Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility.

PubMed

Bruse, Shannon; Moreau, Michael; Bromberg, Yana; Jang, Jun-Ho; Wang, Nan; Ha, Hongseok; Picchi, Maria; Lin, Yong; Langley, Raymond J; Qualls, Clifford; Klensney-Tait, Julia; Zabner, Joseph; Leng, Shuguang; Mao, Jenny; Belinsky, Steven A; Xing, Jinchuan; Nyunoya, Toru

2016-01-07

Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible airflow limitation in response to inhalation of noxious stimuli, such as cigarette smoke. However, only 15-20 % smokers manifest COPD, suggesting a role for genetic predisposition. Although genome-wide association studies have identified common genetic variants that are associated with susceptibility to COPD, effect sizes of the identified variants are modest, as is the total heritability accounted for by these variants. In this study, an extreme phenotype exome sequencing study was combined with in vitro modeling to identify COPD candidate genes. We performed whole exome sequencing of 62 highly susceptible smokers and 30 exceptionally resistant smokers to identify rare variants that may contribute to disease risk or resistance to COPD. This was a cross-sectional case-control study without therapeutic intervention or longitudinal follow-up information. We identified candidate genes based on rare variant analyses and evaluated exonic variants to pinpoint individual genes whose function was computationally established to be significantly different between susceptible and resistant smokers. Top scoring candidate genes from these analyses were further filtered by requiring that each gene be expressed in human bronchial epithelial cells (HBECs). A total of 81 candidate genes were thus selected for in vitro functional testing in cigarette smoke extract (CSE)-exposed HBECs. Using small interfering RNA (siRNA)-mediated gene silencing experiments, we showed that silencing of several candidate genes augmented CSE-induced cytotoxicity in vitro. Our integrative analysis through both genetic and functional approaches identified two candidate genes (TACC2 and MYO1E) that augment cigarette smoke (CS)-induced cytotoxicity and, potentially, COPD susceptibility.

Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI.

PubMed

Vimaleswaran, Karani S; Tachmazidou, Ioanna; Zhao, Jing Hua; Hirschhorn, Joel N; Dudbridge, Frank; Loos, Ruth J F

2012-10-15

Before the advent of genome-wide association studies (GWASs), hundreds of candidate genes for obesity-susceptibility had been identified through a variety of approaches. We examined whether those obesity candidate genes are enriched for associations with body mass index (BMI) compared with non-candidate genes by using data from a large-scale GWAS. A thorough literature search identified 547 candidate genes for obesity-susceptibility based on evidence from animal studies, Mendelian syndromes, linkage studies, genetic association studies and expression studies. Genomic regions were defined to include the genes ±10 kb of flanking sequence around candidate and non-candidate genes. We used summary statistics publicly available from the discovery stage of the genome-wide meta-analysis for BMI performed by the genetic investigation of anthropometric traits consortium in 123 564 individuals. Hypergeometric, rank tail-strength and gene-set enrichment analysis tests were used to test for the enrichment of association in candidate compared with non-candidate genes. The hypergeometric test of enrichment was not significant at the 5% P-value quantile (P = 0.35), but was nominally significant at the 25% quantile (P = 0.015). The rank tail-strength and gene-set enrichment tests were nominally significant for the full set of genes and borderline significant for the subset without SNPs at P < 10(-7). Taken together, the observed evidence for enrichment suggests that the candidate gene approach retains some value. However, the degree of enrichment is small despite the extensive number of candidate genes and the large sample size. Studies that focus on candidate genes have only slightly increased chances of detecting associations, and are likely to miss many true effects in non-candidate genes, at least for obesity-related traits.

An Analysis of Self-Efficacy Perceptions of Physical Education and Sport Teacher Candidates and Other Teacher Candidates on Teaching Profession

ERIC Educational Resources Information Center

Ozer, Tugce; Demirel, Duygu H.

2017-01-01

Aim of this research is to identify the self-efficacy perception levels of teacher candidates studying at department of Physical Education and Sport and other teaching departments towards teaching profession, to present whether these the self-efficacy perceptions differ or not depending on independent variables acquired from the personal…

Breast Tumors with Elevated Expression of 1q Candidate Genes Confer Poor Clinical Outcome and Sensitivity to Ras/PI3K Inhibition

PubMed Central

Viveka Thangaraj, Soundara; Periasamy, Jayaprakash; Bhaskar Rao, Divya; Barnabas, Georgina D.; Raghavan, Swetha; Ganesan, Kumaresan

2013-01-01

Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K / AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA–drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors. PMID:24147022

Cross Matching as Strategy to Find Radio Stars

NASA Astrophysics Data System (ADS)

Christian, Tiffany; Kimball, Amy

2018-01-01

Using cross-matching between the FIRST (20cm) and GPS1 (optical) catalogs, we identified possible radio star candidates. This is an extension of earlier work by Kimball et al. (2009), who sought to identify radiostar candidates by cross-matching the FIRST (radio)and SDSS (optical) catalogs, but did not include the consideration of stellar proper motions. We used proper motions from GPS1 to match with FIRST radio sources; the region of sky where they overlap contains ~900,000 FIRST sources and several million GPS1 sources. We used WISE near-infrared and PanSTARRS optical information to identify matches that have stellar colors. Our selection constraints identified 6 stars (spectroscopically confirmed) as radio star candidates. They are faint in the radio (<1 mJy) indicating we may be searching at the limits of the radio survey. Other candidates had no spectral confirmation or object type identification in SIMBAD, which would make them ideal for follow up radio observations. However, random analysis indicated that many other possible candidates were random associations, which may also be true for these 6 stars.

Biomarkers identified by urinary metabonomics for noninvasive diagnosis of nutritional rickets.

PubMed

Wang, Maoqing; Yang, Xue; Ren, Lihong; Li, Songtao; He, Xuan; Wu, Xiaoyan; Liu, Tingting; Lin, Liqun; Li, Ying; Sun, Changhao

2014-09-05

Nutritional rickets is a worldwide public health problem; however, the current diagnostic methods retain shortcomings for accurate diagnosis of nutritional rickets. To identify urinary biomarkers associated with nutritional rickets and establish a noninvasive diagnosis method, urinary metabonomics analysis by ultra-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry and multivariate statistical analysis were employed to investigate the metabolic alterations associated with nutritional rickets in 200 children with or without nutritional rickets. The pathophysiological changes and pathogenesis of nutritional rickets were illustrated by the identified biomarkers. By urinary metabolic profiling, 31 biomarkers of nutritional rickets were identified and five candidate biomarkers for clinical diagnosis were screened and identified by quantitative analysis and receiver operating curve analysis. Urinary levels of five candidate biomarkers were measured using mass spectrometry or commercial kits. In the validation step, the combination of phosphate and sebacic acid was able to give a noninvasive and accurate diagnostic with high sensitivity (94.0%) and specificity (71.2%). Furthermore, on the basis of the pathway analysis of biomarkers, our urinary metabonomics analysis gives new insight into the pathogenesis and pathophysiology of nutritional rickets.

Electron Microscopy Abrasion Analysis of Candidate Fabrics for Planetary Space Suit Protective Overgarment Application

NASA Technical Reports Server (NTRS)

Hennessy, Mary J.

1992-01-01

The Electron Microscopy Abrasion Analysis of Candidate Fabrics for Planetary Space Suit Protective Overgarment Application is in support of the Abrasion Resistance Materials Screening Test. The fundamental assumption made for the SEM abrasion analysis was that woven fabrics to be used as the outermost layer of the protective overgarment in the design of the future, planetary space suits perform best when new. It is the goal of this study to determine which of the candidate fabrics was abraded the least in the tumble test. The sample that was abraded the least will be identified at the end of the report as the primary candidate fabric for further investigation. In addition, this analysis will determine if the abrasion seen by the laboratory tumbled samples is representative of actual EVA Apollo abrasion.

3p22.1p21.31 microdeletion identifies CCK as Asperger syndrome candidate gene and shows the way for therapeutic strategies in chromosome imbalances.

PubMed

Iourov, Ivan Y; Vorsanova, Svetlana G; Voinova, Victoria Y; Yurov, Yuri B

2015-01-01

In contrast to other autism spectrum disorders, chromosome abnormalities are rare in Asperger syndrome (AS) or high-functioning autism. Consequently, AS was occasionally subjected to classical positional cloning. Here, we report on a case of AS associated with a deletion of the short arm of chromosome 3. Further in silico analysis has identified a candidate gene for AS and has suggested a therapeutic strategy for manifestations of the chromosome rearrangement. Using array comparative genomic hybridization, an interstitial deletion of 3p22.1p21.31 (~2.5 Mb in size) in a child with Asperger's syndrome, seborrheic dermatitis and chronic pancreatitis was detected. Original bioinformatic approach to the prioritization of candidate genes/processes identified CCK (cholecystokinin) as a candidate gene for AS. In addition to processes associated with deleted genes, bioinformatic analysis of CCK gene interactome indicated that zinc deficiency might be a pathogenic mechanism in this case. This suggestion was supported by plasma zinc concentration measurements. The increase of zinc intake produced a rise in zinc plasma concentration and the improvement in the patient's condition. Our study supported previous linkage findings and had suggested a new candidate gene in AS. Moreover, bioinformatic analysis identified the pathogenic mechanism, which was used to propose a therapeutic strategy for manifestations of the deletion. The relative success of this strategy allows speculating that therapeutic or dietary normalization of metabolic processes altered by a chromosome imbalance or genomic copy number variations may be a way for treating at least a small proportion of cases of these presumably incurable genetic conditions.

Analysis of shared homozygosity regions in Saudi siblings with attention deficit hyperactivity disorder

PubMed Central

Al Yemni, Eman A.A.; Alnaemi, Faten M.; Abebe, Dejene; Al-Abdulaziz, Basma S.; Al Mubarak, Bashayer R.; Ghaziuddin, Mohammad; Al Tassan, Nada A.

