen isotopic and geochemical composition of multiple stalagmites that grew across the Toba interval in Gunung Mulu National Park, northern Borneo. New timeseries of stalagmite d18O at 50-micron scales across the Toba horizon revleal a large (>1‰), rapid (segments across the Toba horizon in two well-dated stalagmites previously published in Carolin et al., 2013 and Caroline et al., 2014. The SIMS d18O data reveal high-frequency d18O excursions of +2 and -2 per mil during the transition from GI-20 (warm conditions) to Greenland Stadial GS-20 (cool conditions), suggesting that this period was characterized by large fluctuations in regional hydroclimate in the western tropical Pacific, with potentially profound impacts on global atmospheric circulation. We also present results from synchrotron analyses of ash-related elements (S, P, Si, and Al) to resolve the number and relative magnitude of Toba-related eruptions as recorded in several different stalagmites from Borneo, where ash layers likely exceeded 2cm on the overlying terrain. Together, these results indicate that large, rapid ( 10yr-long) environmental changes with marked effects on both the vegetation and hydroclimate above the cave may have been triggered by discrete eruptions of the Toba caldera. We investigate the regional hydroclimate responses to the Toba super-eruption in the isotope-equipped NASA-GISS coupled climate model across a range of eruption sizes, number, and duration.
Lewis, S L; Holl, H M; Streeter, C; Posbergh, C; Schanbacher, B J; Place, N J; Mallicote, M F; Long, M T; Brooks, S A
Equine obesity can cause life-threatening secondary chronic conditions, similar to those in humans and other animal species. Equine metabolic syndrome (EMS), primarily characterized by hyperinsulinemia, is often present in obese horses and ponies. Due to clinical similarities to conditions such as pituitary pars intermedia dysfunction (formerly equine Cushing's disease), conclusive diagnosis of EMS often proves challenging. Aside from changes in diet and exercise, few targeted treatments are available for EMS, emphasizing the need for early identification of at-risk individuals to enable implementation of preventative measures. A genomewide association study (GWAS) using Arabian horses with a history of severe laminitis secondary to EMS revealed significant genetic markers near a single candidate gene () that may play a role in cholesterol homeostasis. The best marker, BIEC2-263524 (chr14:69276814 T > C), was correlated with elevated insulin values and increased frequency of laminitis ( = 0.0024 and = 9.663 × 10, respectively). In a second population of Arabian horses, the BIEC2-263524 marker maintained its associations with higher modified insulin-to-glucose ratio (MIRG) values ( = 0.0056) and BCS ( = 0.0063). Screening of the predicted coding regions by sequencing identified a polymorphic guanine homopolymer and 5 haplotypes in the 3' untranslated region (UTR). An 11 guanine (11-G) allele at was correlated with elevated insulin values in the GWAS population ( = 0.0008) and, in the second population, elevated MIRG and increased BCS > 6.5 ( = 0.0055 and = 0.0162, respectively). The BIEC2-263524-C and the 3' UTR -11(G) polymorphisms were correlated at a 98% frequency, indicating strong linkage disequilibrium across this 150-kb haplotype. Assays for these markers could diagnose horses with a genetic predisposition to develop obesity. Additionally, discovery of FAM174A function may improve our understanding of the etiology of this troubling illness in the horse and
Haddon, D James; Diep, Vivian K; Price, Jordan V; Limb, Cindy; Utz, Paul J; Balboni, Imelda
nephritis with 91 % accuracy. Autoantigen microarrays are an ideal platform for identifying autoantibodies associated with both pSLE and specific clinical manifestations of pSLE. Using multiple regression analysis to integrate autoantibody and clinical data permits accurate prediction of clinical manifestations with complex etiologies in pSLE.
Sousa, Leijiane F; Portes-Junior, José A; Nicolau, Carolina A; Bernardoni, Juliana L; Nishiyama, Milton Y; Amazonas, Diana R; Freitas-de-Sousa, Luciana A; Mourão, Rosa Hv; Chalkidis, Hipócrates M; Valente, Richard H; Moura-da-Silva, Ana M
Venom variability is commonly reported for venomous snakes including Bothrops atrox. Here, we compared the composition of venoms from B. atrox snakes collected at Amazonian conserved habitats (terra-firme upland forest and várzea) and human modified areas (pasture and degraded areas). Venom samples were submitted to shotgun proteomic analysis as a whole or compared after fractionation by reversed-phase chromatography. Whole venom proteomes revealed a similar composition among the venoms with predominance of SVMPs, CTLs, and SVSPs and intermediate amounts of PLA 2 s and LAAOs. However, when distribution of particular isoforms was analyzed by either method, the venom from várzea snakes showed a decrease in hemorrhagic SVMPs and an increase in SVSPs, and procoagulant SVMPs and PLA 2 s. These differences were validated by experimental approaches including both enzymatic and in vivo assays, and indicated restrictions in respect to antivenom efficacy to variable components. Thus, proteomic analysis at the isoform level combined to in silico prediction of functional properties may indicate venom biological activity. These results also suggest that the prevalence of functionally distinct isoforms contributes to the variability of the venoms and could reflect the adaptation of B. atrox to distinct prey communities in different Amazon habitats. In this report, we compared isoforms present in venoms from snakes collected at different Amazonian habitats. By means of a species venom gland transcriptome and the in silico functional prediction of each isoform, we were able to predict the principal venom activities in vitro and in animal models. We also showed remarkable differences in the venom pools from snakes collected at the floodplain (várzea habitat) compared to other habitats. Not only was this venom less hemorrhagic and more procoagulant, when compared to the venom pools from the other three habitats studied, but also this enhanced procoagulant activity was not
Groenen Martien AM
Full Text Available Abstract Background In many countries, male piglets are castrated shortly after birth because a proportion of un-castrated male pigs produce meat with an unpleasant flavour and odour. Main compounds of boar taint are androstenone and skatole. The aim of this high-density genome-wide association study was to identify single nucleotide polymorphisms (SNPs associated with androstenone levels in a commercial sire line of pigs. The identification of major genetic effects causing boar taint would accelerate the reduction of boar taint through breeding to finally eliminate the need for castration. Results The Illumina Porcine 60K+SNP Beadchip was genotyped on 987 pigs divergent for androstenone concentration from a commercial Duroc-based sire line. The association analysis with 47,897 SNPs revealed that androstenone levels in fat tissue were significantly affected by 37 SNPs on pig chromosomes SSC1 and SSC6. Among them, the 5 most significant SNPs explained together 13.7% of the genetic variance in androstenone. On SSC6, a larger region of 10 Mb was shown to be associated with androstenone covering several candidate genes potentially involved in the synthesis and metabolism of androgens. Besides known candidate genes, such as cytochrome P450 A19 (CYP2A19, sulfotransferases SULT2A1, and SULT2B1, also new members of the cytochrome P450 CYP2 gene subfamilies and of the hydroxysteroid-dehydrogenases (HSD17B14 were found. In addition, the gene encoding the ß-chain of the luteinizing hormone (LHB which induces steroid synthesis in the Leydig cells of the testis at onset of puberty maps to this area on SSC6. Interestingly, the gene encoding the α-chain of LH is also located in one of the highly significant areas on SSC1. Conclusions This study reveals several areas of the genome at high resolution responsible for variation of androstenone levels in intact boars. Major genetic factors on SSC1 and SSC6 showing moderate to large effects on androstenone
Acharya, R.N.; Mondal, R.K.; Burte, P.P.; Nair, A.G.C.; Reddy, N.B.Y.; Reddy, L.K.; Reddy, A.V.R.; Manohar, S.B.
Multi-element analysis was carried out in natural emeralds, their associated rocks and one sample of beryl obtained from Rajasthan, India. The concentrations of 21 elements were assayed by Instrumental Neutron Activation Analysis using the k 0 method (k 0 INAA method) and high-resolution gamma ray spectrometry. The data reveal the segregation of some elements from associated (trapped and host) rocks to the mineral beryl forming the gemstones. A reference rock standard of the US Geological Survey (USGS BCR-1) was also analysed as a control of the method
Acharya; Mondal; Burte; Nair; Reddy; Reddy; Reddy; Manohar
Multi-element analysis was carried out in natural emeralds, their associated rocks and one sample of beryl obtained from Rajasthan, India. The concentrations of 21 elements were assayed by Instrumental Neutron Activation Analysis using the k0 method (k0 INAA method) and high-resolution gamma ray spectrometry. The data reveal the segregation of some elements from associated (trapped and host) rocks to the mineral beryl forming the gemstones. A reference rock standard of the US Geological Survey (USGS BCR-1) was also analysed as a control of the method.
He, Yan; Yang, Zuokun; Hong, Ni; Wang, Guoping; Ning, Guogui; Xu, Wenxing
A bizarre virus-like symptom of a leaf rosette formed by dense small leaves on branches of wild roses (Rosa multiflora Thunb.), designated as 'wild rose leaf rosette disease' (WRLRD), was observed in China. To investigate the presumed causal virus, a wild rose sample affected by WRLRD was subjected to deep sequencing of small interfering RNAs (siRNAs) for a complete survey of the infecting viruses and viroids. The assembly of siRNAs led to the reconstruction of the complete genomes of three known viruses, namely Apple stem grooving virus (ASGV), Blackberry chlorotic ringspot virus (BCRV) and Prunus necrotic ringspot virus (PNRSV), and of a novel virus provisionally named 'rose leaf rosette-associated virus' (RLRaV). Phylogenetic analysis clearly placed RLRaV alongside members of the genus Closterovirus, family Closteroviridae. Genome organization of RLRaV RNA (17,653 nucleotides) showed 13 open reading frames (ORFs), except ORF1 and the quintuple gene block, most of which showed no significant similarities with known viral proteins, but, instead, had detectable identities to fungal or bacterial proteins. Additional novel molecular features indicated that RLRaV seems to be the most complex virus among the known genus members. To our knowledge, this is the first report of WRLRD and its associated closterovirus, as well as two ilarviruses and one capilovirus, infecting wild roses. Our findings present novel information about the closterovirus and the aetiology of this rose disease which should facilitate its control. More importantly, the novel features of RLRaV help to clarify the molecular and evolutionary features of the closterovirus. © 2014 BSPP AND JOHN WILEY & SONS LTD.
Nadeem, A; Maryam, J
Milk yield and quality has been a major selection criterion for genetic improvement in livestock species. Role of Prolactin gene in determining milk quality in terms of protein profile, lactose, lipids and other imperative macromolecules is very important. In this context, genetic profiling of Prolactin gene in riverine buffalo of Pakistan was performed and potential genetic markers were identified illustrating worth of this gene in marker-assisted selection of superior dairy buffaloes. Series of wet and dry lab experimentation was performed starting with genomic DNA isolation from true to breed representatives of indigenous river buffalo (Nili-Ravi). After amplification of coding regions of Prolactin gene, products were eluted and sequenced by Sanger's chain termination method and aligned to get variations in genomic region. A total of 15 novel variations were identified and analyzed statistically for their significance at population level, haplotypes were constructed, and association was estimated. Phylogenetic analysis was performed to evaluate the rate of evolution for Prolactin gene in various mammalian species. Lastly, biological networking for this molecule was predicted to get the bigger pictorial of its functional machinery. Pathway analysis was performed to find its physiological mode of action in milk synthesis. This is a first report toward complete genetic screening of Prolactin gene in Pakistani buffaloes. Results of this study not only provide an insight for potential role of Prolactin gene in milk-producing abilities of buffalo but also suggest new directions for exploration of more genes that may have promising role to enhance future milk production capabilities of river buffalo breeds of Asian region through marker-assisted selection.
Full Text Available This paper is on data analysis strategy in a complex, multidimensional, and dynamic domain. The focus is on the use of data mining techniques to explore the importance of multivariate structures; using climate variables which influences climate change. Techniques involved in data mining exercise vary according to the data structures. The multivariate analysis strategy considered here involved choosing an appropriate tool to analyze a process. Factor analysis is introduced into data mining technique in order to reveal the influencing impacts of factors involved as well as solving for multicolinearity effect among the variables. The temporal nature and multidimensionality of the target variables is revealed in the model using multidimensional regression estimates. The strategy of integrating the method of several statistical techniques, using climate variables in Nigeria was employed. R2 of 0.518 was obtained from the ordinary least square regression analysis carried out and the test was not significant at 5% level of significance. However, factor analysis regression strategy gave a good fit with R2 of 0.811 and the test was significant at 5% level of significance. Based on this study, model building should go beyond the usual confirmatory data analysis (CDA, rather it should be complemented with exploratory data analysis (EDA in order to achieve a desired result.
Full Text Available BACKGROUND: Neural tube defects (NTDs are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs. METHODS: The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined. RESULTS: Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV. Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05. Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87. Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05, corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01. Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways. CONCLUSIONS: Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.
Cecilia L Winata
Full Text Available Zic3 regulates early embryonic patterning in vertebrates. Loss of Zic3 function is known to disrupt gastrulation, left-right patterning, and neurogenesis. However, molecular events downstream of this transcription factor are poorly characterized. Here we use the zebrafish as a model to study the developmental role of Zic3 in vivo, by applying a combination of two powerful genomics approaches--ChIP-seq and microarray. Besides confirming direct regulation of previously implicated Zic3 targets of the Nodal and canonical Wnt pathways, analysis of gastrula stage embryos uncovered a number of novel candidate target genes, among which were members of the non-canonical Wnt pathway and the neural pre-pattern genes. A similar analysis in zic3-expressing cells obtained by FACS at segmentation stage revealed a dramatic shift in Zic3 binding site locations and identified an entirely distinct set of target genes associated with later developmental functions such as neural development. We demonstrate cis-regulation of several of these target genes by Zic3 using in vivo enhancer assay. Analysis of Zic3 binding sites revealed a distribution biased towards distal intergenic regions, indicative of a long distance regulatory mechanism; some of these binding sites are highly conserved during evolution and act as functional enhancers. This demonstrated that Zic3 regulation of developmental genes is achieved predominantly through long distance regulatory mechanism and revealed that developmental transitions could be accompanied by dramatic changes in regulatory landscape.
Wei, Na; Govindarajulu, Rajanikanth; Tennessen, Jacob A; Liston, Aaron; Ashman, Tia-Lynn
With their extraordinary diversity in sexual systems, flowering plants offer unparalleled opportunities to understand sex determination and to reveal generalities in the evolution of sex chromosomes. Comparative genetic mapping of related taxa with good phylogenetic resolution can delineate the extent of sex chromosome diversity within plant groups, and lead the way to understanding the evolutionary drivers of such diversity. The North American octoploid wild strawberries provide such an opportunity. We performed linkage mapping using targeted sequence capture for the subdioecious western Fragaria virginiana ssp. platypetala and compared the location of its sex-determining region (SDR) to those of 2 other (sub)dioecious species, the eastern subspecies, F. virginiana ssp. virginiana (whose SDR is at 0-5.5 Mb on chromosome VI of the B2 subgenome), and the sister species F. chiloensis (whose SDR is at 37 Mb on chromosome VI of the Av subgenome). Male sterility was dominant in F. virginiana ssp. platypetala and mapped to a chromosome also in homeologous group VI. Likewise, one major quantitative trait locus (QTL) for female fertility overlapped the male sterility region. However, the SDR mapped to yet another subgenome (B1), and to a different location (13 Mb), but similar to the location inferred in one population of the naturally occurring hybrid between F. chiloensis and F. virginiana (F. ×ananassa ssp. cuneifolia). Phylogenetic analysis of chromosomes across the octoploid taxa showed consistent subgenomic composition reflecting shared evolutionary history but also reinforced within-species variation in the SDR-carrying chromosome, suggesting either repeated evolution, or recent turnovers in SDR. © The American Genetic Association 2017. All rights reserved. For permissions, please e-mail: email@example.com.
Vilne, Baiba; Skogsberg, Josefin; Foroughi Asl, Hassan; Talukdar, Husain Ahammad; Kessler, Thorsten; Björkegren, Johan L M; Schunkert, Heribert
Mitochondrial damage and augmented production of reactive oxygen species (ROS) may represent an intermediate step by which hypercholesterolemia exacerbates atherosclerotic lesion formation. To test this hypothesis, in mice with severe but genetically reversible hypercholesterolemia (i.e. the so called Reversa mouse model), we performed time-resolved analyses of mitochondrial transcriptome in the aortic arch employing a systems-level network approach. During hypercholesterolemia, we observed a massive down-regulation (>28%) of mitochondrial genes, specifically at the time of rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age. Both phenomena - down-regulation of mitochondrial genes and lesion expansion - were largely reversible by genetically lowering plasma cholesterol (by >80%, from 427 to 54 ± 31 mg/L) at 30 weeks. Co-expression network analysis revealed that both mitochondrial signature genes were highly connected in two modules, negatively correlating with lesion size and supported as causal for coronary artery disease (CAD) in humans, as expression-associated single nucleotide polymorphisms (eSNPs) representing their genes overlapped markedly with established disease risk loci. Within these modules, we identified the transcription factor estrogen related receptor (ERR)-α and its co-factors PGC1-α and -β, i.e. two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators, as key regulatory genes. Together, these factors are known as major orchestrators of mitochondrial biogenesis and antioxidant responses. Using a network approach, we demonstrate how hypercholesterolemia could hamper mitochondrial activity during atherosclerosis progression and pinpoint potential therapeutic targets to counteract these processes. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
Full Text Available The polymicrobial biofilm communities in Mushroom and Octopus Spring in Yellowstone National Park (YNP are well characterized, yet little is known about the phage populations. Dominant species, Synechococcus sp. JA-2-3B'a(2-13, Synechococcus sp. JA-3-3Ab, Chloroflexus sp. Y-400-fl, and Roseiflexus sp. RS-1, contain multiple CRISPR-Cas arrays, suggesting complex interactions with phage predators. To analyze phage populations from Octopus Spring biofilms, we sequenced a viral enriched fraction. To assemble and analyze phage metagenomic data, we developed a custom module, VIRITAS, implemented within the MetAMOS framework. This module bins contigs into groups based on tetranucleotide frequencies and CRISPR spacer-protospacer matching and ORF calling. Using this pipeline we were able to assemble phage sequences into contigs and bin them into three clusters that corroborated with their potential host range. The virome contained 52,348 predicted ORFs; some were clearly phage-like; 9319 ORFs had a recognizable Pfam domain while the rest were hypothetical. Of the recognized domains with CRISPR spacer matches, was the phage endolysin used by lytic phage to disrupt cells. Analysis of the endolysins present in the thermophilic cyanophage contigs revealed a subset of characterized endolysins as well as a Glyco_hydro_108 (PF05838 domain not previously associated with sequenced cyanophages. A search for CRISPR spacer matches to all identified phage endolysins demonstrated that a majority of endolysin domains were targets. This strategy provides a general way to link host and phage as endolysins are known to be widely distributed in bacteriophage. Endolysins can also provide information about host cell wall composition and have the additional potential to be used as targets for novel therapeutics.