2017-01-01

Aim Genetic and clinical complexities are common features of most psychiatric illnesses that pose a major obstacle in risk-gene identification. Attention deficit hyperactivity disorder (ADHD) is the most prevalent child-onset psychiatric illness, with high heritability. Over the past decade, numerous genetic studies utilizing various approaches, such as genome-wide association, candidate-gene association, and linkage analysis, have identified a multitude of candidate loci/genes. However, such studies have yielded diverse findings that are rarely reproduced, indicating that other genetic determinants have not been discovered yet. In this study, we carried out sib-pair analysis on seven multiplex families with ADHD from Saudi Arabia. We aimed to identify the candidate chromosomal regions and genes linked to the disease. Patients and methods A total of 41 individuals from multiplex families were analyzed for shared regions of homozygosity. Genes within these regions were prioritized according to their potential relevance to ADHD. Results We identified multiple genomic regions spanning different chromosomes to be shared among affected members of each family; these included chromosomes 3, 5, 6, 7, 8, 9, 10, 13, 17, and 18. We also found specific regions on chromosomes 8 and 17 to be shared between affected individuals from more than one family. Among the genes present in the regions reported here were involved in neurotransmission (GRM3, SIGMAR1, CHAT, and SLC18A3) and members of the HLA gene family (HLA-A, HLA-DPA1, and MICC). Conclusion The candidate regions identified in this study highlight the genetic diversity of ADHD. Upon further investigation, these loci may reveal candidate genes that enclose variants associated with ADHD. Although most ADHD studies were conducted in other populations, our study provides insight from an understudied, ethnically interesting population. PMID:28452824

Analysis of shared homozygosity regions in Saudi siblings with attention deficit hyperactivity disorder.

PubMed

Shinwari, Jameela M A; Al Yemni, Eman A A; Alnaemi, Faten M; Abebe, Dejene; Al-Abdulaziz, Basma S; Al Mubarak, Bashayer R; Ghaziuddin, Mohammad; Al Tassan, Nada A

2017-08-01

Genetic and clinical complexities are common features of most psychiatric illnesses that pose a major obstacle in risk-gene identification. Attention deficit hyperactivity disorder (ADHD) is the most prevalent child-onset psychiatric illness, with high heritability. Over the past decade, numerous genetic studies utilizing various approaches, such as genome-wide association, candidate-gene association, and linkage analysis, have identified a multitude of candidate loci/genes. However, such studies have yielded diverse findings that are rarely reproduced, indicating that other genetic determinants have not been discovered yet. In this study, we carried out sib-pair analysis on seven multiplex families with ADHD from Saudi Arabia. We aimed to identify the candidate chromosomal regions and genes linked to the disease. A total of 41 individuals from multiplex families were analyzed for shared regions of homozygosity. Genes within these regions were prioritized according to their potential relevance to ADHD. We identified multiple genomic regions spanning different chromosomes to be shared among affected members of each family; these included chromosomes 3, 5, 6, 7, 8, 9, 10, 13, 17, and 18. We also found specific regions on chromosomes 8 and 17 to be shared between affected individuals from more than one family. Among the genes present in the regions reported here were involved in neurotransmission (GRM3, SIGMAR1, CHAT, and SLC18A3) and members of the HLA gene family (HLA-A, HLA-DPA1, and MICC). The candidate regions identified in this study highlight the genetic diversity of ADHD. Upon further investigation, these loci may reveal candidate genes that enclose variants associated with ADHD. Although most ADHD studies were conducted in other populations, our study provides insight from an understudied, ethnically interesting population.

Using whole-exome sequencing to identify variants inherited from mosaic parents

PubMed Central

Rios, Jonathan J; Delgado, Mauricio R

2015-01-01

Whole-exome sequencing (WES) has allowed the discovery of genes and variants causing rare human disease. This is often achieved by comparing nonsynonymous variants between unrelated patients, and particularly for sporadic or recessive disease, often identifies a single or few candidate genes for further consideration. However, despite the potential for this approach to elucidate the genetic cause of rare human disease, a majority of patients fail to realize a genetic diagnosis using standard exome analysis methods. Although genetic heterogeneity contributes to the difficulty of exome sequence analysis between patients, it remains plausible that rare human disease is not caused by de novo or recessive variants. Multiple human disorders have been described for which the variant was inherited from a phenotypically normal mosaic parent. Here we highlight the potential for exome sequencing to identify a reasonable number of candidate genes when dominant disease variants are inherited from a mosaic parent. We show the power of WES to identify a limited number of candidate genes using this disease model and how sequence coverage affects identification of mosaic variants by WES. We propose this analysis as an alternative to discover genetic causes of rare human disorders for which typical WES approaches fail to identify likely pathogenic variants. PMID:24986828

Secretome Characterization and Correlation Analysis Reveal Putative Pathogenicity Mechanisms and Identify Candidate Avirulence Genes in the Wheat Stripe Rust Fungus Puccinia striiformis f. sp. tritici.

PubMed

Xia, Chongjing; Wang, Meinan; Cornejo, Omar E; Jiwan, Derick A; See, Deven R; Chen, Xianming

2017-01-01

Stripe (yellow) rust, caused by Puccinia striiformis f. sp. tritici ( Pst ), is one of the most destructive diseases of wheat worldwide. Planting resistant cultivars is an effective way to control this disease, but race-specific resistance can be overcome quickly due to the rapid evolving Pst population. Studying the pathogenicity mechanisms is critical for understanding how Pst virulence changes and how to develop wheat cultivars with durable resistance to stripe rust. We re-sequenced 7 Pst isolates and included additional 7 previously sequenced isolates to represent balanced virulence/avirulence profiles for several avirulence loci in seretome analyses. We observed an uneven distribution of heterozygosity among the isolates. Secretome comparison of Pst with other rust fungi identified a large portion of species-specific secreted proteins, suggesting that they may have specific roles when interacting with the wheat host. Thirty-two effectors of Pst were identified from its secretome. We identified candidates for Avr genes corresponding to six Yr genes by correlating polymorphisms for effector genes to the virulence/avirulence profiles of the 14 Pst isolates. The putative AvYr76 was present in the avirulent isolates, but absent in the virulent isolates, suggesting that deleting the coding region of the candidate avirulence gene has produced races virulent to resistance gene Yr76 . We conclude that incorporating avirulence/virulence phenotypes into correlation analysis with variations in genomic structure and secretome, particularly presence/absence polymorphisms of effectors, is an efficient way to identify candidate Avr genes in Pst . The candidate effector genes provide a rich resource for further studies to determine the evolutionary history of Pst populations and the co-evolutionary arms race between Pst and wheat. The Avr candidates identified in this study will lead to cloning avirulence genes in Pst , which will enable us to understand molecular mechanisms underlying Pst -wheat interactions, to determine the effectiveness of resistance genes and further to develop durable resistance to stripe rust.

Rapid Communication: MiR-92a as a housekeeping gene for analysis of bovine mastitis-related microRNA in milk.

PubMed

Lai, Y C; Fujikawa, T; Ando, T; Kitahara, G; Koiwa, M; Kubota, C; Miura, N

2017-06-01

Our aim was to identify a suitable microRNA housekeeping gene for real-time PCR analysis of bovine mastitis-related microRNA in milk. We identified , , and as housekeeping gene candidates on the basis of previous Solexa sequencing results. Threshold cycle (CT) values for , , and did not differ between milk from control cows and milk from mastitis-affected cows. NormFinder software identified as the most stable single housekeeping gene. We evaluated the suitability of the housekeeping gene candidates by using them to assess expression levels of the inflammation-related gene . Regardless of the housekeeping gene candidates used for normalization, relative expression levels of were significantly higher in mastitis-affected samples than in control samples. However, of all the housekeeping genes and gene combinations investigated, normalization with alone generated the difference in relative expression between mastitis-affected and control samples with the highest significance. These results suggest that is suitable for use as a housekeeping gene for analysis of bovine mastitis-related microRNA in milk.

Comparative Genomics and Immunoinformatics Approach for the Identification of Vaccine Candidates for Enterohemorrhagic Escherichia coli O157:H7

PubMed Central

García-Angulo, Víctor A.; Kalita, Anjana; Kalita, Mridul; Lozano, Luis

2014-01-01

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 strains are major human food-borne pathogens, responsible for bloody diarrhea and hemolytic-uremic syndrome worldwide. Thus far, there is no vaccine for humans against EHEC infections. In this study, a comparative genomics analysis was performed to identify EHEC-specific antigens useful as potential vaccines. The genes present in both EHEC EDL933 and Sakai strains but absent in nonpathogenic E. coli K-12 and HS strains were subjected to an in silico analysis to identify secreted or surface-expressed proteins. We obtained a total of 65 gene-encoding protein candidates, which were subjected to immunoinformatics analysis. Our criteria of selection aided in categorizing the candidates as high, medium, and low priority. Three members of each group were randomly selected and cloned into pVAX-1. Candidates were pooled accordingly to their priority group and tested for immunogenicity against EHEC O157:H7 using a murine model of gastrointestinal infection. The high-priority (HP) pool, containing genes encoding a Lom-like protein (pVAX-31), a putative pilin subunit (pVAX-12), and a fragment of the type III secretion structural protein EscC (pVAX-56.2), was able to induce the production of EHEC IgG and sIgA in sera and feces. HP candidate-immunized mice displayed elevated levels of Th2 cytokines and diminished cecum colonization after wild-type challenge. Individually tested HP vaccine candidates showed that pVAX-12 and pVAX-56.2 significantly induced Th2 cytokines and production of fecal EHEC sIgA, with pVAX-56.2 reducing EHEC cecum colonization. We describe here a bioinformatics approach able to identify novel vaccine candidates potentially useful for preventing EHEC O157:H7 infections. PMID:24595137

CHROMOSPHERIC EMISSION OF PLANET CANDIDATE HOST STARS: A WAY TO IDENTIFY FALSE POSITIVES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karoff, Christoffer; Knudsen, Mads Faurschou; Albrecht, Simon

2016-10-10

It has been hypothesized that the presence of closely orbiting giant planets is associated with enhanced chromospheric emission of their host stars. The main cause for such a relation would likely be enhanced dynamo action induced by the planet. We present measurements of chromospheric emission in 234 planet candidate systems from the Kepler mission. This ensemble includes 37 systems with giant-planet candidates, which show a clear emission enhancement. The enhancement, however, disappears when systems that are also identified as eclipsing binary candidates are removed from the ensemble. This suggests that a large fraction of the giant-planet candidate systems with chromosphericmore » emission stronger than the Sun are not giant-planet systems, but false positives. Such false-positive systems could be tidally interacting binaries with strong chromospheric emission. This hypothesis is supported by an analysis of 188 eclipsing binary candidates that show increasing chromospheric emission as function of decreasing orbital period.« less

Defense Workforce Training Programs.

ERIC Educational Resources Information Center

Fletcher, J. D.; And Others

This report discusses the amount and kinds of Department of Defense (DoD) interactive courseware (ICW) programs that are candidates for transfer to the private sector. Candidates for transfer were identified through an analysis of the Defense Instructional Technology Information System (DITIS). Out of 4,644 ICW programs that have been reported to…

From genomes to vaccines: Leishmania as a model.

PubMed Central

Almeida, Renata; Norrish, Alan; Levick, Mark; Vetrie, David; Freeman, Tom; Vilo, Jaak; Ivens, Alasdair; Lange, Uta; Stober, Carmel; McCann, Sharon; Blackwell, Jenefer M

2002-01-01

The 35 Mb genome of Leishmania should be sequenced by late 2002. It contains approximately 8500 genes that will probably translate into more than 10 000 proteins. In the laboratory we have been piloting strategies to try to harness the power of the genome-proteome for rapid screening of new vaccine candidate. To this end, microarray analysis of 1094 unique genes identified using an EST analysis of 2091 cDNA clones from spliced leader libraries prepared from different developmental stages of Leishmania has been employed. The plan was to identify amastigote-expressed genes that could be used in high-throughput DNA-vaccine screens to identify potential new vaccine candidates. Despite the lack of transcriptional regulation that polycistronic transcription in Leishmania dictates, the data provide evidence for a high level of post-transcriptional regulation of RNA abundance during the developmental cycle of promastigotes in culture and in lesion-derived amastigotes of Leishmania major. This has provided 147 candidates from the 1094 unique genes that are specifically upregulated in amastigotes and are being used in vaccine studies. Using DNA vaccination, it was demonstrated that pooling strategies can work to identify protective vaccines, but it was found that some potentially protective antigens are masked by other disease-exacerbatory antigens in the pool. A total of 100 new vaccine candidates are currently being tested separately and in pools to extend this analysis, and to facilitate retrospective bioinformatic analysis to develop predictive algorithms for sequences that constitute potentially protective antigens. We are also working with other members of the Leishmania Genome Network to determine whether RNA expression determined by microarray analyses parallels expression at the protein level. We believe we are making good progress in developing strategies that will allow rapid translation of the sequence of Leishmania into potential interventions for disease control in humans. PMID:11839176

CT colonography: influence of 3D viewing and polyp candidate features on interpretation with computer-aided detection.

PubMed

Shi, Rong; Schraedley-Desmond, Pamela; Napel, Sandy; Olcott, Eric W; Jeffrey, R Brooke; Yee, Judy; Zalis, Michael E; Margolis, Daniel; Paik, David S; Sherbondy, Anthony J; Sundaram, Padmavathi; Beaulieu, Christopher F

2006-06-01

To retrospectively determine if three-dimensional (3D) viewing improves radiologists' accuracy in classifying true-positive (TP) and false-positive (FP) polyp candidates identified with computer-aided detection (CAD) and to determine candidate polyp features that are associated with classification accuracy, with known polyps serving as the reference standard. Institutional review board approval and informed consent were obtained; this study was HIPAA compliant. Forty-seven computed tomographic (CT) colonography data sets were obtained in 26 men and 10 women (age range, 42-76 years). Four radiologists classified 705 polyp candidates (53 TP candidates, 652 FP candidates) identified with CAD; initially, only two-dimensional images were used, but these were later supplemented with 3D rendering. Another radiologist unblinded to colonoscopy findings characterized the features of each candidate, assessed colon distention and preparation, and defined the true nature of FP candidates. Receiver operating characteristic curves were used to compare readers' performance, and repeated-measures analysis of variance was used to test features that affect interpretation. Use of 3D viewing improved classification accuracy for three readers and increased the area under the receiver operating characteristic curve to 0.96-0.97 (P<.001). For TP candidates, maximum polyp width (P=.038), polyp height (P=.019), and preparation (P=.004) significantly affected accuracy. For FP candidates, colonic segment (P=.007), attenuation (P<.001), surface smoothness (P<.001), distention (P=.034), preparation (P<.001), and true nature of candidate lesions (P<.001) significantly affected accuracy. Use of 3D viewing increases reader accuracy in the classification of polyp candidates identified with CAD. Polyp size and examination quality are significantly associated with accuracy. Copyright (c) RSNA, 2006.

Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis.

PubMed

Collins, Mahlon A; An, Jiyan; Hood, Brian L; Conrads, Thomas P; Bowser, Robert P

2015-11-06

Analysis of the cerebrospinal fluid (CSF) proteome has proven valuable to the study of neurodegenerative disorders. To identify new protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis (ALS), we performed comparative proteomic profiling of CSF from sporadic ALS (sALS), healthy control (HC), and other neurological disease (OND) subjects using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1712 CSF proteins were detected and relatively quantified by spectral counting. Levels of several proteins with diverse biological functions were significantly altered in sALS samples. Enrichment analysis was used to link these alterations to biological pathways, which were predominantly related to inflammation, neuronal activity, and extracellular matrix regulation. We then used our CSF proteomic profiles to create a support vector machines classifier capable of discriminating training set ALS from non-ALS (HC and OND) samples. Four classifier proteins, WD repeat-containing protein 63, amyloid-like protein 1, SPARC-like protein 1, and cell adhesion molecule 3, were identified by feature selection and externally validated. The resultant classifier distinguished ALS from non-ALS samples with 83% sensitivity and 100% specificity in an independent test set. Collectively, our results illustrate the utility of CSF proteomic profiling for identifying ALS protein/pathway alterations and candidate disease biomarkers.

Fourteen-Genome Comparison Identifies DNA Markers for Severe-Disease-Associated Strains of Clostridium difficile▿†

PubMed Central

Forgetta, Vincenzo; Oughton, Matthew T.; Marquis, Pascale; Brukner, Ivan; Blanchette, Ruth; Haub, Kevin; Magrini, Vince; Mardis, Elaine R.; Gerding, Dale N.; Loo, Vivian G.; Miller, Mark A.; Mulvey, Michael R.; Rupnik, Maja; Dascal, Andre; Dewar, Ken

2011-01-01

Clostridium difficile is a common cause of infectious diarrhea in hospitalized patients. A severe and increased incidence of C. difficile infection (CDI) is associated predominantly with the NAP1 strain; however, the existence of other severe-disease-associated (SDA) strains and the extensive genetic diversity across C. difficile complicate reliable detection and diagnosis. Comparative genome analysis of 14 sequenced genomes, including those of a subset of NAP1 isolates, allowed the assessment of genetic diversity within and between strain types to identify DNA markers that are associated with severe disease. Comparative genome analysis of 14 isolates, including five publicly available strains, revealed that C. difficile has a core genome of 3.4 Mb, comprising ∼3,000 genes. Analysis of the core genome identified candidate DNA markers that were subsequently evaluated using a multistrain panel of 177 isolates, representing more than 50 pulsovars and 8 toxinotypes. A subset of 117 isolates from the panel had associated patient data that allowed assessment of an association between the DNA markers and severe CDI. We identified 20 candidate DNA markers for species-wide detection and 10,683 single nucleotide polymorphisms (SNPs) associated with the predominant SDA strain (NAP1). A species-wide detection candidate marker, the sspA gene, was found to be the same across 177 sequenced isolates and lacked significant similarity to those of other species. Candidate SNPs in genes CD1269 and CD1265 were found to associate more closely with disease severity than currently used diagnostic markers, as they were also present in the toxin A-negative and B-positive (A-B+) strain types. The genetic markers identified illustrate the potential of comparative genomics for the discovery of diagnostic DNA-based targets that are species specific or associated with multiple SDA strains. PMID:21508155

Development and testing of new candidate psoriatic arthritis screening questionnaires combining optimal questions from existing tools.

PubMed

Coates, Laura C; Walsh, Jessica; Haroon, Muhammad; FitzGerald, Oliver; Aslam, Tariq; Al Balushi, Farida; Burden, A D; Burden-Teh, Esther; Caperon, Anna R; Cerio, Rino; Chattopadhyay, Chandrabhusan; Chinoy, Hector; Goodfield, Mark J D; Kay, Lesley; Kelly, Stephen; Kirkham, Bruce W; Lovell, Christopher R; Marzo-Ortega, Helena; McHugh, Neil; Murphy, Ruth; Reynolds, Nick J; Smith, Catherine H; Stewart, Elizabeth J C; Warren, Richard B; Waxman, Robin; Wilson, Hilary E; Helliwell, Philip S

2014-09-01

Several questionnaires have been developed to screen for psoriatic arthritis (PsA), but head-to-head studies have found limitations. This study aimed to develop new questionnaires encompassing the most discriminative questions from existing instruments. Data from the CONTEST study, a head-to-head comparison of 3 existing questionnaires, were used to identify items with a Youden index score of ≥0.1. These were combined using 4 approaches: CONTEST (simple additions of questions), CONTESTw (weighting using logistic regression), CONTESTjt (addition of a joint manikin), and CONTESTtree (additional questions identified by classification and regression tree [CART] analysis). These candidate questionnaires were tested in independent data sets. Twelve individual questions with a Youden index score of ≥0.1 were identified, but 4 of these were excluded due to duplication and redundancy. Weighting for 2 of these questions was included in CONTESTw. Receiver operating characteristic (ROC) curve analysis showed that involvement in 6 joint areas on the manikin was predictive of PsA for inclusion in CONTESTjt. CART analysis identified a further 5 questions for inclusion in CONTESTtree. CONTESTtree was not significant on ROC curve analysis and discarded. The other 3 questionnaires were significant in all data sets, although CONTESTw was slightly inferior to the others in the validation data sets. Potential cut points for referral were also discussed. Of 4 candidate questionnaires combining existing discriminatory items to identify PsA in people with psoriasis, 3 were found to be significant on ROC curve analysis. Testing in independent data sets identified 2 questionnaires (CONTEST and CONTESTjt) that should be pursued for further prospective testing. Copyright © 2014 by the American College of Rheumatology.