Viollet, Coralie; Davis, David A.; Tekeste, Shewit S.; Reczko, Martin; Pezzella, Francesco; Ragoussis, Jiannis
Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases. PMID:28046107
Greenblum, Sharon; Turnbaugh, Peter J; Borenstein, Elhanan
The human microbiome plays a key role in a wide range of host-related processes and has a profound effect on human health. Comparative analyses of the human microbiome have revealed substantial variation in species and gene composition associated with a variety of disease states but may fall short of providing a comprehensive understanding of the impact of this variation on the community and on the host. Here, we introduce a metagenomic systems biology computational framework, integrating metagenomic data with an in silico systems-level analysis of metabolic networks. Focusing on the gut microbiome, we analyze fecal metagenomic data from 124 unrelated individuals, as well as six monozygotic twin pairs and their mothers, and generate community-level metabolic networks of the microbiome. Placing variations in gene abundance in the context of these networks, we identify both gene-level and network-level topological differences associated with obesity and inflammatory bowel disease (IBD). We show that genes associated with either of these host states tend to be located at the periphery of the metabolic network and are enriched for topologically derived metabolic "inputs." These findings may indicate that lean and obese microbiomes differ primarily in their interface with the host and in the way they interact with host metabolism. We further demonstrate that obese microbiomes are less modular, a hallmark of adaptation to low-diversity environments. We additionally link these topological variations to community species composition. The system-level approach presented here lays the foundation for a unique framework for studying the human microbiome, its organization, and its impact on human health.
Serra, Fabienne; Müller, Joachim; Gray, John; Lüthi, Ramona; Dudas, Sandor; Czub, Stefanie; Seuberlich, Torsten
Three different types of bovine spongiform encephalopathy (BSE) are known and supposedly caused by distinct prion strains: the classical (C-) BSE type that was typically found during the BSE epidemic, and two relatively rare atypical BSE types, termed H-BSE and L-BSE. The three BSE types differ in the molecular phenotype of the disease associated prion protein, namely the N-terminally truncated proteinase K (PK) resistant prion protein fragment (PrP res ). In this study, we report and analyze yet another PrP res type (PrP res-2011 ), which was found in severely autolytic brain samples of two cows in the framework of disease surveillance in Switzerland in 2011. Analysis of brain tissues from these animals by PK titration and PK inhibitor assays ruled out the process of autolysis as the cause for the aberrant PrP res profile. Immunochemical characterization of the PrP fragments present in the 2011 cases by epitope mapping indicated that PrP res-2011 corresponds in its primary sequence to the physiologically occurring PrP-C1 fragment. However, high speed centrifugation, sucrose gradient assay and NaPTA precipitation revealed biochemical similarities between PrP res-2011 and the disease-associated prion protein found in BSE affected cattle in terms of detergent insolubility, PK resistance and PrP aggregation. Although it remains to be established whether PrP res-2011 is associated with a transmissible disease, our results point out the need of further research on the role the PrP-C1 aggregation and misfolding in health and disease. Copyright Â© 2017. Published by Elsevier B.V.
Spåhr, H; Samuelsen, C O; Baraznenok, V
. cerevisiae share an essential protein module, which associates with nonessential speciesspecific subunits. In support of this view, sequence analysis of the conserved yeast Mediator components Med4 and Med8 reveals sequence homology to the metazoan Mediator components Trap36 and Arc32. Therefore, 8 of 10...... essential genes conserved between S. pombe and S. cerevisiae also have a metazoan homolog, indicating that an evolutionary conserved Mediator core is present in all eukaryotic cells. Our data suggest a closer functional relationship between yeast and metazoan Mediator than previously anticipated....
Ye, Jie; Hu, Tixu; Yang, Congmei; Li, Hanxia; Yang, Mingze; Ijaz, Raina; Ye, Zhibiao; Zhang, Yuyang
Tomato (Solanum lycopersicum) serves as a research model for fruit development; however, while it is an important dietary source of antioxidant nutrients, the transcriptional regulation of genes that determine nutrient levels remains poorly understood. Here, the transcriptomes of fruit at seven developmental stages (7, 14, 21, 28, 35, 42 and 49 days after flowering) from two tomato cultivars (Ailsa Craig and HG6-61) were evaluated using the Illumina sequencing platform. A total of 26,397 genes, which were expressed in at least one developmental stage, were detected in the two cultivars, and the expression patterns of those genes could be divided into 20 groups using a K-mean cluster analysis. Gene Ontology term enrichment analysis indicated that genes involved in RNA regulation, secondary metabolism, hormone metabolism and cell wall metabolism were the most highly differentially expressed genes during fruit development and ripening. A co-expression analysis revealed several transcription factors whose expression patterns correlated with those of genes associated with ascorbic acid, carotenoid and flavonoid biosynthesis. This transcriptional correlation was confirmed by agroinfiltration mediated transient expression, which showed that most of the enzymatic genes in the ascorbic acid biosynthesis were regulated by the overexpression of each of the three transcription factors that were tested. The metabolic dynamics of ascorbic acid, carotenoid and flavonoid were investigated during fruit development and ripening, and some selected transcription factors showed transcriptional correlation with the accumulation of ascorbic acid, carotenoid and flavonoid. This transcriptome study provides insight into the regulatory mechanism of fruit development and presents candidate transcription factors involved in secondary metabolism. PMID:26133783
Roellig, Daniela; Tan-Cabugao, Johanna; Esaian, Sevan; Bronner, Marianne E
The 'neural plate border' of vertebrate embryos contains precursors of neural crest and placode cells, both defining vertebrate characteristics. How these lineages segregate from neural and epidermal fates has been a matter of debate. We address this by performing a fine-scale quantitative temporal analysis of transcription factor expression in the neural plate border of chick embryos. The results reveal significant overlap of transcription factors characteristic of multiple lineages in individual border cells from gastrula through neurula stages. Cell fate analysis using a Sox2 (neural) enhancer reveals that cells that are initially Sox2+ cells can contribute not only to neural tube but also to neural crest and epidermis. Moreover, modulating levels of Sox2 or Pax7 alters the apportionment of neural tube versus neural crest fates. Our results resolve a long-standing question and suggest that many individual border cells maintain ability to contribute to multiple ectodermal lineages until or beyond neural tube closure.
Full Text Available Mathematical ability is heritable, but few studies have directly investigated its molecular genetic basis. Here we aimed to identify specific genetic contributions to variation in mathematical ability. We carried out a genome wide association scan using pooled DNA in two groups of U.K. samples, based on end of secondary/high school national academic exam achievement: high (n = 419 versus low (n = 183 mathematical ability while controlling for their verbal ability. Significant differences in allele frequencies between these groups were searched for in 906,600 SNPs using the Affymetrix GeneChip Human Mapping version 6.0 array. After meeting a threshold of p<1.5×10(-5, 12 SNPs from the pooled association analysis were individually genotyped in 542 of the participants and analyzed to validate the initial associations (lowest p-value 1.14 ×10(-6. In this analysis, one of the SNPs (rs789859 showed significant association after Bonferroni correction, and four (rs10873824, rs4144887, rs12130910 rs2809115 were nominally significant (lowest p-value 3.278 × 10(-4. Three of the SNPs of interest are located within, or near to, known genes (FAM43A, SFT2D1, C14orf64. The SNP that showed the strongest association, rs789859, is located in a region on chromosome 3q29 that has been previously linked to learning difficulties and autism. rs789859 lies 1.3 kbp downstream of LSG1, and 700 bp upstream of FAM43A, mapping within the potential promoter/regulatory region of the latter. To our knowledge, this is only the second study to investigate the association of genetic variants with mathematical ability, and it highlights a number of interesting markers for future study.
Zhu, Zhihuang; Sun, Yuena; Wang, Rixin; Xu, Tianjun
The innate immune system can recognize non-self through pattern recognition receptors. Toll-like receptors were the best-known members of these receptors, and they could sense, recognize, and bind pathogen-associated molecular patterns. TLRs played an important role in innate immune system and were conserved in both invertebrate and vertebrate lineages. Thereinto, TLR9 could detect unmethylated CpG motifs in dsDNA and was expected to undergo coevolution with its microbial ligands. It was known that aquatic and terrestrial organisms dwelled in different environments which contained different pathogens, and they had to adapt to their local environmental conditions. Therefore, we collected TLR9 genes from invertebrate to vertebrate to further explore whether the huge differences between aquatic and terrestrial environments affected the TLR9s evolution between aquatic and terrestrial organisms. Molecular evolution analysis detected positively selected sites in the ancestral lineages of vertebrates, teleosts, and Perciformes but not in the ancestral lineage of mammals. In PAML, site model revealed that extant mammalian TLR9 genes underwent positive selection. However, the positive selection of extant teleosts appeared primarily in Perciformes in which there were 14 positively selected sites. Among these sites, two of them were located on the amino acid insertions of the leucine-rich repeats which could create DNA binding sites, three were found on the convex surface which might possibly affect the ﬂexibility of the TLR solenoids, and six were located on the β-face of concave surface which contained the ligand-binding sites of the TLR solenoids. In other ML methods, we also found three sites under selection that coincided with the codons identiﬁed by M8 and these sites were all located in LRRs. The diverse aquatic and terrestrial environments might possess different pathogens to make the living organisms adapt to their local environmental conditions. The positive
Japaridze, Natia; Muthuraman, Muthuraman; Moeller, Friederike; Boor, Rainer; Anwar, Abdul Rauf; Deuschl, Günther; Stephani, Urlich; Raethjen, Jan; Siniatchkin, Michael
West syndrome is a severe epileptic encephalopathy of infancy with a poor developmental outcome. This syndrome is associated with the pathognomonic EEG feature of hypsarrhythmia. The aim of the study was to describe neuronal networks underlying hypsarrhythmia using the source analysis method (dynamic imaging of coherent sources or DICS) which represents an inverse solution algorithm in the frequency domain. In order to investigate the interaction within the detected network, a renormalized partial directed coherence (RPDC) method was also applied as a measure of the directionality of information flow between the source signals. Both DICS and RPDC were performed for EEG delta activity (1-4 Hz) in eight patients with West syndrome and in eight patients with partial epilepsies (control group). The brain area with the strongest power in the given frequency range was defined as the reference region. The coherence between this reference region and the entire brain was computed using DICS. After that, the RPDC was applied to the source signals estimated by DICS. The results of electrical source imaging were compared to results of a previous EEG-fMRI study which had been carried out using the same cohort of patients. As revealed by DICS, delta activity in hypsarrhythmia was associated with coherent sources in the occipital cortex (main source) as well as the parietal cortex, putamen, caudate nucleus and brainstem. In patients with partial epilepsies, delta activity could be attributed to sources in the occipital, parietal and sensory-motor cortex. In West syndrome, RPDC showed the strongest and most significant direction of ascending information flow from the brainstem towards the putamen and cerebral cortex. The neuronal network underlying hypsarrhythmia in this study resembles the network which was described in previous EEG-fMRI and PET studies with involvement of the brainstem, putamen and cortical regions in the generation of hypsarrhythmia. The RPDC suggests that
Classification, clustering and association mining are major tasks of data mining and have been widely used for knowledge discovery. Associative classification mining, the combination of both association rule mining and classification, has emerged as an indispensable way to support decision making and scientific research. In particular, it offers a…
Zhao, Zhongtao; Liu, Huiquan; Wang, Chenfang; Xu, Jin-Rong
Fungi produce a variety of carbohydrate activity enzymes (CAZymes) for the degradation of plant polysaccharide materials to facilitate infection and/or gain nutrition. Identifying and comparing CAZymes from fungi with different nutritional modes or infection mechanisms may provide information for better understanding of their life styles and infection models. To date, over hundreds of fungal genomes are publicly available. However, a systematic comparative analysis of fungal CAZymes across the entire fungal kingdom has not been reported. In this study, we systemically identified glycoside hydrolases (GHs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and glycosyltransferases (GTs) as well as carbohydrate-binding modules (CBMs) in the predicted proteomes of 103 representative fungi from Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota. Comparative analysis of these CAZymes that play major roles in plant polysaccharide degradation revealed that fungi exhibit tremendous diversity in the number and variety of CAZymes. Among them, some families of GHs and CEs are the most prevalent CAZymes that are distributed in all of the fungi analyzed. Importantly, cellulases of some GH families are present in fungi that are not known to have cellulose-degrading ability. In addition, our results also showed that in general, plant pathogenic fungi have the highest number of CAZymes. Biotrophic fungi tend to have fewer CAZymes than necrotrophic and hemibiotrophic fungi. Pathogens of dicots often contain more pectinases than fungi infecting monocots. Interestingly, besides yeasts, many saprophytic fungi that are highly active in degrading plant biomass contain fewer CAZymes than plant pathogenic fungi. Furthermore, analysis of the gene expression profile of the wheat scab fungus Fusarium graminearum revealed that most of the CAZyme genes related to cell wall degradation were up-regulated during plant infection. Phylogenetic analysis also revealed a complex
d'Aspremont-Lynden, Claude; Dos Santos Ferreira, Rodolphe
We use a comprehensive model of strategic household behaviour in which the spouses' expenditure on each public good is decomposed into autonomous spending and coordinated spending à la Lindahl. We obtain a continuum of semi-cooperative regimes parameterized by the relative weights put on autonomous spending, by each spouse and for each public good, nesting full cooperative and non-cooperative regimes as limit cases. Testing is approached through revealed preference analysis, by looking for ra...
Background Fungi produce a variety of carbohydrate activity enzymes (CAZymes) for the degradation of plant polysaccharide materials to facilitate infection and/or gain nutrition. Identifying and comparing CAZymes from fungi with different nutritional modes or infection mechanisms may provide information for better understanding of their life styles and infection models. To date, over hundreds of fungal genomes are publicly available. However, a systematic comparative analysis of fungal CAZymes across the entire fungal kingdom has not been reported. Results In this study, we systemically identified glycoside hydrolases (GHs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and glycosyltransferases (GTs) as well as carbohydrate-binding modules (CBMs) in the predicted proteomes of 103 representative fungi from Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota. Comparative analysis of these CAZymes that play major roles in plant polysaccharide degradation revealed that fungi exhibit tremendous diversity in the number and variety of CAZymes. Among them, some families of GHs and CEs are the most prevalent CAZymes that are distributed in all of the fungi analyzed. Importantly, cellulases of some GH families are present in fungi that are not known to have cellulose-degrading ability. In addition, our results also showed that in general, plant pathogenic fungi have the highest number of CAZymes. Biotrophic fungi tend to have fewer CAZymes than necrotrophic and hemibiotrophic fungi. Pathogens of dicots often contain more pectinases than fungi infecting monocots. Interestingly, besides yeasts, many saprophytic fungi that are highly active in degrading plant biomass contain fewer CAZymes than plant pathogenic fungi. Furthermore, analysis of the gene expression profile of the wheat scab fungus Fusarium graminearum revealed that most of the CAZyme genes related to cell wall degradation were up-regulated during plant infection. Phylogenetic analysis also
Zai, Xiaodong; Yang, Qiaoling; Yin, Ying; Li, Ruihua; Qian, Mengying; Zhao, Taoran; Li, Yaohui; Zhang, Jun; Fu, Ling; Xu, Junjie; Chen, Wei
Brucella spp. are facultative intracellular pathogens that cause chronic brucellosis in humans and animals. The virulence of Brucella primarily depends on its successful survival and replication in host cells. During invasion of the host tissue, Brucella is simultaneously subjected to a variety of harsh conditions, including nutrient limitation, low pH, antimicrobial defenses, and extreme levels of reactive oxygen species (ROS) via the host immune response. This suggests that Brucella may be able to regulate its metabolic adaptation in response to the distinct stresses encountered during its intracellular infection of the host. An investigation into the differential proteome expression patterns of Brucella grown under the relevant stress conditions may contribute toward a better understanding of its pathogenesis and adaptive response. Here, we utilized a mass spectrometry-based label-free relative quantitative proteomics approach to investigate and compare global proteomic changes in B. abortus in response to eight different stress treatments. The 3 h short-term in vitro single-stress and multi-stress conditions mimicked the in vivo conditions of B. abortus under intracellular infection, with survival rates ranging from 3.17 to 73.17%. The proteomic analysis identified and quantified a total of 2,272 proteins and 74% of the theoretical proteome, thereby providing wide coverage of the B. abortus proteome. By including eight distinct growth conditions and comparing these with a control condition, we identified a total of 1,221 differentially expressed proteins (DEPs) that were significantly changed under the stress treatments. Pathway analysis revealed that most of the proteins were involved in oxidative phosphorylation, ABC transporters, two-component systems, biosynthesis of secondary metabolites, the citrate cycle, thiamine metabolism, and nitrogen metabolism; constituting major response mechanisms toward the reconstruction of cellular homeostasis and metabolic
Shirasaki, Yuji; Komiya, Yutaka; Ohishi, Masatoshi; Mizumoto, Yoshihiko
We present results of the clustering analysis between active galactic nuclei (AGNs) and galaxies at redshift 0.1-1.0, which was performed to investigate the properties of galaxies associated with the AGNs and reveal the nature of the fueling mechanism of supermassive black holes (SMBHs). We used 8059 AGNs/quasi-stellar objects (QSOs) for which virial masses of individual SMBHs were measured, and divided them into four mass groups.Cross-correlation analysis was performed to reconfirm our previous result that cross-correlation length increases with SMBH mass MBH; we obtained consistent results. A linear bias of AGN for each mass group was measured as 1.47 for MBH = 107.5-108.2 M⊙ and 3.08 for MBH = 109-1010 M⊙. The averaged color and luminosity distributions of galaxies around the AGNs/QSOs were also derived for each mass group. The galaxy color Dopt-IR was estimated from a spectral energy distribution (SED) constructed from a catalog derived by merging the Sloan Digital Sky Survey (SDSS) and the UKIRT Infrared Deep Sky Survey (UKIDSS) catalogs. The distributions of color and luminosity were derived by a subtraction method, which does not require redshift information of galaxies. The main results of this work are as follows. (1) A linear bias increases by a factor of two from the lower-mass group to the highest-mass group. (2) The environment around AGNs with the most massive SMBHs (MBH > 109 M⊙) is dominated by red sequence galaxies. (3) Marginal indication of decline in luminosity function at dimmer side of MIR > -19.5 is found for galaxies around AGNs with MBH = 108.2-109 M⊙ and nearest redshift group (z = 0.1-0.3). These results indicate that AGNs with the most massive SMBHs reside in haloes where a large fraction of galaxies have been transited to the red sequence. The accretion of hot halo gas as well as recycled gas from evolving stars can be one of the plausible mechanisms to fuel the SMBHs above ˜ 109 M⊙.