Quantitative Trait Loci for BMD in an SM/J by NZB/BlNJ Intercross Population and Identification of Trps1 as a Probable Candidate Gene

PubMed Central

Ishimori, Naoki; Stylianou, Ioannis M; Korstanje, Ron; Marion, Michael A; Li, Renhua; Donahue, Leah Rae; Rosen, Clifford J; Beamer, Wesley G; Paigen, Beverly; Churchill, Gary A

2008-01-01

Identification of genes that regulate BMD will enhance our understanding of osteoporosis and could provide novel molecular targets for treatment or prevention. We generated a mouse intercross population and carried out a quantitative trait locus (QTL) analysis of 143 female and 124 male F2 progeny from progenitor strains SM/J and NZB/BlNJ using whole body and vertebral areal BMD (aBMD) as measured by DXA. We found that both whole body and vertebral aBMD was affected by two loci on chromosome 9: one with a significant epistatic interaction on distal chromosome 8 and the other with a sex-specific effect. Two additional significant QTLs were identified on chromosome 12, and several suggestive ones were identified on chromosomes 5, 8, 15, and 19. The chromosome 9, 12, and 15 loci have been previously identified in other crosses. SNP-based haplotype analysis of the progenitor strains identified blocks within the QTL region that distinguish the low allele strains from the high allele strains, significantly narrowing the QTL region and reducing the possible candidate genes to 98 for chromosome 9, 31 for chromosome 12, and only 2 for chromosome 15. Trps1 is the most probable candidate gene for the chromosome 15 QTL. The sex-specific effects may help to elucidate the BMD differences between males and females. This study shows the power of statistical modeling to resolve linked QTLs and the use of haplotype analysis in narrowing the list of candidates. PMID:18442308

Identification and characterization of nuclear genes involved in photosynthesis in Populus

PubMed Central

2014-01-01

Background The gap between the real and potential photosynthetic rate under field conditions suggests that photosynthesis could potentially be improved. Nuclear genes provide possible targets for improving photosynthetic efficiency. Hence, genome-wide identification and characterization of the nuclear genes affecting photosynthetic traits in woody plants would provide key insights on genetic regulation of photosynthesis and identify candidate processes for improvement of photosynthesis. Results Using microarray and bulked segregant analysis strategies, we identified differentially expressed nuclear genes for photosynthesis traits in a segregating population of poplar. We identified 515 differentially expressed genes in this population (FC ≥ 2 or FC ≤ 0.5, P < 0.05), 163 up-regulated and 352 down-regulated. Real-time PCR expression analysis confirmed the microarray data. Singular Enrichment Analysis identified 48 significantly enriched GO terms for molecular functions (28), biological processes (18) and cell components (2). Furthermore, we selected six candidate genes for functional examination by a single-marker association approach, which demonstrated that 20 SNPs in five candidate genes significantly associated with photosynthetic traits, and the phenotypic variance explained by each SNP ranged from 2.3% to 12.6%. This revealed that regulation of photosynthesis by the nuclear genome mainly involves transport, metabolism and response to stimulus functions. Conclusions This study provides new genome-scale strategies for the discovery of potential candidate genes affecting photosynthesis in Populus, and for identification of the functions of genes involved in regulation of photosynthesis. This work also suggests that improving photosynthetic efficiency under field conditions will require the consideration of multiple factors, such as stress responses. PMID:24673936

Partial genome assembly for a candidate division OP11 single cell from an anoxic spring (Zodletone Spring, Oklahoma).

PubMed

Youssef, Noha H; Blainey, Paul C; Quake, Stephen R; Elshahed, Mostafa S

2011-11-01

Members of candidate division OP11 are widely distributed in terrestrial and marine ecosystems, yet little information regarding their metabolic capabilities and ecological role within such habitats is currently available. Here, we report on the microfluidic isolation, multiple-displacement-amplification, pyrosequencing, and genomic analysis of a single cell (ZG1) belonging to candidate division OP11. Genome analysis of the ∼270-kb partial genome assembly obtained showed that it had no particular similarity to a specific phylum. Four hundred twenty-three open reading frames were identified, 46% of which had no function prediction. In-depth analysis revealed a heterotrophic lifestyle, with genes encoding endoglucanase, amylopullulanase, and laccase enzymes, suggesting a capacity for utilization of cellulose, starch, and, potentially, lignin, respectively. Genes encoding several glycolysis enzymes as well as formate utilization were identified, but no evidence for an electron transport chain was found. The presence of genes encoding various components of lipopolysaccharide biosynthesis indicates a Gram-negative bacterial cell wall. The partial genome also provides evidence for antibiotic resistance (β-lactamase, aminoglycoside phosphotransferase), as well as antibiotic production (bacteriocin) and extracellular bactericidal peptidases. Multiple mechanisms for stress response were identified, as were elements of type I and type IV secretion systems. Finally, housekeeping genes identified within the partial genome were used to demonstrate the OP11 affiliation of multiple hitherto unclassified genomic fragments from multiple database-deposited metagenomic data sets. These results provide the first glimpse into the lifestyle of a member of a ubiquitous, yet poorly understood bacterial candidate division.

QTL-seq approach identified genomic regions and diagnostic markers for rust and late leaf spot resistance in groundnut (Arachis hypogaea L.).

PubMed

Pandey, Manish K; Khan, Aamir W; Singh, Vikas K; Vishwakarma, Manish K; Shasidhar, Yaduru; Kumar, Vinay; Garg, Vanika; Bhat, Ramesh S; Chitikineni, Annapurna; Janila, Pasupuleti; Guo, Baozhu; Varshney, Rajeev K

2017-08-01

Rust and late leaf spot (LLS) are the two major foliar fungal diseases in groundnut, and their co-occurrence leads to significant yield loss in addition to the deterioration of fodder quality. To identify candidate genomic regions controlling resistance to rust and LLS, whole-genome resequencing (WGRS)-based approach referred as 'QTL-seq' was deployed. A total of 231.67 Gb raw and 192.10 Gb of clean sequence data were generated through WGRS of resistant parent and the resistant and susceptible bulks for rust and LLS. Sequence analysis of bulks for rust and LLS with reference-guided resistant parent assembly identified 3136 single-nucleotide polymorphisms (SNPs) for rust and 66 SNPs for LLS with the read depth of ≥7 in the identified genomic region on pseudomolecule A03. Detailed analysis identified 30 nonsynonymous SNPs affecting 25 candidate genes for rust resistance, while 14 intronic and three synonymous SNPs affecting nine candidate genes for LLS resistance. Subsequently, allele-specific diagnostic markers were identified for three SNPs for rust resistance and one SNP for LLS resistance. Genotyping of one RIL population (TAG 24 × GPBD 4) with these four diagnostic markers revealed higher phenotypic variation for these two diseases. These results suggest usefulness of QTL-seq approach in precise and rapid identification of candidate genomic regions and development of diagnostic markers for breeding applications. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

A transposon-based genetic screen in mice identifies genes altered in colorectal cancer.

PubMed

Starr, Timothy K; Allaei, Raha; Silverstein, Kevin A T; Staggs, Rodney A; Sarver, Aaron L; Bergemann, Tracy L; Gupta, Mihir; O'Sullivan, M Gerard; Matise, Ilze; Dupuy, Adam J; Collier, Lara S; Powers, Scott; Oberg, Ann L; Asmann, Yan W; Thibodeau, Stephen N; Tessarollo, Lino; Copeland, Neal G; Jenkins, Nancy A; Cormier, Robert T; Largaespada, David A

2009-03-27

Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.

Genome-wide transcriptome study in wheat identified candidate genes related to processing quality, majority of them showing interaction (quality x development) and having temporal and spatial distributions.

PubMed

Singh, Anuradha; Mantri, Shrikant; Sharma, Monica; Chaudhury, Ashok; Tuli, Rakesh; Roy, Joy

2014-01-16

The cultivated bread wheat (Triticum aestivum L.) possesses unique flour quality, which can be processed into many end-use food products such as bread, pasta, chapatti (unleavened flat bread), biscuit, etc. The present wheat varieties require improvement in processing quality to meet the increasing demand of better quality food products. However, processing quality is very complex and controlled by many genes, which have not been completely explored. To identify the candidate genes whose expressions changed due to variation in processing quality and interaction (quality x development), genome-wide transcriptome studies were performed in two sets of diverse Indian wheat varieties differing for chapatti quality. It is also important to understand the temporal and spatial distributions of their expressions for designing tissue and growth specific functional genomics experiments. Gene-specific two-way ANOVA analysis of expression of about 55 K transcripts in two diverse sets of Indian wheat varieties for chapatti quality at three seed developmental stages identified 236 differentially expressed probe sets (10-fold). Out of 236, 110 probe sets were identified for chapatti quality. Many processing quality related key genes such as glutenin and gliadins, puroindolines, grain softness protein, alpha and beta amylases, proteases, were identified, and many other candidate genes related to cellular and molecular functions were also identified. The ANOVA analysis revealed that the expression of 56 of 110 probe sets was involved in interaction (quality x development). Majority of the probe sets showed differential expression at early stage of seed development i.e. temporal expression. Meta-analysis revealed that the majority of the genes expressed in one or a few growth stages indicating spatial distribution of their expressions. The differential expressions of a few candidate genes such as pre-alpha/beta-gliadin and gamma gliadin were validated by RT-PCR. Therefore, this study identified several quality related key genes including many other genes, their interactions (quality x development) and temporal and spatial distributions. The candidate genes identified for processing quality and information on temporal and spatial distributions of their expressions would be useful for designing wheat improvement programs for processing quality either by changing their expression or development of single nucleotide polymorphisms (SNPs) markers.

Genome-wide transcriptome study in wheat identified candidate genes related to processing quality, majority of them showing interaction (quality x development) and having temporal and spatial distributions

PubMed Central

2014-01-01

Background The cultivated bread wheat (Triticum aestivum L.) possesses unique flour quality, which can be processed into many end-use food products such as bread, pasta, chapatti (unleavened flat bread), biscuit, etc. The present wheat varieties require improvement in processing quality to meet the increasing demand of better quality food products. However, processing quality is very complex and controlled by many genes, which have not been completely explored. To identify the candidate genes whose expressions changed due to variation in processing quality and interaction (quality x development), genome-wide transcriptome studies were performed in two sets of diverse Indian wheat varieties differing for chapatti quality. It is also important to understand the temporal and spatial distributions of their expressions for designing tissue and growth specific functional genomics experiments. Results Gene-specific two-way ANOVA analysis of expression of about 55 K transcripts in two diverse sets of Indian wheat varieties for chapatti quality at three seed developmental stages identified 236 differentially expressed probe sets (10-fold). Out of 236, 110 probe sets were identified for chapatti quality. Many processing quality related key genes such as glutenin and gliadins, puroindolines, grain softness protein, alpha and beta amylases, proteases, were identified, and many other candidate genes related to cellular and molecular functions were also identified. The ANOVA analysis revealed that the expression of 56 of 110 probe sets was involved in interaction (quality x development). Majority of the probe sets showed differential expression at early stage of seed development i.e. temporal expression. Meta-analysis revealed that the majority of the genes expressed in one or a few growth stages indicating spatial distribution of their expressions. The differential expressions of a few candidate genes such as pre-alpha/beta-gliadin and gamma gliadin were validated by RT-PCR. Therefore, this study identified several quality related key genes including many other genes, their interactions (quality x development) and temporal and spatial distributions. Conclusions The candidate genes identified for processing quality and information on temporal and spatial distributions of their expressions would be useful for designing wheat improvement programs for processing quality either by changing their expression or development of single nucleotide polymorphisms (SNPs) markers. PMID:24433256

Comparative genomics study for the identification of drug and vaccine targets in Staphylococcus aureus: MurA ligase enzyme as a proposed candidate.