Zai, Xiaodong; Yang, Qiaoling; Yin, Ying; Li, Ruihua; Qian, Mengying; Zhao, Taoran; Li, Yaohui; Zhang, Jun; Fu, Ling; Xu, Junjie; Chen, Wei
Brucella spp. are facultative intracellular pathogens that cause chronic brucellosis in humans and animals. The virulence of Brucella primarily depends on its successful survival and replication in host cells. During invasion of the host tissue, Brucella is simultaneously subjected to a variety of harsh conditions, including nutrient limitation, low pH, antimicrobial defenses, and extreme levels of reactive oxygen species (ROS) via the host immune response. This suggests that Brucella may be able to regulate its metabolic adaptation in response to the distinct stresses encountered during its intracellular infection of the host. An investigation into the differential proteome expression patterns of Brucella grown under the relevant stress conditions may contribute toward a better understanding of its pathogenesis and adaptive response. Here, we utilized a mass spectrometry-based label-free relative quantitative proteomics approach to investigate and compare global proteomic changes in B. abortus in response to eight different stress treatments. The 3 h short-term in vitro single-stress and multi-stress conditions mimicked the in vivo conditions of B. abortus under intracellular infection, with survival rates ranging from 3.17 to 73.17%. The proteomic analysis identified and quantified a total of 2,272 proteins and 74% of the theoretical proteome, thereby providing wide coverage of the B. abortus proteome. By including eight distinct growth conditions and comparing these with a control condition, we identified a total of 1,221 differentially expressed proteins (DEPs) that were significantly changed under the stress treatments. Pathway analysis revealed that most of the proteins were involved in oxidative phosphorylation, ABC transporters, two-component systems, biosynthesis of secondary metabolites, the citrate cycle, thiamine metabolism, and nitrogen metabolism; constituting major response mechanisms toward the reconstruction of cellular homeostasis and metabolic
Full Text Available Molting is an essential biological process throughout the life history of crustaceans, which is regulated by many neuropeptide hormones expressed in the eyestalk. To better understand the molting mechanism in Portunus trituberculatus, we used digital gene expression (DGE to analyze single eyestalk samples during the molting cycle by high-throughput sequencing.We obtained 14,387,942, 12,631,508 and 13,060,062 clean sequence reads from inter-molt (InM, pre-molt (PrM and post-molt (PoM cDNA libraries, respectively. A total of 1,394 molt-related differentially expressed genes (DEGs were identified. GO and KEGG enrichment analysis identified some important processes and pathways with key roles in molting regulation, such as chitin metabolism, peptidase inhibitor activity, and the ribosome. We first observed a pattern associated with the neuromodulator-related pathways during the molting cycle, which were up-regulated in PrM and down-regulated in PoM. Four categories of important molting-related transcripts were clustered and most of them had similar expression patterns, which suggests that there is a connection between these genes throughout the molt cycle.Our work is the first molt-related investigation of P. trituberculatus focusing on the eyestalk at the whole transcriptome level. Together, our results, including DEGs, identification of molting-related biological processes and pathways, and observed expression patterns of important genes, provide a novel insight into the function of the eyestalk in molting regulation.
Caroline H. Johnson
Full Text Available Abstract Background Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production. Methods A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An “autonomous” mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment. Results Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine. Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors. Conclusions Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.
Agarwal, Krishna; Prasad, Dilip K
This paper presents eigen-analysis of image stack of blinking fluorophores to identify the components that enable super-resolved imaging of blinking fluorophores. Eigen-analysis reveals that the contributions of spatial distribution of fluorophores and their temporal photon emission characteristics can be completely separated. While cross-emitter cross-pixel information of spatial distribution that permits super-resolution is encoded in two matrices, temporal statistics weigh the contribution of these matrices to the measured data. The properties and conditions of exploitation of these matrices are investigated. Con-temporary super-resolution imaging methods that use blinking for super-resolution are studied in the context of the presented analysis. Besides providing insight into the capabilities and limitations of existing super-resolution methods, the analysis shall help in designing better super-resolution techniques that directly exploit these matrices.
Liu, Jing-Yu; Chang, Ming-Chang; Meng, Jun-Long; Feng, Cui-Ping; Wang, Yu
In some industrial processes, cold and light stresses are recognized as two important environmental triggers for the transformation of mycelia into fruit-bodies via intermediate primordia in Flammulina velutipes cultivation. To gain insights into the mechanism of regulation of F. velutipes mycelia in response to cold and light stress, proteins expressed abundantly and characteristically at particular stress states were investigated by using the isobaric tags for the relative and absolute quantitation labeling technique. Among the 1046 nonredundant proteins identified with a high degree of confidence, 264 proteins, which were detected as differentially expressed proteins, were associated with 176 specific KEGG pathways. In-depth data analysis revealed that the regulatory network underlying the cold and light response mechanisms of F. velutipes mycelia was complex and multifaceted, as it included varied functions such as rapid energy supply, the biosynthesis of lysine, phenylalanine, tyrosine, and γ-aminobutyric acid, the calcium signal transduction process, dynein-dependent actin and microtubule cytoskeleton formation, autolysis, oxidative stress adaptation, pigment secretion, tissue and organ morphogenesis, and other interesting stress-related processes. Insights into the proteins might shed light on an intuitive understanding of the cold and light stress response mechanism underlying the fruiting processes of F. velutipes. Furthermore, the data might also provide further insights into the stress response mechanism of macro-fungi and valuable information for scientific improvement of some mushroom cultivation techniques in practice.
Full Text Available Abstract Background Microarray gene differential expression analysis is a widely used technique that deals with high dimensional data and is computationally intensive for permutation-based procedures. Microarray gene differential association analysis is even more computationally demanding and must take advantage of multicore computing technology, which is the driving force behind increasing compute power in recent years. In this paper, we present a two-layer hierarchical parallel implementation of gene differential association analysis. It takes advantage of both fine- and coarse-grain (with granularity defined by the frequency of communication parallelism in order to effectively leverage the non-uniform nature of parallel processing available in the cutting-edge systems of today. Results Our results show that this hierarchical strategy matches data sharing behavior to the properties of the underlying hardware, thereby reducing the memory and bandwidth needs of the application. The resulting improved efficiency reduces computation time and allows the gene differential association analysis code to scale its execution with the number of processors. The code and biological data used in this study are downloadable from http://www.urmc.rochester.edu/biostat/people/faculty/hu.cfm. Conclusions The performance sweet spot occurs when using a number of threads per MPI process that allows the working sets of the corresponding MPI processes running on the multicore to fit within the machine cache. Hence, we suggest that practitioners follow this principle in selecting the appropriate number of MPI processes and threads within each MPI process for their cluster configurations. We believe that the principles of this hierarchical approach to parallelization can be utilized in the parallelization of other computationally demanding kernels.
Kang, Yu; Gu, Chaohao; Yuan, Lina; Wang, Yue; Zhu, Yanmin; Li, Xinna; Luo, Qibin; Xiao, Jingfa; Jiang, Daquan; Qian, Minping; Ahmed Khan, Aftab; Chen, Fei; Zhang, Zhang; Yu, Jun
The prokaryotic pangenome partitions genes into core and dispensable genes. The order of core genes, albeit assumed to be stable under selection in general, is frequently interrupted by horizontal gene transfer and rearrangement, but how a core-gene-defined genome maintains its stability or flexibility remains to be investigated. Based on data from 30 species, including 425 genomes from six phyla, we grouped core genes into syntenic blocks in the context of a pangenome according to their stability across multiple isolates. A subset of the core genes, often species specific and lineage associated, formed a core-gene-defined genome organizational framework (cGOF). Such cGOFs are either single segmental (one-third of the species analyzed) or multisegmental (the rest). Multisegment cGOFs were further classified into symmetric or asymmetric according to segment orientations toward the origin-terminus axis. The cGOFs in Gram-positive species are exclusively symmetric and often reversible in orientation, as opposed to those of the Gram-negative bacteria, which are all asymmetric and irreversible. Meanwhile, all species showing strong strand-biased gene distribution contain symmetric cGOFs and often specific DnaE (α subunit of DNA polymerase III) isoforms. Furthermore, functional evaluations revealed that cGOF genes are hub associated with regard to cellular activities, and the stability of cGOF provides efficient indexes for scaffold orientation as demonstrated by assembling virtual and empirical genome drafts. cGOFs show species specificity, and the symmetry of multisegmental cGOFs is conserved among taxa and constrained by DNA polymerase-centric strand-biased gene distribution. The definition of species-specific cGOFs provides powerful guidance for genome assembly and other structure-based analysis. Prokaryotic genomes are frequently interrupted by horizontal gene transfer (HGT) and rearrangement. To know whether there is a set of genes not only conserved in position
Burniston, Jatin G; Kenyani, Jenna; Gray, Donna; Guadagnin, Eleonora; Jarman, Ian H; Cobley, James N; Cuthbertson, Daniel J; Chen, Yi-Wen; Wastling, Jonathan M; Lisboa, Paulo J; Koch, Lauren G; Britton, Steven L
Profiling of protein species is important because gene polymorphisms, splice variations and post-translational modifications may combine and give rise to multiple protein species that have different effects on cellular function. Two-dimensional gel electrophoresis is one of the most robust methods for differential analysis of protein species, but bioinformatic interrogation is challenging because the consequences of changes in the abundance of individual protein species on cell function are unknown and cannot be predicted. We conducted DIGE of soleus muscle from male and female rats artificially selected as either high- or low-capacity runners (HCR and LCR, respectively). In total 696 protein species were resolved and LC-MS/MS identified proteins in 337 spots. Forty protein species were differentially (P<0.05, FDR<10%) expressed between HCR and LCR and conditional independence mapping found distinct networks within these data, which brought insight beyond that achieved by functional annotation. Protein disulphide isomerase A3 emerged as a key node segregating with differences in aerobic capacity and unsupervised bibliometric analysis highlighted further links to signal transducer and activator of transcription 3, which were confirmed by western blotting. Thus, conditional independence mapping is a useful technique for interrogating DIGE data that is capable of highlighting latent features. Quantitative proteome profiling revealed that there is little or no sexual dimorphism in the skeletal muscle response to artificial selection on running capacity. Instead we found that noncanonical STAT3 signalling may be associated with low exercise capacity and skeletal muscle insulin resistance. Importantly, this discovery was made using unsupervised multivariate association mapping and bibliometric network analyses. This allowed our interpretation of the findings to be guided by patterns within the data rather than our preconceptions about which proteins or processes are of
Full Text Available The substantial use of triclosan (TCS has been aimed to kill pathogenic bacteria, but TCS resistance seems to be prevalent in microbial species and limited knowledge exists about TCS resistance determinants in a majority of pathogenic bacteria. We aimed to evaluate the distribution of TCS resistance determinants in major pathogenic bacteria (N = 231 and to assess the enrichment of potentially pathogenic genera in TCS contaminated environments. A TCS-resistant gene (TRG database was constructed and experimentally validated to predict TCS resistance in major pathogenic bacteria. Genome-wide in silico analysis was performed to define the distribution of TCS-resistant determinants in major pathogens. Microbiome analysis of TCS contaminated soil samples was also performed to investigate the abundance of TCS-resistant pathogens. We experimentally confirmed that TCS resistance could be accurately predicted using genome-wide in silico analysis against TRG database. Predicted TCS resistant phenotypes were observed in all of the tested bacterial strains (N = 17, and heterologous expression of selected TCS resistant genes from those strains conferred expected levels of TCS resistance in an alternative host Escherichia coli. Moreover, genome-wide analysis revealed that potential TCS resistance determinants were abundant among the majority of human-associated pathogens (79% and soil-borne plant pathogenic bacteria (98%. These included a variety of enoyl-acyl carrier protein reductase (ENRs homologues, AcrB efflux pumps, and ENR substitutions. FabI ENR, which is the only known effective target for TCS, was either co-localized with other TCS resistance determinants or had TCS resistance-associated substitutions. Furthermore, microbiome analysis revealed that pathogenic genera with intrinsic TCS-resistant determinants exist in TCS contaminated environments. We conclude that TCS may not be as effective against the majority of bacterial pathogens as previously
J.B. Richards (Brent); D. Waterworth (Dawn); S. O'Rahilly (Stephen); M.-F. Hivert (Marie-France); R.J.F. Loos (Ruth); J.R.B. Perry (John); T. Tanaka (Toshiko); N.J. Timpson (Nicholas); R.K. Semple (Robert); N. Soranzo (Nicole); K. Song (Kijoung); N. Rocha (Nuno); E. Grundberg (Elin); J. Dupuis (Josée); J.C. Florez (Jose); C. Langenberg (Claudia); I. Prokopenko (Inga); R. Saxena (Richa); R. Sladek (Rob); Y.S. Aulchenko (Yurii); D.M. Evans (David); G. Waeber (Gérard); M.S. Burnett; N. Sattar (Naveed); J. Devaney (Joseph); C. Willenborg (Christina); A. Hingorani (Aroon); J.C.M. Witteman (Jacqueline); P. Vollenweider (Peter); B. Glaser (Beate); C. Hengstenberg (Christian); L. Ferrucci (Luigi); D. Melzer (David); K. Stark (Klaus); J. Deanfield (John); J. Winogradow (Janina); M. Grassl (Martina); A.S. Hall (Alistair); J.M. Egan (Josephine); J.R. Thompson (John); S.L. Ricketts (Sally); I.R. König (Inke); W. Reinhard (Wibke); S.M. Grundy (Scott); H.E. Wichmann (Heinz Erich); P. Barter (Phil); R. Mahley (Robert); Y.A. Kesaniemi (Antero); D.J. Rader (Daniel); M.P. Reilly (Muredach); S.E. Epstein (Stephen); A.F.R. Stewart (Alexandre); P. Tikka-Kleemola (Päivi); H. Schunkert (Heribert); K.A. Burling (Keith); J. Erdmann (Jeanette); P. Deloukas (Panagiotis); T. Pastinen (Tomi); N.J. Samani (Nilesh); R. McPherson (Ruth); G.D. Smith; T.M. Frayling (Timothy); N.J. Wareham (Nick); J.B. Meigs (James); V. Mooser (Vincent); T.D. Spector (Tim)
textabstractThe adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of
Van Anh Le Thi
Full Text Available Abstract Background In rice, the major part of the post-embryonic root system is made of stem-derived roots named crown roots (CR. Among the few characterized rice mutants affected in root development, crown rootless1 mutant is unable to initiate crown root primordia. CROWN ROOTLESS1 (CRL1 is induced by auxin and encodes an AS2/LOB-domain transcription factor that acts upstream of the gene regulatory network controlling CR development. Results To identify genes involved in CR development, we compared global gene expression profile in stem bases of crl1 mutant and wild-type (WT plants. Our analysis revealed that 250 and 236 genes are down- and up-regulated respectively in the crl1 mutant. Auxin induces CRL1 expression and consequently it is expected that auxin also alters the expression of genes that are early regulated by CRL1. To identify genes under the early control of CRL1, we monitored the expression kinetics of a selected subset of genes, mainly chosen among those exhibiting differential expression, in crl1 and WT following exogenous auxin treatment. This analysis revealed that most of these genes, mainly related to hormone, water and nutrient, development and homeostasis, were likely not regulated directly by CRL1. We hypothesized that the differential expression for these genes observed in the crl1 mutant is likely a consequence of the absence of CR formation. Otherwise, three CRL1-dependent auxin-responsive genes: FSM (FLATENNED SHOOT MERISTEM/FAS1 (FASCIATA1, GTE4 (GENERAL TRANSCRIPTION FACTOR GROUP E4 and MAP (MICROTUBULE-ASSOCIATED PROTEIN were identified. FSM/FAS1 and GTE4 are known in rice and Arabidopsis to be involved in the maintenance of root meristem through chromatin remodelling and cell cycle regulation respectively. Conclusion Our data showed that the differential regulation of most genes in crl1 versus WT may be an indirect consequence of CRL1 inactivation resulting from the absence of CR in the crl1 mutant. Nevertheless
Full Text Available Here, we describe a multiplexed immunohistochemical platform with computational image processing workflows, including image cytometry, enabling simultaneous evaluation of 12 biomarkers in one formalin-fixed paraffin-embedded tissue section. To validate this platform, we used tissue microarrays containing 38 archival head and neck squamous cell carcinomas and revealed differential immune profiles based on lymphoid and myeloid cell densities, correlating with human papilloma virus status and prognosis. Based on these results, we investigated 24 pancreatic ductal adenocarcinomas from patients who received neoadjuvant GVAX vaccination and revealed that response to therapy correlated with degree of mono-myelocytic cell density and percentages of CD8+ T cells expressing T cell exhaustion markers. These data highlight the utility of in situ immune monitoring for patient stratification and provide digital image processing pipelines to the community for examining immune complexity in precious tissue sections, where phenotype and tissue architecture are preserved to improve biomarker discovery and assessment.
Robinson, Philip C.; Claushuis, Theodora A.M.; Cortes, Adrian; Martin, Tammy M.; Evans, David M.; Leo, Paul; Mukhopadhyay, Pamela; Bradbury, Linda A.; Cremin, Katie; Harris, Jessica; Maksymowych, Walter P.; Inman, Robert D.; Rahman, Proton; Haroon, Nigil; Gensler, Lianne; Powell, Joseph E.; van der Horst-Bruinsma, Irene E.; Hewitt, Alex W.; Craig, Jamie E.; Lim, Lyndell L.; Wakefield, Denis; McCluskey, Peter; Voigt, Valentina; Fleming, Peter; Degli-Esposti, Mariapia; Pointon, Jennifer J.; Weisman, Michael H.; Wordsworth, B. Paul; Reveille, John D.; Rosenbaum, James T.; Brown, Matthew A.
Objective To use high density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients both with and without ankylosing spondylitis (AS). Method We genotyped 1,711 patients with AAU (either primary or with AAU and AS), 2,339 AS patients without AAU, and 10,000 controls on the Illumina Immunochip Infinium microarray. We also used data on AS patients from previous genomewide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by RT-PCR. Results Comparing all AAU cases with HC, strong association was seen over HLA-B corresponding to the HLA-B27 tag SNP rs116488202. Three non-MHC loci IL23R, the intergenic region 2p15 and ERAP1 were associated at genome-wide significance (P < 5×10−8). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye related gene EYS, were also associated at a suggestive level of significance (P < 5×10−6). A number of previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression was found to vary across eye compartments. Conclusion These findings, with both novel AAU specific associations, and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways. PMID:25200001
O'Brien Andersen, L.; Karim, A. B.; Roager, Henrik Munch
Several studies have shown associations between groups of intestinal bacterial or specific ratios between bacterial groups and various disease traits. Meanwhile, little is known about interactions and associations between eukaryotic and prokaryotic microorganisms in the human gut. In this work, we...... set out to investigate potential associations between common single-celled parasites such as Blastocystis spp. and Dientamoeba fragilis and intestinal bacteria. Stool DNA from patients with intestinal symptoms were selected based on being Blastocystis spp.-positive (B+)/negative (B-) and D. fragilis...
Tae Seung Kim
Full Text Available In the single cargo market, the ordinary market share analysis method has been the representative tool for revealed competitiveness analysis. This paper develops and employs an applied market share index called the additive market share (AMS. Data are collected from 15 major container ports for the 1998-2013 period. In comparison to the results of an ordinary market share analysis, the highest AMS is observed for the Bohai Rim port cluster from 2008, not for the Yangtze River cluster or the Pearl River cluster. There are substitutable relationships between Yangtze River and non-Chinese ports and between Pearl River and Bohai Rim ports from 2001. Finally, there is an internal competition at Pearl River and Yangtze River ports, whereas Bohai Rim and non-Chinese ports show internally complementary relationships.
Full Text Available Oysters, as a major group of marine bivalves, can tolerate a wide range of natural and anthropogenic stressors including heat stress. Recent studies have shown that oysters pretreated with heat shock can result in induced heat tolerance. A systematic study of cellular recovery from heat shock may provide insights into the mechanism of acquired thermal tolerance. In this study, we performed the first network analysis of oyster transcriptome by reanalyzing microarray data from a previous study. Network analysis revealed a cascade of cellular responses during oyster recovery after heat shock and identified responsive gene modules and key genes. Our study demonstrates the power of network analysis in a non-model organism with poor gene annotations, which can lead to new discoveries that go beyond the focus on individual genes.
Wei, Caihong; Wang, Huihua; Liu, Gang; Wu, Mingming; Cao, Jiaxve; Liu, Zhen; Liu, Ruizao; Zhao, Fuping; Zhang, Li; Lu, Jian; Liu, Chousheng; Du, Lixin
Traditionally, Chinese indigenous sheep were classified geographically and morphologically into three groups: Mongolian, Kazakh and Tibetan. Herein, we aimed to evaluate the population structure and genome selection among 140 individuals from ten representative Chinese indigenous sheep breeds: Ujimqin, Hu, Tong, Large-Tailed Han and Lop breed (Mongolian group); Duolang and Kazakh (Kazakh group); and Diqing, Plateau-type Tibetan, and Valley-type Tibetan breed (Tibetan group). We analyzed the population using principal component analysis (PCA), STRUCTURE and a Neighbor-Joining (NJ)-tree. In PCA plot, the Tibetan and Mongolian groups were clustered as expected; however, Duolang and Kazakh (Kazakh group) were segregated. STRUCTURE analyses suggested two subpopulations: one from North China (Kazakh and Mongolian groups) and the other from the Southwest (Tibetan group). In the NJ-tree, the Tibetan group formed an independent branch and the Kazakh and Mongolian groups were mixed. We then used the d i statistic approach to reveal selection in Chinese indigenous sheep breeds. Among the 599 genome sequence windows analyzed, sixteen (2.7%) exhibited signatures of selection in four or more breeds. We detected three strong selection windows involving three functional genes: RXFP2, PPP1CC and PDGFD. PDGFD, one of the four subfamilies of PDGF, which promotes proliferation and inhibits differentiation of preadipocytes, was significantly selected in fat type breeds by the Rsb (across pairs of populations) approach. Two consecutive selection regions in Duolang sheep were obviously different to other breeds. One region was in OAR2 including three genes (NPR2, SPAG8 and HINT2) the influence growth traits. The other region was in OAR 6 including four genes (PKD2, SPP1, MEPE, and IBSP) associated with a milk production quantitative trait locus. We also identified known candidate genes such as BMPR1B, MSRB3, and three genes (KIT, MC1R, and FRY) that influence lambing percentage, ear size
Lei, Yunting; Xu, Yuxing; Hettenhausen, Christian; Lu, Chengkai; Shen, Guojing; Zhang, Cuiping; Li, Jing; Song, Juan; Lin, Honghui; Wu, Jianqiang
Soil salinity is an important factor affecting growth, development, and productivity of almost all land plants, including the forage crop alfalfa (Medicago sativa). However, little is known about how alfalfa responds and adapts to salt stress, particularly among different salt-tolerant cultivars. Among seven alfalfa cultivars, we found that Zhongmu-1 (ZM) is relatively salt-tolerant and Xingjiang Daye (XJ) is salt-sensitive. Compared to XJ, ZM showed slower growth under low-salt conditions, but exhibited stronger tolerance to salt stress. RNA-seq analysis revealed 2237 and 1125 differentially expressed genes (DEGs) between ZM and XJ in the presence and absence of salt stress, among which many genes are involved in stress-related pathways. After salt treatment, compared with the controls, the number of DEGs in XJ (19373) was about four times of that in ZM (4833). We also detected specific differential gene expression patterns: In response to salt stress, compared with XJ, ZM maintained relatively more stable expression levels of genes related to the ROS and Ca 2+ pathways, phytohormone biosynthesis, and Na + /K + transport. Notably, several salt resistance-associated genes always showed greater levels of expression in ZM than in XJ, including a transcription factor. Consistent with the suppression of plant growth resulting from salt stress, the expression of numerous photosynthesis- and growth hormone-related genes decreased more dramatically in XJ than in ZM. By contrast, the expression levels of photosynthetic genes were lower in ZM under low-salt conditions. Compared with XJ, ZM is a salt-tolerant alfalfa cultivar possessing specific regulatory mechanisms conferring exceptional salt tolerance, likely by maintaining high transcript levels of abiotic and biotic stress resistance-related genes. Our results suggest that maintaining this specific physiological status and/or plant adaptation to salt stress most likely arises by inhibition of plant growth in ZM through
Full Text Available Gram-negative bacterial outer membrane proteins play important roles in the interaction of bacteria with their environment including nutrient acquisition, adhesion and invasion, and antibiotic resistance. In this study we identified 47 proteins within the Sarkosyl-insoluble fraction of Campylobacter jejuni 81-176, using LC–ESI-MS/MS. Comparative analysis of outer membrane protein sequences was visualised to reveal protein distribution within a panel of Campylobacter spp., identifying several C. jejuni-specific proteins. Smith–Waterman analyses of C. jejuni homologues revealed high sequence conservation amongst a number of hypothetical proteins, sequence heterogeneity of other proteins and several proteins which are absent in a proportion of strains.
K. Rooijers (Koos); F. Loayza-Puch (Fabricio); L.G.J. Nijtmans (Leo); R. Agami (Reuven)
textabstractMitochondria are essential cellular organelles for generation of energy and their dysfunction may cause diabetes, Parkinson's disease and multi-systemic failure marked by failure to thrive, gastrointestinal problems, lactic acidosis and early lethality. Disease-associated mitochondrial
Shah, Anup D; Inder, Kerry L; Shah, Alok K; Cristino, Alexandre S; McKie, Arthur B; Gabra, Hani; Davis, Melissa J; Hill, Michelle M
Lipid rafts are dynamic membrane microdomains that orchestrate molecular interactions and are implicated in cancer development. To understand the functions of lipid rafts in cancer, we performed an integrated analysis of quantitative lipid raft proteomics data sets modeling progression in breast cancer, melanoma, and renal cell carcinoma. This analysis revealed that cancer development is associated with increased membrane raft-cytoskeleton interactions, with ∼40% of elevated lipid raft proteins being cytoskeletal components. Previous studies suggest a potential functional role for the raft-cytoskeleton in the action of the putative tumor suppressors PTRF/Cavin-1 and Merlin. To extend the observation, we examined lipid raft proteome modulation by an unrelated tumor suppressor opioid binding protein cell-adhesion molecule (OPCML) in ovarian cancer SKOV3 cells. In agreement with the other model systems, quantitative proteomics revealed that 39% of OPCML-depleted lipid raft proteins are cytoskeletal components, with microfilaments and intermediate filaments specifically down-regulated. Furthermore, protein-protein interaction network and simulation analysis showed significantly higher interactions among cancer raft proteins compared with general human raft proteins. Collectively, these results suggest increased cytoskeleton-mediated stabilization of lipid raft domains with greater molecular interactions as a common, functional, and reversible feature of cancer cells.
J Brent Richards
Full Text Available The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D and coronary heart disease (CHD. We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531 and sought validation of the lead single nucleotide polymorphisms (SNPs in 5 additional cohorts (n = 6,202. Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8. We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19 for lead SNP, rs266717, n = 14,733. A novel variant in the ARL15 (ADP-ribosylation factor-like 15 gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8, n = 14,733. This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6, n = 22,421 more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3, n = 10,128, and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
Wu, Yi-Hsuan; Graff, Rebecca E; Passarelli, Michael N; Hoffman, Joshua D; Ziv, Elad; Hoffmann, Thomas J; Witte, John S
Background: There exists compelling evidence that some genetic variants are associated with the risk of multiple cancer sites (i.e., pleiotropy). However, the biological mechanisms through which the pleiotropic variants operate are unclear. Methods: We obtained all cancer risk associations from the National Human Genome Research Institute-European Bioinformatics Institute GWAS Catalog, and correlated cancer risk variants were clustered into groups. Pleiotropic variant groups and genes were functionally annotated. Associations of pleiotropic cancer risk variants with noncancer traits were also obtained. Results: We identified 1,431 associations between variants and cancer risk, comprised of 989 unique variants associated with 27 unique cancer sites. We found 20 pleiotropic variant groups (2.1%) composed of 33 variants (3.3%), including novel pleiotropic variants rs3777204 and rs56219066 located in the ELL2 gene. Relative to single-cancer risk variants, pleiotropic variants were more likely to be in genes (89.0% vs. 65.3%, P = 2.2 × 10 -16 ), and to have somewhat larger risk allele frequencies (median RAF = 0.49 versus 0.39, P = 0.046). The 27 genes to which the pleiotropic variants mapped were suggestive for enrichment in response to radiation and hypoxia, alpha-linolenic acid metabolism, cell cycle, and extension of telomeres. In addition, we observed that 8 of 33 pleiotropic cancer risk variants were associated with 16 traits other than cancer. Conclusions: This study identified and functionally characterized genetic variants showing pleiotropy for cancer risk. Impact: Our findings suggest biological pathways common to different cancers and other diseases, and provide a basis for the study of genetic testing for multiple cancers and repurposing cancer treatments. Cancer Epidemiol Biomarkers Prev; 27(1); 75-85. ©2017 AACR . ©2017 American Association for Cancer Research.
Nicholls, Andrew W.; Salek, Reza M.; Marques-Vidal, Pedro; Morya, Edgard; Sameshima, Koichi; Montoliu, Ivan; Da Silva, Laeticia; Collino, Sebastiano; Martin, François-Pierre; Rezzi, Serge; Steinbeck, Christoph; Waterworth, Dawn M.; Waeber, Gérard; Vollenweider, Peter; Beckmann, Jacques S.; Le Coutre, Johannes; Mooser, Vincent; Bergmann, Sven; Genick, Ulrich K.; Kutalik, Zoltán
Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on 1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10−8) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10−44) and lysine (rs8101881, P = 1.2×10−33), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers. PMID:24586186
Full Text Available Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8 and independent associations between single nucleotide polymorphisms (SNP and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44 and lysine (rs8101881, P = 1.2×10(-33, respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.
Rauschert, Sebastian; Uhl, Olaf; Koletzko, Berthold; Kirchberg, Franca; Mori, Trevor A; Huang, Rae-Chi; Beilin, Lawrence J; Hellmuth, Christian; Oddy, Wendy H
Obesity and related diseases have become a global public health burden. Identifying biomarkers will lead to a better understanding of the underlying mechanisms associated with obesity and the pathways leading to insulin resistance (IR) and diabetes. This study aimed to identify the lipidomic biomarkers associated with obesity and IR using plasma samples from a population-based cohort of young adults. The Western Australian Pregnancy Cohort (Raine) study enrolled 2900 pregnant women from 1989 to 1991. The 20-year follow-up was conducted between March 2010 and April 2012. Participants and Samples: Plasma samples from 1176 subjects aged 20 years were analyzed using mass spectrometry-based metabolomics. Associations of analytes with markers of obesity and IR including body mass index, waist circumference, homeostasis model assessment (HOMA-IR), and insulin were examined. Analyses were stratified by body mass index and adjusted for lifestyle and other factors. Waist circumference was positively associated with seven sphingomyelins and five diacylphosphatidylcholines and negatively associated with two lysophosphatidylcholines. HOMA-IR was negatively associated with two diacylphosphatidylcholines and positively with one lysophosphatidylcholine and one diacylphosphatidylcholine. No significant association was found in the obese/overweight group of the HOMA-IR model. In the normal-weight group, one lysophosphatidylcholine was increased. A possible discriminative effect of sphingomyelins, particularly those with two double bonds, and lysophosphatidylcholines was identified between subjects with normal weight and obesity independent of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentrations. Our results suggest weight status-dependent mechanisms for the development of IR with lysophosphatidylcholine C14:0 as a key metabolite in nonobese IR.
Full Text Available A novel high throughput phylogenomic analysis (HTP was applied to the rhodopsin G-protein coupled receptor (GPCR family. Instances of phylogenetic mosaicism between receptors were found to be frequent, often as instances of correlated mosaicism and repeated mosaicism. A null data set was constructed with the same phylogenetic topology as the rhodopsin GPCRs. Comparison of the two data sets revealed that mosaicism was found in GPCRs in a higher frequency than would be expected by homoplasy or the effects of topology alone. Various evolutionary models of differential conservation, recombination and homoplasy are explored which could result in the patterns observed in this analysis. We find that the results are most consistent with frequent recombination events. A complex evolutionary history is illustrated in which it is likely frequent recombination has endowed GPCRs with new functions. The pattern of mosaicism is shown to be informative for functional prediction for orphan receptors. HTP analysis is complementary to conventional phylogenomic analyses revealing mosaicism that would not otherwise have been detectable through conventional phylogenetics.
Sun, Wei; Zhang, Fengli; He, Liming; Li, Zhiyong
Diverse sessile organisms inhabit the coral reef ecosystems, including corals, sponges, and sea anemones. In the past decades, scleractinian corals (Cnidaria, Anthozoa, Scleractinia) and their associated microorganisms have attracted much attention. Zoanthids (Cnidaria, Anthozoa, Zoanthidea) are commonly found in coral reefs. However, little is known about the community structure of zoanthid-associated microbiota. In this study, the microbial community associated with the zoanthid Palythoa australiae in the South China Sea was investigated by 454 pyrosequencing. As a result, 2,353 bacterial, 583 archaeal, and 36 eukaryotic microbial ribotypes were detected, respectively. A total of 22 bacterial phyla (16 formally described phyla and six candidate phyla) were recovered. Proteobacteria was the most abundant group, followed by Chloroflexi and Actinobacteria. High-abundance Rhizobiales and diverse Chloroflexi were observed in the bacterial community. The archaeal population was composed of Crenarchaeota and Euryarchaeota, with Marine Group I as the dominant lineage. In particular, Candidatus Nitrosopumilus dominated the archaeal community. Besides bacteria and archaea, the zoanthid harbored eukaryotic microorganisms including fungi and algae though their diversity was very low. This study provided the first insights into the microbial community associated with P. australiae by 454 pyrosequencing, consequently laid a basis for the understanding of the association of P. australiae-microbes symbioses.