PubMed

Ghosh, Soma; Prava, Jyoti; Samal, Himanshu Bhusan; Suar, Mrutyunjay; Mahapatra, Rajani Kanta

2014-06-01

Now-a-days increasing emergence of antibiotic-resistant pathogenic microorganisms is one of the biggest challenges for management of disease. In the present study comparative genomics, metabolic pathways analysis and additional parameters were defined for the identification of 94 non-homologous essential proteins in Staphylococcus aureus genome. Further study prioritized 19 proteins as vaccine candidates where as druggability study reports 34 proteins suitable as drug targets. Enzymes from peptidoglycan biosynthesis, folate biosynthesis were identified as candidates for drug development. Furthermore, bacterial secretory proteins and few hypothetical proteins identified in our analysis fulfill the criteria of vaccine candidates. As a case study, we built a homology model of one of the potential drug target, MurA ligase, using MODELLER (9v12) software. The model has been further selected for in silico docking study with inhibitors from the DrugBank database. Results from this study could facilitate selection of proteins for entry into drug design and vaccine production pipelines. Copyright © 2014 Elsevier B.V. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Batalha, Natalie M.; /San Jose State U.; Rowe, Jason F.

New transiting planet candidates are identified in sixteen months (May 2009 - September 2010) of data from the Kepler spacecraft. Nearly five thousand periodic transit-like signals are vetted against astrophysical and instrumental false positives yielding 1091 viable new planet candidates, bringing the total count up to over 2,300. Improved vetting metrics are employed, contributing to higher catalog reliability. Most notable is the noise-weighted robust averaging of multiquarter photo-center offsets derived from difference image analysis which identifies likely background eclipsing binaries. Twenty-two months of photometry are used for the purpose of characterizing each of the new candidates. Ephemerides (transit epoch, T{submore » 0}, and orbital period, P) are tabulated as well as the products of light curve modeling: reduced radius (R{sub P}/R{sub {star}}), reduced semi-major axis (d/R{sub {star}}), and impact parameter (b). The largest fractional increases are seen for the smallest planet candidates (197% for candidates smaller than 2R{sub {circle_plus}} compared to 52% for candidates larger than 2R{sub {circle_plus}}) and those at longer orbital periods (123% for candidates outside of 50 day orbits versus 85% for candidates inside of 50 day orbits). The gains are larger than expected from increasing the observing window from thirteen months (Quarter 1 - Quarter 5) to sixteen months (Quarter 1 - Quarter 6). This demonstrates the benefit of continued development of pipeline analysis software. The fraction of all host stars with multiple candidates has grown from 17% to 20%, and the paucity of short-period giant planets in multiple systems is still evident. The progression toward smaller planets at longer orbital periods with each new catalog release suggests that Earth-size planets in the Habitable Zone are forthcoming if, indeed, such planets are abundant.« less

Young Stellar Object Candidates in the Aquila Rift Region

NASA Astrophysics Data System (ADS)

Zhang, Miao-miao; Wang, Hong-chi; Stecklum, B.

2010-10-01

Using the 2m telescope of the Turingia State Observatory at Tauten-berg (TLS), imaging observations in 3 wavebands (H α, R and I) are performed in the 16 fields in the Aquila Rift region. The observed fields cover about 7 square degrees. Excluding the 3 fields with unqualified data, the photometrical analysis is made for the remaining 13 fields, from which point sources are identified, and finally 7 H α emission-line star candidates are identified by color-color diagrams. The 7 candidates are located in five fields. Three of them are located near the Galactic plane, while the galactic latitudes of the rest are greater than 4°. The 2 M ASS counterparts of the point sources are identified, and the properties of the 7 H α emission-line star candidates are further analyzed by using the two-color diagrams. It is found that the near-infrared radiation from these H α emission-line star candidates has no obvious infrared excess, one of them even falls on the main-sequence branch. This indicates that the H α-emissive young stellar objects (YSOs) are not always accompanied with the infrared excess, and that the results of the H α emission line observation and the infrared excess observation are mutually supplemented. If the 7 H α emission-line star candidates are regarded as YSO candidates, then the number of YSOs in the Aquila Rift region is quite small. The further confirmation of these candidates needs subsequent spectral observations.

E+A Galaxy Properties and Post-Starburst Galaxy Evolution Data through SDSS-IV MaNGA and Illustris: A Co-Analysis

NASA Astrophysics Data System (ADS)

Ojanen, Winonah; Dudley, Raymond; Edwards, Kay; Gonzalez, Andrea; Johnson, Amalya; Kerrison, Nicole; Marinelli, Mariarosa; Melchert, Nancy; Liu, Charles; Sloan Collaboration, SDSS-IV MaNGA

2018-01-01

E+A galaxies (Elliptical + A-type stars) are post-starburst galaxies that have experienced a sudden quenching phase. Using previous research methods, 39 candidates out of 2,812 galaxies observed, or 1.4%, were selected from the SDSS-IV MaNGA survey. We then identified morphological characteristics of the 39 galaxies including stellar kinematics, Gini coefficient, gas density and distribution and stellar ages. To study the origin of how E+A galaxies evolved to their present state, galaxy simulation data from the Illustris simulation was utilized to identify similar quenched post-starburst candidates. Seven post-starburst candidates were identified through star formation rate histories of Illustris simulated galaxies. The evolution of these galaxies is studied from 0 to 13.8 billion years ago to identify what caused the starburst and quenching of the Illustris candidates. Similar morphological characteristics of Illustris post-starburst candidates are pulled from before, during, and post-starburst and compared to the same morphological characteristics of the E+A galaxies from SDSS-IV MaNGA. The characteristics and properties of the Illustris galaxies are used to identify the possible evolutionary histories of the observed E+A galaxies. This work was supported by grants AST-1460860 from the National Science Foundation and SDSS FAST/SSP-483 from the Alfred P. Sloan Foundation to the CUNY College of Staten Island.

Combined semi-empirical screening and design of experiments (DOE) approach to identify candidate formulations of a lyophilized live attenuated tetravalent viral vaccine candidate.

PubMed

Patel, Ashaben; Erb, Steven M; Strange, Linda; Shukla, Ravi S; Kumru, Ozan S; Smith, Lee; Nelson, Paul; Joshi, Sangeeta B; Livengood, Jill A; Volkin, David B

2018-05-24

A combination experimental approach, utilizing semi-empirical excipient screening followed by statistical modeling using design of experiments (DOE), was undertaken to identify stabilizing candidate formulations for a lyophilized live attenuated Flavivirus vaccine candidate. Various potential pharmaceutical compounds used in either marketed or investigative live attenuated viral vaccine formulations were first identified. The ability of additives from different categories of excipients, either alone or in combination, were then evaluated for their ability to stabilize virus against freeze-thaw, freeze-drying, and accelerated storage (25°C) stresses by measuring infectious virus titer. An exploratory data analysis and predictive DOE modeling approach was subsequently undertaken to gain a better understanding of the interplay between the key excipients and stability of virus as well as to determine which combinations were interacting to improve virus stability. The lead excipient combinations were identified and tested for stabilizing effects using a tetravalent mixture of viruses in accelerated and real time (2-8°C) stability studies. This work demonstrates the utility of combining semi-empirical excipient screening and DOE experimental design strategies in the formulation development of lyophilized live attenuated viral vaccine candidates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Exome Sequencing and Linkage Analysis Identified Novel Candidate Genes in Recessive Intellectual Disability Associated with Ataxia.

PubMed

Jazayeri, Roshanak; Hu, Hao; Fattahi, Zohreh; Musante, Luciana; Abedini, Seyedeh Sedigheh; Hosseini, Masoumeh; Wienker, Thomas F; Ropers, Hans Hilger; Najmabadi, Hossein; Kahrizi, Kimia

2015-10-01

Intellectual disability (ID) is a neuro-developmental disorder which causes considerable socio-economic problems. Some ID individuals are also affected by ataxia, and the condition includes different mutations affecting several genes. We used whole exome sequencing (WES) in combination with homozygosity mapping (HM) to identify the genetic defects in five consanguineous families among our cohort study, with two affected children with ID and ataxia as major clinical symptoms. We identified three novel candidate genes, RIPPLY1, MRPL10, SNX14, and a new mutation in known gene SURF1. All are autosomal genes, except RIPPLY1, which is located on the X chromosome. Two are housekeeping genes, implicated in transcription and translation regulation and intracellular trafficking, and two encode mitochondrial proteins. The pathogenesis of these variants was evaluated by mutation classification, bioinformatic methods, review of medical and biological relevance, co-segregation studies in the particular family, and a normal population study. Linkage analysis and exome sequencing of a small number of affected family members is a powerful new technique which can be used to decrease the number of candidate genes in heterogenic disorders such as ID, and may even identify the responsible gene(s).

Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis.

PubMed

Thomassen, Mads; Tan, Qihua; Kruse, Torben A

2009-01-01

Breast cancer cells exhibit complex karyotypic alterations causing deregulation of numerous genes. Some of these genes are probably causal for cancer formation and local growth whereas others are causal for the various steps of metastasis. In a fraction of tumors deregulation of the same genes might be caused by epigenetic modulations, point mutations or the influence of other genes. We have investigated the relation of gene expression and chromosomal position, using eight datasets including more than 1200 breast tumors, to identify chromosomal regions and candidate genes possibly causal for breast cancer metastasis. By use of "Gene Set Enrichment Analysis" we have ranked chromosomal regions according to their relation to metastasis. Overrepresentation analysis identified regions with increased expression for chromosome 1q41-42, 8q24, 12q14, 16q22, 16q24, 17q12-21.2, 17q21-23, 17q25, 20q11, and 20q13 among metastasizing tumors and reduced gene expression at 1p31-21, 8p22-21, and 14q24. By analysis of genes with extremely imbalanced expression in these regions we identified DIRAS3 at 1p31, PSD3, LPL, EPHX2 at 8p21-22, and FOS at 14q24 as candidate metastasis suppressor genes. Potential metastasis promoting genes includes RECQL4 at 8q24, PRMT7 at 16q22, GINS2 at 16q24, and AURKA at 20q13.