Benjamin J Winter
Full Text Available To investigate whether polyomaviruses contribute to interstitial cystitis pathogenesis.A prospective study was performed with 50 interstitial cystitis cases compared with 50 age-matched, disease-free controls for the frequency of polyomaviruria. Associations between polyomaviruria and disease characteristics were analysed in cases. Polyomavirus in urine and bladder tissue was detected with species (JC virus vs. BK virus specific, real-time PCR.Case patients were reflective of interstitial cystitis epidemiology with age range from 26-88 years (median 58 and female predominance (41/50 F. There was a significant increase in the frequency of polyomavirus shedding between cases and controls (p<0.02. Polyomavirus shedding, in particular BK viruria, was associated with vesical ulceration, a marker of disease severity, among interstitial cystitis cases after adjustment for age and sex (OR 6.8, 95% CI 1.89-24.4. There was a significant association among cases between the presence of BK viruria and response to intravesical Clorpactin therapy (OR 4.50, 95% CI 1.17-17.4.The presence of polyomaviruria was found to be associated with the ulcerative form of interstitial cystitis. Clorpactin, which has anti-DNA virus activity, was more likely to improve symptoms in the presence of BK viruria. These data from this pilot study suggest associations between polyomaviruria and interstitial cystitis warranting further investigation.
Abstract The version of this article published in BMC Genomics 2013, 14: 274, contains 9 unpublished genomes (Botryobasidium botryosum, Gymnopus luxurians, Hypholoma sublateritium, Jaapia argillacea, Hebeloma cylindrosporum, Conidiobolus coronatus, Laccaria amethystina, Paxillus involutus, and P. rubicundulus) downloaded from JGI website. In this correction, we removed these genomes after discussion with editors and data producers whom we should have contacted before downloading these genomes. Removing these data did not alter the principle results and conclusions of our original work. The relevant Figures 1, 2, 3, 4 and 6; and Table 1 have been revised. Additional files 1, 3, 4, and 5 were also revised. We would like to apologize for any confusion or inconvenience this may have caused. Background Fungi produce a variety of carbohydrate activity enzymes (CAZymes) for the degradation of plant polysaccharide materials to facilitate infection and/or gain nutrition. Identifying and comparing CAZymes from fungi with different nutritional modes or infection mechanisms may provide information for better understanding of their life styles and infection models. To date, over hundreds of fungal genomes are publicly available. However, a systematic comparative analysis of fungal CAZymes across the entire fungal kingdom has not been reported. Results In this study, we systemically identified glycoside hydrolases (GHs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and glycosyltransferases (GTs) as well as carbohydrate-binding modules (CBMs) in the predicted proteomes of 94 representative fungi from Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota. Comparative analysis of these CAZymes that play major roles in plant polysaccharide degradation revealed that fungi exhibit tremendous diversity in the number and variety of CAZymes. Among them, some families of GHs and CEs are the most prevalent CAZymes that are distributed in all of the fungi analyzed
Zhao, Zhongtao; Liu, Huiquan; Wang, Chenfang; Xu, Jin-Rong
The version of this article published in BMC Genomics 2013, 14: 274, contains 9 unpublished genomes (Botryobasidium botryosum, Gymnopus luxurians, Hypholoma sublateritium, Jaapia argillacea, Hebeloma cylindrosporum, Conidiobolus coronatus, Laccaria amethystina, Paxillus involutus, and P. rubicundulus) downloaded from JGI website. In this correction, we removed these genomes after discussion with editors and data producers whom we should have contacted before downloading these genomes. Removing these data did not alter the principle results and conclusions of our original work. The relevant Figures 1, 2, 3, 4 and 6; and Table 1 have been revised. Additional files 1, 3, 4, and 5 were also revised. We would like to apologize for any confusion or inconvenience this may have caused. Fungi produce a variety of carbohydrate activity enzymes (CAZymes) for the degradation of plant polysaccharide materials to facilitate infection and/or gain nutrition. Identifying and comparing CAZymes from fungi with different nutritional modes or infection mechanisms may provide information for better understanding of their life styles and infection models. To date, over hundreds of fungal genomes are publicly available. However, a systematic comparative analysis of fungal CAZymes across the entire fungal kingdom has not been reported. In this study, we systemically identified glycoside hydrolases (GHs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and glycosyltransferases (GTs) as well as carbohydrate-binding modules (CBMs) in the predicted proteomes of 94 representative fungi from Ascomycota, Basidiomycota, Chytridiomycota, and Zygomycota. Comparative analysis of these CAZymes that play major roles in plant polysaccharide degradation revealed that fungi exhibit tremendous diversity in the number and variety of CAZymes. Among them, some families of GHs and CEs are the most prevalent CAZymes that are distributed in all of the fungi analyzed. Importantly, cellulases of some GH
Fan, Ruzong; Zhang, Yiwei; Albert, Paul S.; Liu, Aiyi; Wang, Yuanjia; Xiong, Momiao
Longitudinal genetic studies provide a valuable resource for exploring key genetic and environmental factors that affect complex traits over time. Genetic analysis of longitudinal data that incorporate temporal variations is important for understanding genetic architecture and biological variations of common complex diseases. Although they are important, there is a paucity of statistical methods to analyze longitudinal human genetic data. In this article, longitudinal methods are developed for temporal association mapping to analyze population longitudinal data. Both parametric and nonparametric models are proposed. The models can be applied to multiple diallelic genetic markers such as single-nucleotide polymorphisms and multiallelic markers such as microsatellites. By analytical formulae, we show that the models take both the linkage disequilibrium and temporal trends into account simultaneously. Variance-covariance structure is constructed to model the single measurement variation and multiple measurement correlations of an individual based on the theory of stochastic processes. Novel penalized spline models are used to estimate the time-dependent mean functions and regression coefficients. The methods were applied to analyze Framingham Heart Study data of Genetic Analysis Workshop (GAW) 13 and GAW 16. The temporal trends and genetic effects of the systolic blood pressure are successfully detected by the proposed approaches. Simulation studies were performed to find out that the nonparametric penalized linear model is the best choice in fitting real data. The research sheds light on the important area of longitudinal genetic analysis, and it provides a basis for future methodological investigations and practical applications. PMID:22965819
The face-name association task can be employed to examine functional alterations of hippocampal activation during encoding of both verbal and non-verbal material in one fMRI paradigm. Further, the left SFG seems to be a convergence region for encoding of verbal and non-verbal material.
van de Water, Jeroen A J M
Gorgonians are key habitat-forming species of Mediterranean benthic communities, but their populations have suffered from mass mortality events linked to high summer seawater temperatures and microbial disease. However, our knowledge on the diversity, dynamics and function of gorgonian-associated microbial communities is limited. Here, we analysed the spatial variability of the microbiomes of five sympatric gorgonian species (Eunicella singularis, Eunicella cavolini, Eunicella verrucosa, Leptogorgia sarmentosa and Paramuricea clavata), collected from the Mediterranean Sea over a scale of ∼1100 km, using next-generation amplicon sequencing of the 16S rRNA gene. The microbiomes of all gorgonian species were generally dominated by members of the genus Endozoicomonas, which were at very low abundance in the surrounding seawater. Although the composition of the core microbiome (operational taxonomic units consistently present in a species) was found to be unique for each host species, significant overlap was observed. These spatially consistent associations between gorgonians and their core bacteria suggest intricate symbiotic relationships and regulation of the microbiome composition by the host. At the same time, local variations in microbiome composition were observed. Functional predictive profiling indicated that these differences could be attributed to seawater pollution. Taken together, our data indicate that gorgonian-associated microbiomes are composed of spatially conserved bacteria (core microbiome members) and locally variant members, and that local pollution may influence these local associations, potentially impacting gorgonian health.
Reimer, James Davis; Hirose, Mamiko; Nishisaka, Taiki; Sinniger, Frederic; Itani, Gyo
Zoanthids (Cnidaria, Hexacorallia) of the genus Epizoanthus are often found in association with other marine invertebrates, including gastropods and hermit crabs. However, little information exists on the specificity and nature of these associations due to a lack of investigation into Epizoanthus species diversity, and the taxonomy of Epizoanthus is therefore confused. In this study, analyses of morphological data (tentacle number, polyp size, etc) and molecular data (mitochondrial cytochrome oxidase subunit 1 = COI, 16S ribosomal DNA = 16S rDNA) were used to examine Epizoanthus specimens from Tosa Bay, Kochi, Japan. The Epizoanthus specimens were found on both live gastropods (Gemmula unedo) and hermit crabs (Paguristes palythophilus) inhabiting G. unedo and G. cosmoi shells. While morphological analyses did not show clear differences between examined specimens, both COI and mt 16S rDNA clearly divided the specimens into two groups, one associated only with hermit crabs (= Epizoanthus sp. C), and another associated only with living gastropods (= Epizoanthus sp. S). Unexpectedly, DNA sequences from both groups did not match with two previously reported Epizoanthus species from Japan (E. indicus, E. ramosus), indicating they both may be undescribed species. These results highlight the utility of DNA "barcoding" of unknown zoanthids, and will provide a foundation for re-examinations of Epizoanthus species diversity and specificity, which will be critical in understanding the evolution of these unique marine invertebrates.
Winter, Benjamin J; O'Connell, Helen E; Bowden, Scott; Carey, Marcus; Eisen, Damon P
To investigate whether polyomaviruses contribute to interstitial cystitis pathogenesis. A prospective study was performed with 50 interstitial cystitis cases compared with 50 age-matched, disease-free controls for the frequency of polyomaviruria. Associations between polyomaviruria and disease characteristics were analysed in cases. Polyomavirus in urine and bladder tissue was detected with species (JC virus vs. BK virus) specific, real-time PCR. Case patients were reflective of interstitial cystitis epidemiology with age range from 26-88 years (median 58) and female predominance (41/50 F). There was a significant increase in the frequency of polyomavirus shedding between cases and controls (pinterstitial cystitis cases after adjustment for age and sex (OR 6.8, 95% CI 1.89-24.4). There was a significant association among cases between the presence of BK viruria and response to intravesical Clorpactin therapy (OR 4.50, 95% CI 1.17-17.4). The presence of polyomaviruria was found to be associated with the ulcerative form of interstitial cystitis. Clorpactin, which has anti-DNA virus activity, was more likely to improve symptoms in the presence of BK viruria. These data from this pilot study suggest associations between polyomaviruria and interstitial cystitis warranting further investigation.
Brassat, D; Motsinger, AA; Caillier, SJ; Erlich, HA; Walker, K; Steiner, LL; Cree, BAC; Barcellos, LF; Pericak-Vance, MA; Schmidt, S; Gregory, S; Hauser, SL; Haines, JL; Oksenberg, JR; Ritchie, MD
Multiple sclerosis (MS) is a common disease of the central nervous system characterized by inflammation, myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Multiple sclerosis exhibits many of the characteristics that distinguish complex genetic disorders including polygenic inheritance and environmental exposure risks. Here, we used a highly efficient multilocus genotyping assay representing variation in 34 genes associated with inflammatory p...
Robinson, Philip C; Claushuis, Theodora A M; Cortes, Adrian; Martin, Tammy M; Evans, David M; Leo, Paul; Mukhopadhyay, Pamela; Bradbury, Linda A; Cremin, Katie; Harris, Jessica; Maksymowych, Walter P; Inman, Robert D; Rahman, Proton; Haroon, Nigil; Gensler, Lianne; Powell, Joseph E; van der Horst-Bruinsma, Irene E; Hewitt, Alex W; Craig, Jamie E; Lim, Lyndell L; Wakefield, Denis; McCluskey, Peter; Voigt, Valentina; Fleming, Peter; Degli-Esposti, Mariapia; Pointon, Jennifer J; Weisman, Michael H; Wordsworth, B Paul; Reveille, John D; Rosenbaum, James T; Brown, Matthew A
To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS). We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription-polymerase chain reaction. A comparison between all patients with AAU and healthy control subjects showed strong association over HLA-B, corresponding to the HLA-B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non-major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P pathways. Copyright © 2015 by the American College of Rheumatology.
Ayling Roger D
Full Text Available Abstract Background Mycoplasma agalactiae is the main cause of contagious agalactia, a serious disease of sheep and goats, which has major clinical and economic impacts. Previous studies of M. agalactiae have shown it to be unusually homogeneous and there are currently no available epidemiological techniques which enable a high degree of strain differentiation. Results We have developed variable number tandem repeat (VNTR analysis using the sequenced genome of the M. agalactiae type strain PG2. The PG2 genome was found to be replete with tandem repeat sequences and 4 were chosen for further analysis. VNTR 5 was located within the hypothetical protein MAG6170 a predicted lipoprotein. VNTR 14 was intergenic between the hypothetical protein MAG3350 and the hypothetical protein MAG3340. VNTR 17 was intergenic between the hypothetical protein MAG4060 and the hypothetical protein MAG4070 and VNTR 19 spanned the 5' end of the pseudogene for a lipoprotein MAG4310 and the 3' end of the hypothetical lipoprotein MAG4320. We have investigated the genetic diversity of 88 M. agalactiae isolates of wide geographic origin using VNTR analysis and compared it with pulsed field gel electrophoresis (PFGE and random amplified polymorphic DNA (RAPD analysis. Simpson's index of diversity was calculated to be 0.324 for PFGE and 0.574 for VNTR analysis. VNTR analysis revealed unexpected diversity within M. agalactiae with 9 different VNTR types discovered. Some correlation was found between geographical origin and the VNTR type of the isolates. Conclusion VNTR analysis represents a useful, rapid first-line test for use in molecular epidemiological analysis of M. agalactiae for outbreak tracing and control.
Full Text Available This study used NMR-based metabolomics to compare the metabolic profile of different anatomical compartments of cereal grains i.e. bran and endosperm in order to gain further insightsinto their possible role in the beneficial health effects of whole grain products (WG. Polar watersoluble metabolites in 64 bran and endosperm, samples from rye and wheat were observed using600 MHz NMR. Bran samples had higher contents of 12 metabolites than endosperm samples. A comparative approach revealed higher contents of azelaic acid and sebacic acid in bran than in endosperm. In a pilot study, the consumption of WG rye bread (485 g caused NMR signals in 24h urine corresponding to azelaic acid. The relatively high abundance, anatomical specificity, patternof metabolism, urinary excretion in human, antibacterial, and anticancer activities suggest further studying of azelaic acid when exposure to WG or beneficial effects of WG are investigated.
John R Shaffer
Full Text Available Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array imputed to the 1000 Genomes reference panel (Phase 3. We observed genome-wide significant associations (p < 5 x 10-8 for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.
Full Text Available In order to identify and reveal the proteins related to encystment of the ciliate Euplotes encysticus, we analyzed variation in the abundance of the proteins isolated from the resting cyst comparing with proteins in the vegetative cell. 2-D electrophoresis, MALDI-TOF MS techniques and Bioinformatics were used for proteome separation, quantification and identification. The comparative proteomics studies revealed 26 proteins with changes on the expression in the resting cysts, including 12 specific proteins and 14 differential proteins. 12 specific proteins and 10 out of the 14 differential proteins were selected and identified by MALDI-TOF MS. The identified specific proteins with known functions included type II cytoskeletal 1, keratin, Nop16 domain containing protein, protein arginine n-methyltransferase, epsilon-trimethyllysine hydroxylase and calpain-like protein. The identified differential proteins with known functions included Lysozyme C, keratinocyte growth factor, lysozyme homolog AT-2, formate acetyltransferase, alpha S1 casein and cold-shock protein. We discussed the functions of these proteins as well as their contribution in the process of encystment. These identified proteins covered a wide range of molecular functions, including gene regulation, RNA regulation, proteins degradation and oxidation resistance, stress response, material transport and cytoskeleton organization. Therefore, differential expression of these proteins was essential for cell morphological and physiological changes during encystment. This suggested that the peculiar proteins and differential proteins might play important roles in the process of the vegetative cells transforming into the resting cysts. These observations may be novel findings that bring new insights into the detailed mechanisms of dormancy.
Full Text Available Boar taint is an offensive odour and/or taste from a proportion of non-castrated male pigs caused by skatole and androstenone accumulation during sexual maturity. Castration is widely used to avoid boar taint but is currently under debate because of animal welfare concerns. This study aimed to identify expression quantitative trait loci (eQTLs with potential effects on boar taint compounds to improve breeding possibilities for reduced boar taint. Danish Landrace male boars with low, medium and high genetic merit for skatole and human nose score (HNS were slaughtered at ~100 kg. Gene expression profiles were obtained by RNA-Seq, and genotype data were obtained by an Illumina 60K Porcine SNP chip. Following quality control and filtering, 10,545 and 12,731 genes from liver and testis were included in the eQTL analysis, together with 20,827 SNP variants. A total of 205 and 109 single-tissue eQTLs associated with 102 and 58 unique genes were identified in liver and testis, respectively. By employing a multivariate Bayesian hierarchical model, 26 eQTLs were identified as significant multi-tissue eQTLs. The highest densities of eQTLs were found on pig chromosomes SSC12, SSC1, SSC13, SSC9 and SSC14. Functional characterisation of eQTLs revealed functions within regulation of androgen and the intracellular steroid hormone receptor signalling pathway and of xenobiotic metabolism by cytochrome P450 system and cellular response to oestradiol. A QTL enrichment test revealed 89 QTL traits curated by the Animal Genome PigQTL database to be significantly overlapped by the genomic coordinates of cis-acting eQTLs. Finally, a subset of 35 cis-acting eQTLs overlapped with known boar taint QTL traits. These eQTLs could be useful in the development of a DNA test for boar taint but careful monitoring of other overlapping QTL traits should be performed to avoid any negative consequences of selection.