High performance, high density hydrocarbon fuels

NASA Technical Reports Server (NTRS)

Frankenfeld, J. W.; Hastings, T. W.; Lieberman, M.; Taylor, W. F.

1978-01-01

The fuels were selected from 77 original candidates on the basis of estimated merit index and cost effectiveness. The ten candidates consisted of 3 pure compounds, 4 chemical plant streams and 3 refinery streams. Critical physical and chemical properties of the candidate fuels were measured including heat of combustion, density, and viscosity as a function of temperature, freezing points, vapor pressure, boiling point, thermal stability. The best all around candidate was found to be a chemical plant olefin stream rich in dicyclopentadiene. This material has a high merit index and is available at low cost. Possible problem areas were identified as low temperature flow properties and thermal stability. An economic analysis was carried out to determine the production costs of top candidates. The chemical plant and refinery streams were all less than 44 cent/kg while the pure compounds were greater than 44 cent/kg. A literature survey was conducted on the state of the art of advanced hydrocarbon fuel technology as applied to high energy propellents. Several areas for additional research were identified.

Discovery of Colorectal Cancer Biomarker Candidates by Membrane Proteomic Analysis and Subsequent Verification using Selected Reaction Monitoring (SRM) and Tissue Microarray (TMA) Analysis*

PubMed Central

Kume, Hideaki; Muraoka, Satoshi; Kuga, Takahisa; Adachi, Jun; Narumi, Ryohei; Watanabe, Shio; Kuwano, Masayoshi; Kodera, Yoshio; Matsushita, Kazuyuki; Fukuoka, Junya; Masuda, Takeshi; Ishihama, Yasushi; Matsubara, Hisahiro; Nomura, Fumio; Tomonaga, Takeshi

2014-01-01

Recent advances in quantitative proteomic technology have enabled the large-scale validation of biomarkers. We here performed a quantitative proteomic analysis of membrane fractions from colorectal cancer tissue to discover biomarker candidates, and then extensively validated the candidate proteins identified. A total of 5566 proteins were identified in six tissue samples, each of which was obtained from polyps and cancer with and without metastasis. GO cellular component analysis predicted that 3087 of these proteins were membrane proteins, whereas TMHMM algorithm predicted that 1567 proteins had a transmembrane domain. Differences were observed in the expression of 159 membrane proteins and 55 extracellular proteins between polyps and cancer without metastasis, while the expression of 32 membrane proteins and 17 extracellular proteins differed between cancer with and without metastasis. A total of 105 of these biomarker candidates were quantitated using selected (or multiple) reaction monitoring (SRM/MRM) with stable synthetic isotope-labeled peptides as an internal control. The results obtained revealed differences in the expression of 69 of these proteins, and this was subsequently verified in an independent set of patient samples (polyps (n = 10), cancer without metastasis (n = 10), cancer with metastasis (n = 10)). Significant differences were observed in the expression of 44 of these proteins, including ITGA5, GPRC5A, PDGFRB, and TFRC, which have already been shown to be overexpressed in colorectal cancer, as well as proteins with unknown function, such as C8orf55. The expression of C8orf55 was also shown to be high not only in colorectal cancer, but also in several cancer tissues using a multicancer tissue microarray, which included 1150 cores from 14 cancer tissues. This is the largest verification study of biomarker candidate membrane proteins to date; our methods for biomarker discovery and subsequent validation using SRM/MRM will contribute to the identification of useful biomarker candidates for various cancers. Data are available via ProteomeXchange with identifier PXD000851. PMID:24687888

Combining mouse mammary gland gene expression and comparative mapping for the identification of candidate genes for QTL of milk production traits in cattle

PubMed Central

Ron, Micha; Israeli, Galit; Seroussi, Eyal; Weller, Joel I; Gregg, Jeffrey P; Shani, Moshe; Medrano, Juan F

2007-01-01

Background Many studies have found segregating quantitative trait loci (QTL) for milk production traits in different dairy cattle populations. However, even for relatively large effects with a saturated marker map the confidence interval for QTL location by linkage analysis spans tens of map units, or hundreds of genes. Combining mapping and arraying has been suggested as an approach to identify candidate genes. Thus, gene expression analysis in the mammary gland of genes positioned in the confidence interval of the QTL can bridge the gap between fine mapping and quantitative trait nucleotide (QTN) determination. Results We hybridized Affymetrix microarray (MG-U74v2), containing 12,488 murine probes, with RNA derived from mammary gland of virgin, pregnant, lactating and involuting C57BL/6J mice in a total of nine biological replicates. We combined microarray data from two additional studies that used the same design in mice with a total of 75 biological replicates. The same filtering and normalization was applied to each microarray data using GeneSpring software. Analysis of variance identified 249 differentially expressed probe sets common to the three experiments along the four developmental stages of puberty, pregnancy, lactation and involution. 212 genes were assigned to their bovine map positions through comparative mapping, and thus form a list of candidate genes for previously identified QTLs for milk production traits. A total of 82 of the genes showed mammary gland-specific expression with at least 3-fold expression over the median representing all tissues tested in GeneAtlas. Conclusion This work presents a web tool for candidate genes for QTL (cgQTL) that allows navigation between the map of bovine milk production QTL, potential candidate genes and their level of expression in mammary gland arrays and in GeneAtlas. Three out of four confirmed genes that affect QTL in livestock (ABCG2, DGAT1, GDF8, IGF2) were over expressed in the target organ. Thus, cgQTL can be used to determine priority of candidate genes for QTN analysis based on differential expression in the target organ. PMID:17584498

Discovery of colorectal cancer biomarker candidates by membrane proteomic analysis and subsequent verification using selected reaction monitoring (SRM) and tissue microarray (TMA) analysis.

PubMed

Kume, Hideaki; Muraoka, Satoshi; Kuga, Takahisa; Adachi, Jun; Narumi, Ryohei; Watanabe, Shio; Kuwano, Masayoshi; Kodera, Yoshio; Matsushita, Kazuyuki; Fukuoka, Junya; Masuda, Takeshi; Ishihama, Yasushi; Matsubara, Hisahiro; Nomura, Fumio; Tomonaga, Takeshi

2014-06-01

Recent advances in quantitative proteomic technology have enabled the large-scale validation of biomarkers. We here performed a quantitative proteomic analysis of membrane fractions from colorectal cancer tissue to discover biomarker candidates, and then extensively validated the candidate proteins identified. A total of 5566 proteins were identified in six tissue samples, each of which was obtained from polyps and cancer with and without metastasis. GO cellular component analysis predicted that 3087 of these proteins were membrane proteins, whereas TMHMM algorithm predicted that 1567 proteins had a transmembrane domain. Differences were observed in the expression of 159 membrane proteins and 55 extracellular proteins between polyps and cancer without metastasis, while the expression of 32 membrane proteins and 17 extracellular proteins differed between cancer with and without metastasis. A total of 105 of these biomarker candidates were quantitated using selected (or multiple) reaction monitoring (SRM/MRM) with stable synthetic isotope-labeled peptides as an internal control. The results obtained revealed differences in the expression of 69 of these proteins, and this was subsequently verified in an independent set of patient samples (polyps (n = 10), cancer without metastasis (n = 10), cancer with metastasis (n = 10)). Significant differences were observed in the expression of 44 of these proteins, including ITGA5, GPRC5A, PDGFRB, and TFRC, which have already been shown to be overexpressed in colorectal cancer, as well as proteins with unknown function, such as C8orf55. The expression of C8orf55 was also shown to be high not only in colorectal cancer, but also in several cancer tissues using a multicancer tissue microarray, which included 1150 cores from 14 cancer tissues. This is the largest verification study of biomarker candidate membrane proteins to date; our methods for biomarker discovery and subsequent validation using SRM/MRM will contribute to the identification of useful biomarker candidates for various cancers. Data are available via ProteomeXchange with identifier PXD000851. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

A national survey of candidates: II: motivations, obstacles, and ideas on increasing interest in psychoanalytic training.

PubMed

Katz, Debra A; Kaplan, Marcia; Stromberg, Sarah E

2012-10-01

A national survey of candidates was conducted to identify motivations for pursuing psychoanalytic training, obstacles that prevent progression or completion, and candidates' ideas on how best to increase interest among potential trainees. In 2009-2010, 40 percent of candidates on the affiliate member e-mail list completed an anonymous web-based survey. Candidates strongly endorsed contact with a personal psychotherapist, psychoanalyst, or supervisor as the most important influence in discovering psychoanalysis and deciding to pursue training. They identified the total cost of analytic training as the greatest obstacle. This was followed by the cost of personal analysis, loss of income for low-fee cases, time away from family, and difficulty finding cases. To enhance training, local institutes should work to improve institute atmosphere and provide assistance with finding cases; national organizations should increase outreach activities and publicize psychoanalysis. Psychoanalytic institutes could recruit future candidates by working to increase personal contact with psychoanalysts, reducing the cost of training, improving institute atmosphere, assisting with case-finding, enhancing outreach activities, and widely publicizing psychoanalysis. Narrative comments from candidates and the implications of these findings regarding engagement of future trainees are discussed.

Identification of genes from the Treacher Collins candidate region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dixon, M.; Dixon, J.; Edwards, S.

Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development. The TCOF1 locus has previously been mapped to chromosome 5q32-33. The candidate gene region has been defined as being between two flanking markers, ribosomal protein S14 (RPS14) and Annexin 6 (ANX6), by analyzing recombination events in affected individuals. It is estimated that the distance between these flanking markers is 500 kb by three separate analysis methods: (1) radiation hybrid mapping; (2) genetic linkage; and (3) YAC contig analysis. A cosmid contig which spans the candidate gene region for TCOF1 has been constructed by screening the Los Alamos Nationalmore » Laboratory flow-sorted chromosome 5 cosmid library. Cosmids were obtained by using a combination of probes generated from YAC end clones, Alu-PCR fragments from YACs, and asymmetric PCR fragments from both T7 and T3 cosmid ends. Exon amplifications, the selection of genomic coding sequences based upon the presence of functional splice acceptor and donor sites, was used to identify potential exon sequences. Sequences found to be conserved between species were then used to screen cDNA libraries in order to identify candidate genes. To date, four different cDNAs have been isolated from this region and are being analyzed as potential candidate genes for TCOF1. These include the genes encoding plasma glutathione peroxidase (GPX3), heparin sulfate sulfotransferase (HSST), a gene with homology to the ETS family of proteins and one which shows no homology to any known genes. Work is also in progress to identify and characterize additional cDNAs from the candidate gene region.« less

Evaluating Reported Candidate Gene Associations with Polycystic Ovary Syndrome

PubMed Central

Pau, Cindy; Saxena, Richa; Welt, Corrine Kolka

2013-01-01

Objective To replicate variants in candidate genes associated with PCOS in a population of European PCOS and control subjects. Design Case-control association analysis and meta-analysis. Setting Major academic hospital Patients Women of European ancestry with PCOS (n=525) and controls (n=472), aged 18 to 45 years. Intervention Variants previously associated with PCOS in candidate gene studies were genotyped (n=39). Metabolic, reproductive and anthropomorphic parameters were examined as a function of the candidate variants. All genetic association analyses were adjusted for age, BMI and ancestry and were reported after correction for multiple testing. Main Outcome Measure Association of candidate gene variants with PCOS. Results Three variants, rs3797179 (SRD5A1), rs12473543 (POMC), and rs1501299 (ADIPOQ), were nominally associated with PCOS. However, they did not remain significant after correction for multiple testing and none of the variants replicated in a sufficiently powered meta-analysis. Variants in the FBN3 gene (rs17202517 and rs73503752) were associated with smaller waist circumferences and variant rs727428 in the SHBG gene was associated with lower SHBG levels. Conclusion Previously identified variants in candidate genes do not appear to be associated with PCOS risk. PMID:23375202

Independent Orbiter Assessment (IOA): Weibull analysis report

NASA Technical Reports Server (NTRS)

Raffaelli, Gary G.

1987-01-01

The Auxiliary Power Unit (APU) and Hydraulic Power Unit (HPU) Space Shuttle Subsystems were reviewed as candidates for demonstrating the Weibull analysis methodology. Three hardware components were identified as analysis candidates: the turbine wheel, the gearbox, and the gas generator. Detailed review of subsystem level wearout and failure history revealed the lack of actual component failure data. In addition, component wearout data were not readily available or would require a separate data accumulation effort by the vendor. Without adequate component history data being available, the Weibull analysis methodology application to the APU and HPU subsystem group was terminated.

Comparative analysis of protein interactome networks prioritizes candidate genes with cancer signatures.

PubMed

Li, Yongsheng; Sahni, Nidhi; Yi, Song

2016-11-29

Comprehensive understanding of human cancer mechanisms requires the identification of a thorough list of cancer-associated genes, which could serve as biomarkers for diagnoses and therapies in various types of cancer. Although substantial progress has been made in functional studies to uncover genes involved in cancer, these efforts are often time-consuming and costly. Therefore, it remains challenging to comprehensively identify cancer candidate genes. Network-based methods have accelerated this process through the analysis of complex molecular interactions in the cell. However, the extent to which various interactome networks can contribute to prediction of candidate genes responsible for cancer is still enigmatic. In this study, we evaluated different human protein-protein interactome networks and compared their application to cancer gene prioritization. Our results indicate that network analyses can increase the power to identify novel cancer genes. In particular, such predictive power can be enhanced with the use of unbiased systematic protein interaction maps for cancer gene prioritization. Functional analysis reveals that the top ranked genes from network predictions co-occur often with cancer-related terms in literature, and further, these candidate genes are indeed frequently mutated across cancers. Finally, our study suggests that integrating interactome networks with other omics datasets could provide novel insights into cancer-associated genes and underlying molecular mechanisms.

Outlier Analysis Defines Zinc Finger Gene Family DNA Methylation in Tumors and Saliva of Head and Neck Cancer Patients.

PubMed

Gaykalova, Daria A; Vatapalli, Rajita; Wei, Yingying; Tsai, Hua-Ling; Wang, Hao; Zhang, Chi; Hennessey, Patrick T; Guo, Theresa; Tan, Marietta; Li, Ryan; Ahn, Julie; Khan, Zubair; Westra, William H; Bishop, Justin A; Zaboli, David; Koch, Wayne M; Khan, Tanbir; Ochs, Michael F; Califano, Joseph A

2015-01-01

Head and Neck Squamous Cell Carcinoma (HNSCC) is the fifth most common cancer, annually affecting over half a million people worldwide. Presently, there are no accepted biomarkers for clinical detection and surveillance of HNSCC. In this work, a comprehensive genome-wide analysis of epigenetic alterations in primary HNSCC tumors was employed in conjunction with cancer-specific outlier statistics to define novel biomarker genes which are differentially methylated in HNSCC. The 37 identified biomarker candidates were top-scoring outlier genes with prominent differential methylation in tumors, but with no signal in normal tissues. These putative candidates were validated in independent HNSCC cohorts from our institution and TCGA (The Cancer Genome Atlas). Using the top candidates, ZNF14, ZNF160, and ZNF420, an assay was developed for detection of HNSCC cancer in primary tissue and saliva samples with 100% specificity when compared to normal control samples. Given the high detection specificity, the analysis of ZNF DNA methylation in combination with other DNA methylation biomarkers may be useful in the clinical setting for HNSCC detection and surveillance, particularly in high-risk patients. Several additional candidates identified through this work can be further investigated toward future development of a multi-gene panel of biomarkers for the surveillance and detection of HNSCC.

Discovering Cepheid and RR Lyrae Stars: Pan-STARRS Science Archive @ STScI and Robotically Controlled Telescopes

NASA Astrophysics Data System (ADS)

Johnson, Elizabeth; Strolger, Louis-Gregory; Engle, Scott G.; Anderson, Richard I.; Rest, Armin; Calamida, Annalisa; Dosovitz Fox, Ori; Laney, David

2017-01-01

Cepheid and RR Lyrae stars are an integral part of the cosmic distance ladder and are also useful for studying galactic structure and stellar ages. This project aims to greatly expand the number of known periodic variables in our galaxy by identifying candidates in the PanSTARRS-1 3pi catalog, and carrying out systematically targeted characterization with robotically controlled telescopes. Candidate targets are selected from available detection tables based on color and variability indices and are then fully vetted using robotic telescopes: the RCT 1.3 meter (Kitt Peak National Observatory) and RATIR 1.5 meter (Mexico). Here we present work to develop a full, semi-automated prescription for candidate selection, targeted follow-up photometry, cataloging, and classification, which allows the review of approximately 25 variable candidates every two weeks. We make comparisons of our sample selection and purity from a similar study based on Pan-STARRS data (Hernitschek et al. 2016), as well as candidates identified in Gaia DR1. The goal, through continued observation and analysis, is to identify at least 10,000 new variables, hundreds of which will be new Cepheid and RR Lyrae stars.

Transcriptomic Analysis Using Olive Varieties and Breeding Progenies Identifies Candidate Genes Involved in Plant Architecture.

PubMed

González-Plaza, Juan J; Ortiz-Martín, Inmaculada; Muñoz-Mérida, Antonio; García-López, Carmen; Sánchez-Sevilla, José F; Luque, Francisco; Trelles, Oswaldo; Bejarano, Eduardo R; De La Rosa, Raúl; Valpuesta, Victoriano; Beuzón, Carmen R

2016-01-01

Plant architecture is a critical trait in fruit crops that can significantly influence yield, pruning, planting density and harvesting. Little is known about how plant architecture is genetically determined in olive, were most of the existing varieties are traditional with an architecture poorly suited for modern growing and harvesting systems. In the present study, we have carried out microarray analysis of meristematic tissue to compare expression profiles of olive varieties displaying differences in architecture, as well as seedlings from their cross pooled on the basis of their sharing architecture-related phenotypes. The microarray used, previously developed by our group has already been applied to identify candidates genes involved in regulating juvenile to adult transition in the shoot apex of seedlings. Varieties with distinct architecture phenotypes and individuals from segregating progenies displaying opposite architecture features were used to link phenotype to expression. Here, we identify 2252 differentially expressed genes (DEGs) associated to differences in plant architecture. Microarray results were validated by quantitative RT-PCR carried out on genes with functional annotation likely related to plant architecture. Twelve of these genes were further analyzed in individual seedlings of the corresponding pool. We also examined Arabidopsis mutants in putative orthologs of these targeted candidate genes, finding altered architecture for most of them. This supports a functional conservation between species and potential biological relevance of the candidate genes identified. This study is the first to identify genes associated to plant architecture in olive, and the results obtained could be of great help in future programs aimed at selecting phenotypes adapted to modern cultivation practices in this species.

Application of proteomics in the discovery of candidate protein biomarkers in a Diabetes Autoantibody Standardization Program (DASP) sample subset

PubMed Central

Metz, Thomas O.; Qian, Wei-Jun; Jacobs, Jon M.; Gritsenko, Marina A.; Moore, Ronald J.; Polpitiya, Ashoka D.; Monroe, Matthew E.; Camp, David G.; Mueller, Patricia W.; Smith, Richard D.

2009-01-01

Novel biomarkers of type 1 diabetes must be identified and validated in initial, exploratory studies before they can be assessed in proficiency evaluations. Currently, untargeted “-omics” approaches are under-utilized in profiling studies of clinical samples. This report describes the evaluation of capillary liquid chromatography (LC) coupled with mass spectrometry (MS) in a pilot proteomic analysis of human plasma and serum from a subset of control and type 1 diabetic individuals enrolled in the Diabetes Autoantibody Standardization Program with the goal of identifying candidate biomarkers of type 1 diabetes. Initial high-resolution capillary LC-MS/MS experiments were performed to augment an existing plasma peptide database, while subsequent LC-FTICR studies identified quantitative differences in the abundance of plasma proteins. Analysis of LC-FTICR proteomic data identified five candidate protein biomarkers of type 1 diabetes. Alpha-2-glycoprotein 1 (zinc), corticosteroid-binding globulin, and lumican were 2-fold up-regulated in type 1 diabetic samples relative to control samples, whereas clusterin and serotransferrin were 2-fold up-regulated in control samples relative to type 1 diabetic samples. Observed perturbations in the levels of all five proteins are consistent with the metabolic aberrations found in type 1 diabetes. While the discovery of these candidate protein biomarkers of type 1 diabetes is encouraging, follow up studies are required for validation in a larger population of individuals and for determination of laboratory-defined sensitivity and specificity values using blinded samples. PMID:18092746

Application of proteomics in the discovery of candidate protein biomarkers in a diabetes autoantibody standardization program sample subset.