Cunningham, Bridget K; Khromykh, Alina; Martinez, Ariel F; Carney, Tyler; Hadley, Donald W; Solomon, Benjamin D
VACTERL association refers to a combination of congenital anomalies that can include: vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula with esophageal atresia, renal anomalies (typically structural renal anomalies), and limb anomalies. We conducted a description of a case series to characterize renal findings in a cohort of patients with VACTERL association. Out of the overall cohort, 48 patients (with at least three component features of VACTERL and who had abdominal ultrasound performed) met criteria for analysis. Four other patients were additionally analyzed separately, with the hypothesis that subtle renal system anomalies may occur in patients who would not otherwise meet criteria for VACTERL association. Thirty-three (69%) of the 48 patients had a clinical manifestation affecting the renal system. The most common renal manifestation (RM) was vesicoureteral reflux (VUR) in addition to a structural defect (present in 27%), followed by unilateral renal agenesis (24%), and then dysplastic/multicystic kidneys or duplicated collected system (18% for each). Twenty-two (88%) of the 25 patients with a structural RM had an associated anorectal malformation. Individuals with either isolated lower anatomic anomalies, or both upper and lower anatomic anomalies were not statistically more likely to have a structural renal defect than those with isolated upper anatomic anomalies (p = 0.22, p = 0.284, respectively). Given the high prevalence of isolated VUR in our cohort, we recommend a screening VCUG or other imaging modality be obtained to evaluate for VUR if initial renal ultrasound shows evidence of obstruction or renal scarring, as well as ongoing evaluation of renal health. © 2014 Wiley Periodicals, Inc.
Krohn-Molt, Ines; Wemheuer, Bernd; Alawi, Malik; Poehlein, Anja; Güllert, Simon; Schmeisser, Christel; Pommerening-Röser, Andreas; Grundhoff, Adam; Daniel, Rolf; Hanelt, Dieter; Streit, Wolfgang R.
Photobioreactors (PBRs) are very attractive for sunlight-driven production of biofuels and capturing of anthropogenic CO2. One major problem associated with PBRs however, is that the bacteria usually associated with microalgae in nonaxenic cultures can lead to biofouling and thereby affect algal productivity. Here, we report on a phylogenetic, metagenome, and functional analysis of a mixed-species bacterial biofilm associated with the microalgae Chlorella vulgaris and Scenedesmus obliquus in ...
Gallo, G.; Renzone, G.; Alduina, R.
A differential proteomic analysis, based on 2-DE and MS procedures, was performed on Amycolatopsis balhimycina DSM5908, the actinomycete producing the vancomycin-like antibiotic balhimycin. A comparison of proteomic profiles before and during balhimycin production characterized differentially...... available over the World Wide Web as interactive web pages (http://www.unipa.it/ampuglia/Abal-proteome-maps). Functional clustering analysis revealed that differentially expressed proteins belong to functional groups involved in central carbon metabolism, amino acid metabolism and protein biosynthesis......, energetic and redox balance, sugar/amino sugar metabolism, balhimycin biosynthesis and transcriptional regulation or with hypothetical and/or unknown function. Interestingly, proteins involved in the biosynthesis of balhimycin precursors, such as amino acids, amino sugars and central carbon metabolism...
Drag, Markus; Hansen, Mathias Brygger; Kadarmideen, Haja N
. Gene expression profiles were obtained by RNA-Seq and genotype data was obtained by Illumina 60K Porcine SNP-chip. Following quality control and filtering, 10,545 and 12,731 genes from liver and testis were included in eQTL analysis by the Matrix eQTL software together with 20,827 SNP variants. A total...
Campanaro, Stefano; Treu, Laura; Kougias, Panagiotis
In the past few years, many studies investigated the anaerobic digestion microbiome by means of 16S rRNA amplicon sequencing. Results obtained from these studies were compared to each other without taking into consideration the followed procedure for amplicons preparation and data analysis...
Full Text Available BACKGROUND: Graves' disease (GD is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA alleles are associated with GD in Asians. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a case-control association study (499 unrelated GD cases and 504 controls and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families. To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR] = 1.33, Bonferroni corrected combined P [P(Bc] = 1.17 x 10⁻², DPB1*05:01 (OR = 2.34, P(Bc = 2.58 x 10⁻¹⁰, DQB1*03:02 (OR = 0.62, P(Bc = 1.97 x 10⁻², DRB1*15:01 (OR = 1.68, P(Bc = 1.22 x 10⁻² and DRB1*16:02 (OR = 2.63, P(Bc = 1.46 x 10⁻⁵ were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk. CONCLUSIONS/SIGNIFICANCE: These GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future
Collins, Ryan L; Hu, Ting; Wejse, Christian; Sirugo, Giorgio; Williams, Scott M; Moore, Jason H
Identifying high-order genetics associations with non-additive (i.e. epistatic) effects in population-based studies of common human diseases is a computational challenge. Multifactor dimensionality reduction (MDR) is a machine learning method that was designed specifically for this problem. The goal of the present study was to apply MDR to mining high-order epistatic interactions in a population-based genetic study of tuberculosis (TB). The study used a previously published data set consisting of 19 candidate single-nucleotide polymorphisms (SNPs) in 321 pulmonary TB cases and 347 healthy controls from Guniea-Bissau in Africa. The ReliefF algorithm was applied first to generate a smaller set of the five most informative SNPs. MDR with 10-fold cross-validation was then applied to look at all possible combinations of two, three, four and five SNPs. The MDR model with the best testing accuracy (TA) consisted of SNPs rs2305619, rs187084, and rs11465421 (TA = 0.588) in PTX3, TLR9 and DC-Sign, respectively. A general 1000-fold permutation test of the null hypothesis of no association confirmed the statistical significance of the model (p = 0.008). An additional 1000-fold permutation test designed specifically to test the linear null hypothesis that the association effects are only additive confirmed the presence of non-additive (i.e. nonlinear) or epistatic effects (p = 0.013). An independent information-gain measure corroborated these results with a third-order epistatic interaction that was stronger than any lower-order associations. We have identified statistically significant evidence for a three-way epistatic interaction that is associated with susceptibility to TB. This interaction is stronger than any previously described one-way or two-way associations. This study highlights the importance of using machine learning methods that are designed to embrace, rather than ignore, the complexity of common diseases such as TB. We recommend future studies of the
Olds, Hayley T.; Dila, Deborah K.; Bootsma, Melinda J.; Corsi, Steven; McLellan, Sandra L.
Sewage contamination of urban waterways from sewer overflows and failing infrastructure is a major environmental and public health concern. Fecal coliforms (FC) are commonly employed as fecal indicator bacteria, but do not distinguish between human and non-human sources of fecal contamination. Human Bacteroides and humanLachnospiraceae, two genetic markers for human-associated indicator bacteria, were used to identify sewage signals in two urban rivers and the estuary that drains to Lake Michigan. Grab samples were collected from the rivers throughout 2012 and 2013 and hourly samples were collected in the estuary across the hydrograph during summer 2013. Human Bacteroides and human Lachnospiraceae were highly correlated with each other in river samples (Pearson’s r = 0.86), with average concentrations at most sites elevated during wet weather. These human indicators were found during baseflow, indicating that sewage contamination is chronic in these waterways. FC are used for determining total maximum daily loads (TMDLs) in management plans; however, FC concentrations alone failed to prioritize river reaches with potential health risks. While 84% of samples with >1000 CFU/100 ml FC had sewage contamination, 52% of samples with moderate (200–1000 CFU/100 ml) and 46% of samples with low (<200 CFU/100 ml) FC levels also had evidence of human sewage. Load calculations in the in the Milwaukee estuary revealed storm-driven sewage contamination varied greatly among events and was highest during an event with a short duration of intense rain. This work demonstrates urban areas have unrecognized sewage inputs that may not be adequately prioritized for remediation by the TMDL process. Further analysis using these approaches could determine relationships between land use, storm characteristics, and other factors that drive sewage contamination in urban waterways.
Li, Zhiqing; Cheng, Daojun; Mon, Hiroaki; Tatsuke, Tsuneyuki; Zhu, Li; Xu, Jian; Lee, Jae Man; Xia, Qingyou; Kusakabe, Takahiro
Polycomb group (PcG) proteins are evolutionarily conserved chromatin modifiers and act together in three multimeric complexes, Polycomb repressive complex 1 (PRC1), Polycomb repressive complex 2 (PRC2), and Pleiohomeotic repressive complex (PhoRC), to repress transcription of the target genes. Here, we identified Polycomb target genes in Bombyx mori with holocentric centromere using genome-wide expression screening based on the knockdown of BmSCE, BmESC, BmPHO, or BmSCM gene, which represent the distinct complexes. As a result, the expressions of 29 genes were up-regulated after knocking down 4 PcG genes. Particularly, there is a significant overlap between targets of BmPho (331 out of 524) and BmScm (331 out of 532), and among these, 190 genes function as regulator factors playing important roles in development. We also found that BmPho, as well as BmScm, can interact with other Polycomb components examined in this study. Further detailed analysis revealed that the C-terminus of BmPho containing zinc finger domain is involved in the interaction between BmPho and BmScm. Moreover, the zinc finger domain in BmPho contributes to its inhibitory function and ectopic overexpression of BmScm is able to promote transcriptional repression by Gal4-Pho fusions including BmScm-interacting domain. Loss of BmPho expression causes relocalization of BmScm into the cytoplasm. Collectively, we provide evidence of a functional link between BmPho and BmScm, and propose two Polycomb-related repression mechanisms requiring only BmPho associated with BmScm or a whole set of PcG complexes.
Full Text Available Polycomb group (PcG proteins are evolutionarily conserved chromatin modifiers and act together in three multimeric complexes, Polycomb repressive complex 1 (PRC1, Polycomb repressive complex 2 (PRC2, and Pleiohomeotic repressive complex (PhoRC, to repress transcription of the target genes. Here, we identified Polycomb target genes in Bombyx mori with holocentric centromere using genome-wide expression screening based on the knockdown of BmSCE, BmESC, BmPHO, or BmSCM gene, which represent the distinct complexes. As a result, the expressions of 29 genes were up-regulated after knocking down 4 PcG genes. Particularly, there is a significant overlap between targets of BmPho (331 out of 524 and BmScm (331 out of 532, and among these, 190 genes function as regulator factors playing important roles in development. We also found that BmPho, as well as BmScm, can interact with other Polycomb components examined in this study. Further detailed analysis revealed that the C-terminus of BmPho containing zinc finger domain is involved in the interaction between BmPho and BmScm. Moreover, the zinc finger domain in BmPho contributes to its inhibitory function and ectopic overexpression of BmScm is able to promote transcriptional repression by Gal4-Pho fusions including BmScm-interacting domain. Loss of BmPho expression causes relocalization of BmScm into the cytoplasm. Collectively, we provide evidence of a functional link between BmPho and BmScm, and propose two Polycomb-related repression mechanisms requiring only BmPho associated with BmScm or a whole set of PcG complexes.
Poulsen, Michael; Oh, Dong-Chan; Clardy, Jon
Identifying new sources for small molecule discovery is necessary to help mitigate the continuous emergence of antibiotic-resistance in pathogenic microbes. Recent studies indicate that one potentially rich source of novel natural products is Actinobacterial symbionts associated with social...... and solitary Hymenoptera. Here we test this possibility by examining two species of solitary mud dauber wasps, Sceliphron caementarium and Chalybion californicum. We performed enrichment isolations from 33 wasps and obtained more than 200 isolates of Streptomyces Actinobacteria. Chemical analyses of 15...... and antibacterial activity. The prevalence and anti-microbial properties of Actinobacteria associated with these two solitary wasp species suggest the potential role of these Streptomyces as antibiotic-producing symbionts, potentially helping defend their wasp hosts from pathogenic microbes. Finding...
Full Text Available Chronic kidney disease (CKD is an increasing global public health concern, particularly among populations of African ancestry. We performed an interrogation of known renal loci, genome-wide association (GWA, and IBC candidate-gene SNP association analyses in African Americans from the CARe Renal Consortium. In up to 8,110 participants, we performed meta-analyses of GWA and IBC array data for estimated glomerular filtration rate (eGFR, CKD (eGFR 30 mg/g and interrogated the 250 kb flanking region around 24 SNPs previously identified in European Ancestry renal GWAS analyses. Findings were replicated in up to 4,358 African Americans. To assess function, individually identified genes were knocked down in zebrafish embryos by morpholino antisense oligonucleotides. Expression of kidney-specific genes was assessed by in situ hybridization, and glomerular filtration was evaluated by dextran clearance. Overall, 23 of 24 previously identified SNPs had direction-consistent associations with eGFR in African Americans, 2 of which achieved nominal significance (UMOD, PIP5K1B. Interrogation of the flanking regions uncovered 24 new index SNPs in African Americans, 12 of which were replicated (UMOD, ANXA9, GCKR, TFDP2, DAB2, VEGFA, ATXN2, GATM, SLC22A2, TMEM60, SLC6A13, and BCAS3. In addition, we identified 3 suggestive loci at DOK6 (p-value = 5.3×10(-7 and FNDC1 (p-value = 3.0×10(-7 for UACR, and KCNQ1 with eGFR (p = 3.6×10(-6. Morpholino knockdown of kcnq1 in the zebrafish resulted in abnormal kidney development and filtration capacity. We identified several SNPs in association with eGFR in African Ancestry individuals, as well as 3 suggestive loci for UACR and eGFR. Functional genetic studies support a role for kcnq1 in glomerular development in zebrafish.
Li, Bingbing; Taylor, Jason R; Wang, Wei; Gao, Chuanji; Guo, Chunyan
Processing fluency appears to influence recognition memory judgements, and the manipulation of fluency, if misattributed to an effect of prior exposure, can result in illusory memory. Although it is well established that fluency induced by masked repetition priming leads to increased familiarity, manipulations of conceptual fluency have produced conflicting results, variously affecting familiarity or recollection. Some recent studies have found that masked conceptual priming increases correct recollection (Taylor & Henson, 2012), and the magnitude of this behavioural effect correlates with analogous fMRI BOLD priming effects in brain regions associated with recollection (Taylor, Buratto, & Henson, 2013). However, the neural correlates and time-courses of masked repetition and conceptual priming were not compared directly in previous studies. The present study used event-related potentials (ERPs) to identify and compare the electrophysiological correlates of masked repetition and conceptual priming and investigate how they contribute to recognition memory. Behavioural results were consistent with previous studies: Repetition primes increased familiarity, whereas conceptual primes increased correct recollection. Masked repetition and conceptual priming also decreased the latency of late parietal component (LPC). Masked repetition priming was associated with an early P200 effect and a later parietal maximum N400 effect, whereas masked conceptual priming was only associated with a central-parietal maximum N400 effect. In addition, the topographic distributions of the N400 repetition priming and conceptual priming effects were different. These results suggest that fluency at different levels of processing is associated with different ERP components, and contributes differentially to subjective recognition memory experiences. Copyright © 2017 Elsevier Inc. All rights reserved.
Cindi L Schwartz
Full Text Available Giardia lamblia is a flagellated, unicellular parasite of mammals infecting over one billion people worldwide. Giardia's two-stage life cycle includes a motile trophozoite stage that colonizes the host small intestine and an infectious cyst form that can persist in the environment. Similar to many eukaryotic cells, Giardia contains several complex microtubule arrays that are involved in motility, chromosome segregation, organelle transport, maintenance of cell shape and transformation between the two life cycle stages. Giardia trophozoites also possess a unique spiral microtubule array, the ventral disc, made of approximately 50 parallel microtubules and associated microribbons, as well as a variety of associated proteins. The ventral disc maintains trophozoite attachment to the host intestinal epithelium. With the help of a combined SEM/microtome based slice and view method called 3View® (Gatan Inc., Pleasanton, CA, we present an entire trophozoite cell reconstruction and describe the arrangement of the major cytoskeletal elements. To aid in future analyses of disc-mediated attachment, we used electron-tomography of freeze-substituted, plastic-embedded trophozoites to explore the detailed architecture of ventral disc microtubules and their associated components. Lastly, we examined the disc microtubule array in three dimensions in unprecedented detail using cryo-electron tomography combined with internal sub-tomogram volume averaging of repetitive domains. We discovered details of protein complexes stabilizing microtubules by attachment to their inner and outer wall. A unique tri-laminar microribbon structure is attached vertically to the disc microtubules and is connected to neighboring microribbons via crossbridges. This work provides novel insight into the structure of the ventral disc microtubules, microribbons and associated proteins. Knowledge of the components comprising these structures and their three-dimensional organization is
Federoff, Monica; Jimenez-Rolando, Belen; Nalls, Michael A; Singleton, Andrew B
Background Research focusing on the role of APOE in Parkinson’s disease (PD) has been largely inconclusive, creating a broad discrepancy in association studies. Objective To elucidate the role of APOE alleles in PD risk by studying a large sample size and controlling for population substructure. Patients and Methods In total, 3465 case and control samples were genotyped, obtained from the NINDS Neurogenetics repository. Results No significant differences in ε4 dosages exist between PD cases and controls. The frequency of ε4 carriers differed slightly between cases and controls at 24% (580/2412) and 26% (270/1053), respectively. Likewise, mean dosages of APOE ε2 were not significantly different between cases and controls. APOE ε2 carriers were observed at a frequency of 13.6% (329/2412) among cases and 15% (158/1053) among controls. Logistic regression models evaluating PD as possibly associated with ε4 or ε2 carrier status and allele dosages yielded no significant results. The mean MMSE score among all PD cases was 28.35 (SD = 2.58) and memory loss was reported in only 11.9% (105/879) of cases. Linear regression models comparing MMSE scores as predicted by ε4 or ε2 carrier status and allele dosages were not significant. Conclusions There is no association between APOE epsilon alleles and Parkinson’s disease. PMID:22349451
Full Text Available Identifying new sources for small molecule discovery is necessary to help mitigate the continuous emergence of antibiotic-resistance in pathogenic microbes. Recent studies indicate that one potentially rich source of novel natural products is Actinobacterial symbionts associated with social and solitary Hymenoptera. Here we test this possibility by examining two species of solitary mud dauber wasps, Sceliphron caementarium and Chalybion californicum. We performed enrichment isolations from 33 wasps and obtained more than 200 isolates of Streptomyces Actinobacteria. Chemical analyses of 15 of these isolates identified 11 distinct and structurally diverse secondary metabolites, including a novel polyunsaturated and polyoxygenated macrocyclic lactam, which we name sceliphrolactam. By pairing the 15 Streptomyces strains against a collection of fungi and bacteria, we document their antifungal and antibacterial activity. The prevalence and anti-microbial properties of Actinobacteria associated with these two solitary wasp species suggest the potential role of these Streptomyces as antibiotic-producing symbionts, potentially helping defend their wasp hosts from pathogenic microbes. Finding phylogenetically diverse and chemically prolific Actinobacteria from solitary wasps suggests that insect-associated Actinobacteria can provide a valuable source of novel natural products of pharmaceutical interest.
Full Text Available To localize the neural generators of the musically elicited mismatch negativity with high temporal resolution we conducted a beamformer analysis (Synthetic Aperture Magnetometry, SAM on magnetoencephalography (MEG data from a previous musical mismatch study. The stimuli consisted of a six-tone melodic sequence comprising broken chords in C- and G-major. The musical sequence was presented within an oddball paradigm in which the last tone was lowered occasionally (20% by a minor third. The beamforming analysis revealed significant right hemispheric neural activation in the superior temporal (STC, inferior frontal (IFC, superior frontal (SFC and orbitofrontal (OFC cortices within a time window of 100-200 ms after the occurrence of a deviant tone. IFC and SFC activation was also observed in the left hemisphere. The pronounced early right inferior frontal activation of the auditory mismatch negativity has not been shown in MEG studies so far. The activation in STC and IFC is consistent with earlier electroencephalography (EEG, optical imaging and functional magnetic resonance imaging (fMRI studies that reveal the auditory and inferior frontal cortices as main generators of the auditory MMN. The observed right hemispheric IFC is also in line with some previous music studies showing similar activation patterns after harmonic syntactic violations. The results demonstrate that a deviant tone within a musical sequence recruits immediately a distributed neural network in frontal and prefrontal areas suggesting that top-down processes are involved when expectation violation occurs within well-known stimuli.
Background Analysis of global gene expression by DNA microarrays is widely used in experimental molecular biology. However, the complexity of such high-dimensional data sets makes it difficult to fully understand the underlying biological features present in the data. The aim of this study is to introduce a method for DNA microarray analysis that provides an intuitive interpretation of data through dimension reduction and pattern recognition. We present the first “Archetypal Analysis” of global gene expression. The analysis is based on microarray data from five integrated studies of Pseudomonas aeruginosa isolated from the airways of cystic fibrosis patients. Results Our analysis clustered samples into distinct groups with comprehensible characteristics since the archetypes representing the individual groups are closely related to samples present in the data set. Significant changes in gene expression between different groups identified adaptive changes of the bacteria residing in the cystic fibrosis lung. The analysis suggests a similar gene expression pattern between isolates with a high mutation rate (hypermutators) despite accumulation of different mutations for these isolates. This suggests positive selection in the cystic fibrosis lung environment, and changes in gene expression for these isolates are therefore most likely related to adaptation of the bacteria. Conclusions Archetypal analysis succeeded in identifying adaptive changes of P. aeruginosa. The combination of clustering and matrix factorization made it possible to reveal minor similarities among different groups of data, which other analytical methods failed to identify. We suggest that this analysis could be used to supplement current methods used to analyze DNA microarray data. PMID:24059747
Pan, Weiran; Li, Gang; Yang, Xiaoxiao; Miao, Jinming
This study aims to explore the potential mechanism of glioma through bioinformatic approaches. The gene expression profile (GSE4290) of glioma tumor and non-tumor samples was downloaded from Gene Expression Omnibus database. A total of 180 samples were available, including 23 non-tumor and 157 tumor samples. Then the raw data were preprocessed using robust multiarray analysis, and 8,890 differentially expressed genes (DEGs) were identified by using t-test (false discovery rate What' more, for the top 10 sub-networks, Gene Ontology (GO) enrichment analysis (p value tissue-specific genes were calculated (p value = 1.0, 1.0, and 0.00014, respectively) and visualized by Venn Diagram package in R. About 61% of human tissue-specific genes were DEGs as well. This research shed new light on the pathogenesis of glioma based on DEGs and GAPN, and our findings might provide potential targets for clinical glioma treatment.
Sliusarenko, Tamara; Clemmensen, Line Katrine Harder
correlation analysis (CCA) to investigate the association between how students evaluate the course and how students evaluate the teacher and to reveal the structure of this association. Student’s evaluation data is characterized by high correlation between the variables (questions) and insufficient sample...
Jun, James J; Longtin, André; Maler, Leonard
Active sensing behaviors reveal what an animal is attending to and how it changes with learning. Gymnotus sp, a gymnotiform weakly electric fish, generates an electric organ discharge (EOD) as discrete pulses to actively sense its surroundings. We monitored freely behaving gymnotid fish in a large dark "maze" and extracted their trajectories and EOD pulse pattern and rate while they learned to find food with electrically detectable landmarks as cues. After training, they more rapidly found food using shorter, more stereotyped trajectories and spent more time near the food location. We observed three forms of active sensing: sustained high EOD rates per unit distance (sampling density), transient large increases in EOD rate (E-scans) and stereotyped scanning movements (B-scans) were initially strong at landmarks and food, but, after learning, intensified only at the food location. During probe (no food) trials, after learning, the fish's search area and intense active sampling was still centered on the missing food location, but now also increased near landmarks. We hypothesize that active sensing is a behavioral manifestation of attention and essential for spatial learning; the fish use spatial memory of landmarks and path integration to reach the expected food location and confine their attention to this region. Copyright © 2016 the American Physiological Society.
Walker, Olivia S; Elsässer, Simon J; Mahesh, Mohan; Bachman, Martin; Balasubramanian, Shankar; Chin, Jason W
Isocitrate dehydrogenase is mutated at a key active site arginine residue (Arg172 in IDH2) in many cancers, leading to the synthesis of the oncometabolite (R)-2-hydroxyglutarate (2HG). To investigate the early events following acquisition of this mutation in mammalian cells we created a photoactivatable version of IDH2(R172K), in which K172 is replaced with a photocaged lysine (PCK), via genetic code expansion. Illumination of cells expressing this mutant protein led to a rapid increase in the levels of 2HG, with 2HG levels reaching those measured in patient tumor samples, within 8 h. 2HG accumulation is closely followed by a global decrease in 5-hydroxymethylcytosine (5-hmC) in DNA, demonstrating that perturbations in epigenetic DNA base modifications are an early consequence of mutant IDH2 in cells. Our results provide a paradigm for rapidly and synchronously uncloaking diverse oncogenic mutations in live cells to reveal the sequence of events through which they may ultimately cause transformation.
Anderson Silva Machado
Full Text Available Toxoplasma gondii is the main infectious cause of human posterior retinochoroiditis, the most frequent clinical manifestation of congenital toxoplasmosis. This investigation was performed after neonatal screening to identify biomarkers of immunity associated with immunopathological features of the disease by flow cytometry. The study included infected infants without NRL and with retinochoroidal lesions (ARL, ACRL, and CRL as well as noninfected individuals (NI. Our data demonstrated that leukocytosis, with increased monocytes and lymphocytes, was a relevant hematological biomarker of ARL. Immunophenotypic analysis also revealed expansion of CD14+CD16+HLA-DRhigh monocytes and CD56dim cytotoxic NK-cells in ARL. Moreover, augmented TCRγδ+ and CD8+ T-cell counts were apparently good biomarkers of morbidity. Biomarker network analysis revealed that complex and intricated networks underscored the negative correlation of monocytes with NK- and B-cells in NRL. The remarkable lack of connections involving B-cells and a relevant shift of NK-cell connections from B-cells toward T-cells observed in ARL were outstanding. A tightly connected biomarker network was observed in CRL, with relevant connections of NK- and CD8+ T-cells with a broad range of cell subsets. Our findings add novel elements to the current knowledge on the innate and adaptive immune responses in congenital toxoplasmosis.
Peng, Qianqian; Li, Jinxi; Tan, Jingze; Yang, Yajun; Zhang, Manfei; Wu, Sijie; Liu, Yu; Zhang, Juan; Qin, Pengfei; Guan, Yaqun; Jiao, Yi; Zhang, Zhaoxia; Sabeti, Pardis C; Tang, Kun; Xu, Shuhua; Jin, Li; Wang, Sijia
An adaptive variant of human Ectodysplasin receptor, EDARV370A, had undergone strong positive selection in East Asia. In mice and humans, EDARV370A was found to affect ectodermal-derived characteristics, including hair thickness, hair shape, active sweat gland density and teeth formation. Facial characteristics are also largely ectodermal derived. In this study, taking advantage of an admixed population of East Asian and European ancestry-the Uyghur, we aim to test whether EDARV370A is affecting facial characteristics and to investigate its pleiotropic nature and genetic model. In a sample of 1027 Uyghurs, we discover that EDARV370A is significantly associated with several facial characteristics, in particular shape of earlobe (P = 3.64 × 10 (-6) ) and type of chin (P = 9.23 × 10 (-5) ), with successful replication in other East Asian populations. Additionally, in this Uyghur population, we replicate previous association findings of incisors shoveling (P = 1.02 × 10 (-7) ), double incisors shoveling (P = 1.86 × 10 (-12) ) and hair straightness (P = 3.99 × 10 (-16) ), providing strong evidence supporting an additive model for the EDARV370A associations. Partial least square path model confirms EDARV370A systematically affect these weakly related ectodermal-derived characteristics, suggesting the pleiotropic effect of EDARV370A mainly plays roles in early embryo development. This study extends our knowledge about the pleiotropic nature of EDARV370A and provides potential clues to its adaptation fitness in human evolution.
Wei, Feifei; Ito, Kengo; Sakata, Kenji; Date, Yasuhiro; Kikuchi, Jun
Extracting useful information from high dimensionality and large data sets is a major challenge for data-driven approaches. The present study was aimed at developing novel integrated analytical strategies for comprehensively characterizing seaweed similarities based on chemical diversity. The chemical compositions of 107 seaweed and 2 seagrass samples were analyzed using multiple techniques, including Fourier transform infrared (FT-IR) and solid- and solution-state nuclear magnetic resonance (NMR) spectroscopy, thermogravimetry-differential thermal analysis (TG-DTA), inductively coupled plasma-optical emission spectrometry (ICP-OES), CHNS/O total elemental analysis, and isotope ratio mass spectrometry (IR-MS). The spectral data were preprocessed using non-negative matrix factorization (NMF) and NMF combined with multivariate curve resolution-alternating least-squares (MCR-ALS) methods in order to separate individual component information from the overlapping and/or broad spectral peaks. Integrated analysis of the preprocessed chemical data demonstrated distinct discrimination of differential seaweed species. Further network analysis revealed a close correlation between the heavy metal elements and characteristic components of brown algae, such as cellulose, alginic acid, and sulfated mucopolysaccharides, providing a componential basis for its metal-sorbing potential. These results suggest that this integrated analytical strategy is useful for extracting and identifying the chemical characteristics of diverse seaweeds based on large chemical data sets, particularly complicated overlapping spectral data.
Mortuza, Gulnahar B; Cavazza, Tommaso; Garcia-Mayoral, Maria Flor
215 (chTOG), dissecting the mechanism by which their interaction promotes microtubule elongation during spindle assembly. Using SAXS, we show that the TACC domain (TD) is an elongated structure that mediates the interaction with the C terminus of XMAP215. Our data suggest that one TD and two XMAP215...... molecules associate to form a four-helix coiled-coil complex. A hybrid methods approach was used to define the precise regions of the TACC heptad repeat and the XMAP215 C terminus required for assembly and functioning of the complex. We show that XTACC3 can induce the recruitment of larger amounts of XMAP...
Full Text Available Pest control in agriculture employs diverse strategies, among which the use of predatory insects has steadily increased. The use of several species within the genus Orius in pest control is widely spread, particularly in Mediterranean Europe. Commercial mass rearing of predatory insects is costly, and research efforts have concentrated on diet manipulation and selective breeding to reduce costs and improve efficacy. The characterisation and contribution of microbial symbionts to Orius sp. fitness, behaviour, and potential impact on human health has been neglected. This paper provides the first genome sequence level description of the predominant culturable facultative bacterial symbionts associated with five Orius species (O. laevigatus, O. niger, O. pallidicornis, O. majusculus, and O. albidipennis from several geographical locations. Two types of symbionts were broadly classified as members of the genera Serratia and Leucobacter, while a third constitutes a new genus within the Erwiniaceae. These symbionts were found to colonise all the insect specimens tested, which evidenced an ancestral symbiotic association between these bacteria and the genus Orius. Pangenome analyses of the Serratia sp. isolates offered clues linking Type VI secretion system effector–immunity proteins from the Tai4 sub-family to the symbiotic lifestyle.
Brassat, D; Motsinger, AA; Caillier, SJ; Erlich, HA; Walker, K; Steiner, LL; Cree, BAC; Barcellos, LF; Pericak-Vance, MA; Schmidt, S; Gregory, S; Hauser, SL; Haines, JL; Oksenberg, JR; Ritchie, MD
Multiple sclerosis (MS) is a common disease of the central nervous system characterized by inflammation, myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Multiple sclerosis exhibits many of the characteristics that distinguish complex genetic disorders including polygenic inheritance and environmental exposure risks. Here, we used a highly efficient multilocus genotyping assay representing variation in 34 genes associated with inflammatory pathways to explore gene–gene interactions and disease susceptibility in a well-characterized African-American case–control MS data set. We applied the multifactor dimensionality reduction (MDR) test to detect epistasis, and identified single-IL4R(Q576R)- and three-IL4R(Q576R), IL5RA(-80), CD14(-260)- locus association models that predict MS risk with 75–76% accuracy (P < 0.01). These results demonstrate the importance of exploring both main effects and gene–gene interactions in the study of complex diseases. PMID:16625214
Brassat, D; Motsinger, A A; Caillier, S J; Erlich, H A; Walker, K; Steiner, L L; Cree, B A C; Barcellos, L F; Pericak-Vance, M A; Schmidt, S; Gregory, S; Hauser, S L; Haines, J L; Oksenberg, J R; Ritchie, M D
Multiple sclerosis (MS) is a common disease of the central nervous system characterized by inflammation, myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Multiple sclerosis exhibits many of the characteristics that distinguish complex genetic disorders including polygenic inheritance and environmental exposure risks. Here, we used a highly efficient multilocus genotyping assay representing variation in 34 genes associated with inflammatory pathways to explore gene-gene interactions and disease susceptibility in a well-characterized African-American case-control MS data set. We applied the multifactor dimensionality reduction (MDR) test to detect epistasis, and identified single-IL4R(Q576R)- and three-IL4R(Q576R), IL5RA(-80), CD14(-260)- locus association models that predict MS risk with 75-76% accuracy (P<0.01). These results demonstrate the importance of exploring both main effects and gene-gene interactions in the study of complex diseases.
Stanton Lawrence W
Full Text Available Abstract Background Transcriptional control of embryonic stem (ES cell pluripotency has been a subject of intense study. Transcriptional regulators including Oct4 (Oct3/4 index, Sox2 and Nanog are fundamental for maintaining the undifferentiated state. However, the ES cell transcriptome is not limited to their targets, and exhibits considerable complexity when assayed with microarray, MPSS, cDNA/EST sequencing, and SAGE technologies. To identify novel genes associated with pluripotency, we globally searched for ES transcripts not corresponding to known genes, validated their sequences, determined their expression profiles, and employed RNAi to test their function. Results Gene Identification Signature (GIS analysis, a SAGE derivative distinguished by paired 5' and 3' transcript end tags, identified 153 candidate novel transcriptional units (TUs distinct from known genes in a mouse E14 ES mRNA library. We focused on 16 TUs free of artefacts and mapping discrepancies, five of which were validated by RTPCR product sequencing. Two of the TUs were revealed by annotation to represent novel protein-coding genes: a PRY-domain cluster member and a KRAB-domain zinc finger. The other three TUs represented intergenic splicing events involving adjacent, functionally unrelated protein-coding genes transcribed in the same orientation, with one event potentially encoding a fusion protein containing domains from both component genes (Clk2 and Scamp3. Expression profiling using embryonic samples and adult tissue panels confirmed that three of the TUs were unique to or most highly expressed in ES cells. Expression levels of all five TUs dropped dramatically during three distinct chemically induced differentiation treatments of ES cells in culture. However, siRNA knockdowns of the TUs did not alter mRNA levels of pluripotency or differentiation markers, and did not affect cell morphology. Conclusion Transcriptome libraries retain considerable potential for novel
Bauer-Mehren, Anna; Bundschus, Markus; Rautschka, Michael; Mayer, Miguel A; Sanz, Ferran; Furlong, Laura I
Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. The
Su, Wen-Hui; Chiu, Chi-Cking; Yao Shugart, Yin
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy highly prevalent in southern China, and incidence rates among Han Chinese people vary according to geographic region. Recently, three independent genome-wide association studies (GWASs) confirmed that HLA-A is the main risk gene for NPC. However, the results of studies conducted in regions with dissimilar incidence rates contradicted the claims that HLA-A is the sole risk gene and that the association of rs29232 is independent of the HLA-A effect in the chromosome 6p21.3 region. We performed a meta-analysis, selecting five single-nucleotide polymorphisms (SNPs) in chromosome 6p21.3 mapped in three published GWASs and four case–control studies. The studies involved 8994 patients with NPC and 11,157 healthy controls, all of whom were Han Chinese. The rs2517713 SNP located downstream of HLA-A was significantly associated with NPC (P = 1.08 × 10 −91 , odds ratio [OR] = 0.58, 95 % confidence interval [CI] = 0.55–0.61). The rs29232 SNP exhibited a moderate level of heterogeneity (I 2 = 47 %) that disappeared (I 2 = 0 %) after stratification by moderate- and high-incidence NPC regions. Our results suggested that the HLA-A gene is strongly associated with NPC risk. In addition, the heterogeneity revealed by the meta-analysis of rs29232 might be associated with regional differences in NPC incidence among Han Chinese people. The higher OR of rs29232 and the fact that rs29232 was independent of the HLA-A effect in the moderate-incidence population suggested that rs29232 might have greater relevance to NPC incidence in a moderate-incidence population than in a high-incidence population. The online version of this article (doi:10.1186/s12885-015-1607-0) contains supplementary material, which is available to authorized users
Jiang, Yue; Xiong, Xuejian; Danska, Jayne; Parkinson, John
Metatranscriptomics is emerging as a powerful technology for the functional characterization of complex microbial communities (microbiomes). Use of unbiased RNA-sequencing can reveal both the taxonomic composition and active biochemical functions of a complex microbial community. However, the lack of established reference genomes, computational tools and pipelines make analysis and interpretation of these datasets challenging. Systematic studies that compare data across microbiomes are needed to demonstrate the ability of such pipelines to deliver biologically meaningful insights on microbiome function. Here, we apply a standardized analytical pipeline to perform a comparative analysis of metatranscriptomic data from diverse microbial communities derived from mouse large intestine, cow rumen, kimchi culture, deep-sea thermal vent and permafrost. Sequence similarity searches allowed annotation of 19 to 76% of putative messenger RNA (mRNA) reads, with the highest frequency in the kimchi dataset due to its relatively low complexity and availability of closely related reference genomes. Metatranscriptomic datasets exhibited distinct taxonomic and functional signatures. From a metabolic perspective, we identified a common core of enzymes involved in amino acid, energy and nucleotide metabolism and also identified microbiome-specific pathways such as phosphonate metabolism (deep sea) and glycan degradation pathways (cow rumen). Integrating taxonomic and functional annotations within a novel visualization framework revealed the contribution of different taxa to metabolic pathways, allowing the identification of taxa that contribute unique functions. The application of a single, standard pipeline confirms that the rich taxonomic and functional diversity observed across microbiomes is not simply an artefact of different analysis pipelines but instead reflects distinct environmental influences. At the same time, our findings show how microbiome complexity and availability of
Price, Jordan V.; Haddon, David J.; Kemmer, Dodge; Delepine, Guillaume; Mandelbaum, Gil; Jarrell, Justin A.; Gupta, Rohit; Balboni, Imelda; Chakravarty, Eliza F.; Sokolove, Jeremy; Shum, Anthony K.; Anderson, Mark S.; Cheng, Mickie H.; Robinson, William H.; Browne, Sarah K.; Holland, Steven M.; Baechler, Emily C.; Utz, Paul J.
Autoantibodies against cytokines, chemokines, and growth factors inhibit normal immunity and are implicated in inflammatory autoimmune disease and diseases of immune deficiency. In an effort to evaluate serum from autoimmune and immunodeficient patients for Abs against cytokines, chemokines, and growth factors in a high-throughput and unbiased manner, we constructed a multiplex protein microarray for detection of serum factor–binding Abs and used the microarray to detect autoantibody targets in SLE. We designed a nitrocellulose-surface microarray containing human cytokines, chemokines, and other circulating proteins and demonstrated that the array permitted specific detection of serum factor–binding probes. We used the arrays to detect previously described autoantibodies against cytokines in samples from individuals with autoimmune polyendocrine syndrome type 1 and chronic mycobacterial infection. Serum profiling from individuals with SLE revealed that among several targets, elevated IgG autoantibody reactivity to B cell–activating factor (BAFF) was associated with SLE compared with control samples. BAFF reactivity correlated with the severity of disease-associated features, including IFN-α–driven SLE pathology. Our results showed that serum factor protein microarrays facilitate detection of autoantibody reactivity to serum factors in human samples and that BAFF-reactive autoantibodies may be associated with an elevated inflammatory disease state within the spectrum of SLE. PMID:24270423
Richard Allen White III
Full Text Available Within the subarctic climate of Clinton Creek, Yukon, Canada, lies an abandoned and flooded open-pit asbestos mine that harbors rapidly growing microbialites. To understand their formation we completed a metagenomic community profile of the microbialites and their surrounding sediments. Assembled metagenomic data revealed that bacteria within the phylum Proteobacteria numerically dominated this system, although the relative abundances of taxa within the phylum varied among environments. Bacteria belonging to Alphaproteobacteria and Gammaproteobacteria were dominant in the microbialites and sediments, respectively. The microbialites were also home to many other groups associated with microbialite formation including filamentous cyanobacteria and dissimilatory sulfate-reducing Deltaproteobacteria, consistent with the idea of a shared global microbialite microbiome. Other members were present that are typically not associated with microbialites including Gemmatimonadetes and iron-oxidizing Betaproteobacteria, which participate in carbon metabolism and iron cycling. Compared to the sediments, the microbialite microbiome has significantly more genes associated with photosynthetic processes (e.g., photosystem II reaction centers, carotenoid and chlorophyll biosynthesis and carbon fixation (e.g., CO dehydrogenase. The Clinton Creek microbialite communities had strikingly similar functional potentials to non-lithifying microbial mats from the Canadian High Arctic and Antarctica, but are functionally distinct, from non-lithifying mats or biofilms from Yellowstone. Clinton Creek microbialites also share metabolic genes (R2 0.900. These metagenomic profiles from an anthropogenic microbialite-forming ecosystem provide context to microbialite formation on a human-relevant timescale.
Younis, Sidra; Javed, Qamar; Blumenberg, Miroslav
EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways. Here we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors. The metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis. This metaanalysis suggests that ‘combination therapies’ can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding
Pannekoek, Yvonne; Dickx, Veerle; Beeckman, Delphine S A; Jolley, Keith A; Keijzers, Wendy C; Vretou, Evangelia; Maiden, Martin C J; Vanrompay, Daisy; van der Ende, Arie
Chlamydia comprises a group of obligate intracellular bacterial parasites responsible for a variety of diseases in humans and animals, including several zoonoses. Chlamydia trachomatis causes diseases such as trachoma, urogenital infection and lymphogranuloma venereum with severe morbidity. Chlamydia pneumoniae is a common cause of community-acquired respiratory tract infections. Chlamydia psittaci, causing zoonotic pneumonia in humans, is usually hosted by birds, while Chlamydia abortus, causing abortion and fetal death in mammals, including humans, is mainly hosted by goats and sheep. We used multi-locus sequence typing to asses the population structure of Chlamydia. In total, 132 Chlamydia isolates were analyzed, including 60 C. trachomatis, 18 C. pneumoniae, 16 C. abortus, 34 C. psittaci and one of each of C. pecorum, C. caviae, C. muridarum and C. felis. Cluster analyses utilizing the Neighbour-Joining algorithm with the maximum composite likelihood model of concatenated sequences of 7 housekeeping fragments showed that C. psittaci 84/2334 isolated from a parrot grouped together with the C. abortus isolates from goats and sheep. Cluster analyses of the individual alleles showed that in all instances C. psittaci 84/2334 formed one group with C. abortus. Moving 84/2334 from the C. psittaci group to the C. abortus group resulted in a significant increase in the number of fixed differences and elimination of the number of shared mutations between C. psittaci and C. abortus. C. psittaci M56 from a muskrat branched separately from the main group of C. psittaci isolates. C. psittaci genotypes appeared to be associated with host species. The phylogenetic tree of C. psittaci did not follow that of its host bird species, suggesting host species jumps. In conclusion, we report for the first time an association between C. psittaci genotypes with host species.
Full Text Available Chlamydia comprises a group of obligate intracellular bacterial parasites responsible for a variety of diseases in humans and animals, including several zoonoses. Chlamydia trachomatis causes diseases such as trachoma, urogenital infection and lymphogranuloma venereum with severe morbidity. Chlamydia pneumoniae is a common cause of community-acquired respiratory tract infections. Chlamydia psittaci, causing zoonotic pneumonia in humans, is usually hosted by birds, while Chlamydia abortus, causing abortion and fetal death in mammals, including humans, is mainly hosted by goats and sheep. We used multi-locus sequence typing to asses the population structure of Chlamydia. In total, 132 Chlamydia isolates were analyzed, including 60 C. trachomatis, 18 C. pneumoniae, 16 C. abortus, 34 C. psittaci and one of each of C. pecorum, C. caviae, C. muridarum and C. felis. Cluster analyses utilizing the Neighbour-Joining algorithm with the maximum composite likelihood model of concatenated sequences of 7 housekeeping fragments showed that C. psittaci 84/2334 isolated from a parrot grouped together with the C. abortus isolates from goats and sheep. Cluster analyses of the individual alleles showed that in all instances C. psittaci 84/2334 formed one group with C. abortus. Moving 84/2334 from the C. psittaci group to the C. abortus group resulted in a significant increase in the number of fixed differences and elimination of the number of shared mutations between C. psittaci and C. abortus. C. psittaci M56 from a muskrat branched separately from the main group of C. psittaci isolates. C. psittaci genotypes appeared to be associated with host species. The phylogenetic tree of C. psittaci did not follow that of its host bird species, suggesting host species jumps. In conclusion, we report for the first time an association between C. psittaci genotypes with host species.
Deshpande, Nandan P; Kaakoush, Nadeem O; Wilkins, Marc R; Mitchell, Hazel M
In spite of its association with gastroenteritis and inflammatory bowel diseases, the isolation of Campylobacter concisus from both diseased and healthy individuals has led to controversy regarding its role as an intestinal pathogen. One proposed reason for this is the presence of high genetic diversity among the genomes of C. concisus strains. In this study the genomes of six C. concisus strains were sequenced, assembled and annotated including two strains isolated from Crohn's disease patients (UNSW2 and UNSW3), three from gastroenteritis patients (UNSW1, UNSWCS and ATCC 51562) and one from a healthy individual (ATCC 51561). The genomes of C. concisus BAA-1457 and UNSWCD, available from NCBI, were included in subsequent comparative genomic analyses. The Pan and Core genomes for the sequenced C. concisus strains consisted of 3254 and 1556 protein coding genes, respectively. Genes were identified with specific conservation in C. concisus strains grouped by phenotypes such as invasiveness, adherence, motility and diseased states. Phylogenetic trees based on ribosomal RNA sequences and concatenated host-related pathways for the eight C. concisus strains were generated using the neighbor-joining method, of which the 16S rRNA gene and peptidoglycan biosynthesis grouped the C. concisus strains according to their pathogenic phenotypes. Furthermore, 25 non-synonymous amino acid changes with 14 affecting functional domains, were identified within proteins of conserved host-related pathways, which had possible associations with the pathogenic potential of C. concisus strains. Finally, the genomes of the eight C. concisus strains were compared to the nine available genomes of the well-established pathogen Campylobacter jejuni, which identified several important differences in the respiration pathways of these two species. Our findings indicate that C. concisus strains are genetically diverse, and suggest the genomes of this bacterium contain respiration pathways and
Full Text Available Metagenomic methods amplifying 16S ribosomal RNA genes have been used to describe the microbial diversity of healthy skin and lesion stages of bovine digital dermatitis (DD and to detect critical pathogens involved with disease pathogenesis. In this study, we characterized the microbiome and for the first time, the composition of functional genes of healthy skin (HS, active (ADD and inactive (IDD lesion stages using a whole-genome shotgun approach. Metagenomic sequences were annotated using MG-RAST pipeline. Six phyla were identified as the most abundant. Firmicutes and Actinobacteria were the predominant bacterial phyla in the microbiome of HS, while Spirochetes, Bacteroidetes and Proteobacteria were highly abundant in ADD and IDD. T. denticola-like, T. vincentii-like and T. phagedenis-like constituted the most abundant species in ADD and IDD. Recruitment plots comparing sequences from HS, ADD and IDD samples to the genomes of specific Treponema spp., supported the presence of T. denticola and T. vincentii in ADD and IDD. Comparison of the functional composition of HS to ADD and IDD identified a significant difference in genes associated with motility/chemotaxis and iron acquisition/metabolism. We also provide evidence that the microbiome of ADD and IDD compared to that of HS had significantly higher abundance of genes associated with resistance to copper and zinc, which are commonly used in footbaths to prevent and control DD. In conclusion, the results from this study provide new insights into the HS, ADD and IDD microbiomes, improve our understanding of the disease pathogenesis and generate unprecedented knowledge regarding the functional genetic composition of the digital dermatitis microbiome.
Full Text Available This is the first report on the phylogenetic analysis of the community diversity of a single spontaneous cocoa bean box fermentation sample through a metagenomic approach involving 454 pyrosequencing. Several sequence-based and composition-based taxonomic profiling tools were used and evaluated to avoid software-dependent results and their outcome was validated by comparison with previously obtained culture-dependent and culture-independent data. Overall, this approach revealed a wider bacterial (mainly γ-Proteobacteria and fungal diversity than previously found. Further, the use of a combination of different classification methods, in a software-independent way, helped to understand the actual composition of the microbial ecosystem under study. In addition, bacteriophage-related sequences were found. The bacterial diversity depended partially on the methods used, as composition-based methods predicted a wider diversity than sequence-based methods, and as classification methods based solely on phylogenetic marker genes predicted a more restricted diversity compared with methods that took all reads into account. The metagenomic sequencing analysis identified Hanseniaspora uvarum, Hanseniaspora opuntiae, Saccharomyces cerevisiae, Lactobacillus fermentum, and Acetobacter pasteurianus as the prevailing species. Also, the presence of occasional members of the cocoa bean fermentation process was revealed (such as Erwinia tasmaniensis, Lactobacillus brevis, Lactobacillus casei, Lactobacillus rhamnosus, Lactococcus lactis, Leuconostoc mesenteroides, and Oenococcus oeni. Furthermore, the sequence reads associated with viral communities were of a restricted diversity, dominated by Myoviridae and Siphoviridae, and reflecting Lactobacillus as the dominant host. To conclude, an accurate overview of all members of a cocoa bean fermentation process sample was revealed, indicating the superiority of metagenomic sequencing over previously used techniques.
Illeghems, Koen; De Vuyst, Luc; Papalexandratou, Zoi; Weckx, Stefan
This is the first report on the phylogenetic analysis of the community diversity of a single spontaneous cocoa bean box fermentation sample through a metagenomic approach involving 454 pyrosequencing. Several sequence-based and composition-based taxonomic profiling tools were used and evaluated to avoid software-dependent results and their outcome was validated by comparison with previously obtained culture-dependent and culture-independent data. Overall, this approach revealed a wider bacterial (mainly γ-Proteobacteria) and fungal diversity than previously found. Further, the use of a combination of different classification methods, in a software-independent way, helped to understand the actual composition of the microbial ecosystem under study. In addition, bacteriophage-related sequences were found. The bacterial diversity depended partially on the methods used, as composition-based methods predicted a wider diversity than sequence-based methods, and as classification methods based solely on phylogenetic marker genes predicted a more restricted diversity compared with methods that took all reads into account. The metagenomic sequencing analysis identified Hanseniaspora uvarum, Hanseniaspora opuntiae, Saccharomyces cerevisiae, Lactobacillus fermentum, and Acetobacter pasteurianus as the prevailing species. Also, the presence of occasional members of the cocoa bean fermentation process was revealed (such as Erwinia tasmaniensis, Lactobacillus brevis, Lactobacillus casei, Lactobacillus rhamnosus, Lactococcus lactis, Leuconostoc mesenteroides, and Oenococcus oeni). Furthermore, the sequence reads associated with viral communities were of a restricted diversity, dominated by Myoviridae and Siphoviridae, and reflecting Lactobacillus as the dominant host. To conclude, an accurate overview of all members of a cocoa bean fermentation process sample was revealed, indicating the superiority of metagenomic sequencing over previously used techniques.
Full Text Available Streptococcus suis is a zoonotic pathogen that can cause severe pathologies such as septicemia and meningitis in its natural porcine host as well as in humans. Establishment of disease requires not only virulence of the infecting strain but also an appropriate metabolic activity of the pathogen in its host environment. However, it is yet largely unknown how the streptococcal metabolism adapts to the different host niches encountered during infection. Our previous isotopologue profiling studies on S. suis grown in porcine blood and cerebrospinal fluid (CSF revealed conserved activities of central carbon metabolism in both body fluids. On the other hand, they suggested differences in the de novo amino acid biosynthesis. This prompted us to further dissect S. suis adaptation to porcine blood and CSF by RNA deep sequencing (RNA-seq. In blood, the majority of differentially expressed genes were associated with transport of alternative carbohydrate sources and the carbohydrate metabolism (pentose phosphate pathway, glycogen metabolism. In CSF, predominantly genes involved in the biosynthesis of branched-chain and aromatic amino acids were differentially expressed. Especially, isoleucine biosynthesis seems to be of major importance for S. suis in CSF because several related biosynthetic genes were more highly expressed. In conclusion, our data revealed niche-specific metabolic gene activity which emphasizes a selective adaptation of S. suis to host environments.