PubMed

Metz, Thomas O; Qian, Wei-Jun; Jacobs, Jon M; Gritsenko, Marina A; Moore, Ronald J; Polpitiya, Ashoka D; Monroe, Matthew E; Camp, David G; Mueller, Patricia W; Smith, Richard D

2008-02-01

Novel biomarkers of type 1 diabetes must be identified and validated in initial, exploratory studies before they can be assessed in proficiency evaluations. Currently, untargeted "-omics" approaches are underutilized in profiling studies of clinical samples. This report describes the evaluation of capillary liquid chromatography (LC) coupled with mass spectrometry (MS) in a pilot proteomic analysis of human plasma and serum from a subset of control and type 1 diabetic individuals enrolled in the Diabetes Autoantibody Standardization Program, with the goal of identifying candidate biomarkers of type 1 diabetes. Initial high-resolution capillary LC-MS/MS experiments were performed to augment an existing plasma peptide database, while subsequent LC-FTICR studies identified quantitative differences in the abundance of plasma proteins. Analysis of LC-FTICR proteomic data identified five candidate protein biomarkers of type 1 diabetes. alpha-2-Glycoprotein 1 (zinc), corticosteroid-binding globulin, and lumican were 2-fold up-regulated in type 1 diabetic samples relative to control samples, whereas clusterin and serotransferrin were 2-fold up-regulated in control samples relative to type 1 diabetic samples. Observed perturbations in the levels of all five proteins are consistent with the metabolic aberrations found in type 1 diabetes. While the discovery of these candidate protein biomarkers of type 1 diabetes is encouraging, follow up studies are required for validation in a larger population of individuals and for determination of laboratory-defined sensitivity and specificity values using blinded samples.

Planet Hunters: New Kepler Planet Candidates from Analysis of Quarter 2

NASA Astrophysics Data System (ADS)

Lintott, Chris J.; Schwamb, Megan E.; Barclay, Thomas; Sharzer, Charlie; Fischer, Debra A.; Brewer, John; Giguere, Matthew; Lynn, Stuart; Parrish, Michael; Batalha, Natalie; Bryson, Steve; Jenkins, Jon; Ragozzine, Darin; Rowe, Jason F.; Schwainski, Kevin; Gagliano, Robert; Gilardi, Joe; Jek, Kian J.; Pääkkönen, Jari-Pekka; Smits, Tjapko

2013-06-01

We present new planet candidates identified in NASA Kepler Quarter 2 public release data by volunteers engaged in the Planet Hunters citizen science project. The two candidates presented here survive checks for false positives, including examination of the pixel offset to constrain the possibility of a background eclipsing binary. The orbital periods of the planet candidates are 97.46 days (KIC 4552729) and 284.03 (KIC 10005758) days and the modeled planet radii are 5.3 and 3.8 R ⊕. The latter star has an additional known planet candidate with a radius of 5.05 R ⊕ and a period of 134.49 days, which was detected by the Kepler pipeline. The discovery of these candidates illustrates the value of massively distributed volunteer review of the Kepler database to recover candidates which were otherwise uncataloged. .

Integrative strategies to identify candidate genes in rodent models of human alcoholism.

PubMed

Treadwell, Julie A

2006-01-01

The search for genes underlying alcohol-related behaviours in rodent models of human alcoholism has been ongoing for many years with only limited success. Recently, new strategies that integrate several of the traditional approaches have provided new insights into the molecular mechanisms underlying ethanol's actions in the brain. We have used alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) genetic strains of mice in an integrative strategy combining high-throughput gene expression screening, genetic segregation analysis, and mapping to previously published quantitative trait loci to uncover candidate genes for the ethanol-preference phenotype. In our study, 2 genes, retinaldehyde binding protein 1 (Rlbp1) and syntaxin 12 (Stx12), were found to be strong candidates for ethanol preference. Such experimental approaches have the power and the potential to greatly speed up the laborious process of identifying candidate genes for the animal models of human alcoholism.

Exome sequencing of a large family identifies potential candidate genes contributing risk to bipolar disorder.

PubMed

Zhang, Tianxiao; Hou, Liping; Chen, David T; McMahon, Francis J; Wang, Jen-Chyong; Rice, John P

2018-03-01

Bipolar disorder is a mental illness with lifetime prevalence of about 1%. Previous genetic studies have identified multiple chromosomal linkage regions and candidate genes that might be associated with bipolar disorder. The present study aimed to identify potential susceptibility variants for bipolar disorder using 6 related case samples from a four-generation family. A combination of exome sequencing and linkage analysis was performed to identify potential susceptibility variants for bipolar disorder. Our study identified a list of five potential candidate genes for bipolar disorder. Among these five genes, GRID1(Glutamate Receptor Delta-1 Subunit), which was previously reported to be associated with several psychiatric disorders and brain related traits, is particularly interesting. Variants with functional significance in this gene were identified from two cousins in our bipolar disorder pedigree. Our findings suggest a potential role for these genes and the related rare variants in the onset and development of bipolar disorder in this one family. Additional research is needed to replicate these findings and evaluate their patho-biological significance. Copyright © 2017 Elsevier B.V. All rights reserved.

Genome-wide detection and characterization of positive selection in human populations.

PubMed

Sabeti, Pardis C; Varilly, Patrick; Fry, Ben; Lohmueller, Jason; Hostetter, Elizabeth; Cotsapas, Chris; Xie, Xiaohui; Byrne, Elizabeth H; McCarroll, Steven A; Gaudet, Rachelle; Schaffner, Stephen F; Lander, Eric S; Frazer, Kelly A; Ballinger, Dennis G; Cox, David R; Hinds, David A; Stuve, Laura L; Gibbs, Richard A; Belmont, John W; Boudreau, Andrew; Hardenbol, Paul; Leal, Suzanne M; Pasternak, Shiran; Wheeler, David A; Willis, Thomas D; Yu, Fuli; Yang, Huanming; Zeng, Changqing; Gao, Yang; Hu, Haoran; Hu, Weitao; Li, Chaohua; Lin, Wei; Liu, Siqi; Pan, Hao; Tang, Xiaoli; Wang, Jian; Wang, Wei; Yu, Jun; Zhang, Bo; Zhang, Qingrun; Zhao, Hongbin; Zhao, Hui; Zhou, Jun; Gabriel, Stacey B; Barry, Rachel; Blumenstiel, Brendan; Camargo, Amy; Defelice, Matthew; Faggart, Maura; Goyette, Mary; Gupta, Supriya; Moore, Jamie; Nguyen, Huy; Onofrio, Robert C; Parkin, Melissa; Roy, Jessica; Stahl, Erich; Winchester, Ellen; Ziaugra, Liuda; Altshuler, David; Shen, Yan; Yao, Zhijian; Huang, Wei; Chu, Xun; He, Yungang; Jin, Li; Liu, Yangfan; Shen, Yayun; Sun, Weiwei; Wang, Haifeng; Wang, Yi; Wang, Ying; Xiong, Xiaoyan; Xu, Liang; Waye, Mary M Y; Tsui, Stephen K W; Xue, Hong; Wong, J Tze-Fei; Galver, Luana M; Fan, Jian-Bing; Gunderson, Kevin; Murray, Sarah S; Oliphant, Arnold R; Chee, Mark S; Montpetit, Alexandre; Chagnon, Fanny; Ferretti, Vincent; Leboeuf, Martin; Olivier, Jean-François; Phillips, Michael S; Roumy, Stéphanie; Sallée, Clémentine; Verner, Andrei; Hudson, Thomas J; Kwok, Pui-Yan; Cai, Dongmei; Koboldt, Daniel C; Miller, Raymond D; Pawlikowska, Ludmila; Taillon-Miller, Patricia; Xiao, Ming; Tsui, Lap-Chee; Mak, William; Song, You Qiang; Tam, Paul K H; Nakamura, Yusuke; Kawaguchi, Takahisa; Kitamoto, Takuya; Morizono, Takashi; Nagashima, Atsushi; Ohnishi, Yozo; Sekine, Akihiro; Tanaka, Toshihiro; Tsunoda, Tatsuhiko; Deloukas, Panos; Bird, Christine P; Delgado, Marcos; Dermitzakis, Emmanouil T; Gwilliam, Rhian; Hunt, Sarah; Morrison, Jonathan; Powell, Don; Stranger, Barbara E; Whittaker, Pamela; Bentley, David R; Daly, Mark J; de Bakker, Paul I W; Barrett, Jeff; Chretien, Yves R; Maller, Julian; McCarroll, Steve; Patterson, Nick; Pe'er, Itsik; Price, Alkes; Purcell, Shaun; Richter, Daniel J; Sabeti, Pardis; Saxena, Richa; Schaffner, Stephen F; Sham, Pak C; Varilly, Patrick; Altshuler, David; Stein, Lincoln D; Krishnan, Lalitha; Smith, Albert Vernon; Tello-Ruiz, Marcela K; Thorisson, Gudmundur A; Chakravarti, Aravinda; Chen, Peter E; Cutler, David J; Kashuk, Carl S; Lin, Shin; Abecasis, Gonçalo R; Guan, Weihua; Li, Yun; Munro, Heather M; Qin, Zhaohui Steve; Thomas, Daryl J; McVean, Gilean; Auton, Adam; Bottolo, Leonardo; Cardin, Niall; Eyheramendy, Susana; Freeman, Colin; Marchini, Jonathan; Myers, Simon; Spencer, Chris; Stephens, Matthew; Donnelly, Peter; Cardon, Lon R; Clarke, Geraldine; Evans, David M; Morris, Andrew P; Weir, Bruce S; Tsunoda, Tatsuhiko; Johnson, Todd A; Mullikin, James C; Sherry, Stephen T; Feolo, Michael; Skol, Andrew; Zhang, Houcan; Zeng, Changqing; Zhao, Hui; Matsuda, Ichiro; Fukushima, Yoshimitsu; Macer, Darryl R; Suda, Eiko; Rotimi, Charles N; Adebamowo, Clement A; Ajayi, Ike; Aniagwu, Toyin; Marshall, Patricia A; Nkwodimmah, Chibuzor; Royal, Charmaine D M; Leppert, Mark F; Dixon, Missy; Peiffer, Andy; Qiu, Renzong; Kent, Alastair; Kato, Kazuto; Niikawa, Norio; Adewole, Isaac F; Knoppers, Bartha M; Foster, Morris W; Clayton, Ellen Wright; Watkin, Jessica; Gibbs, Richard A; Belmont, John W; Muzny, Donna; Nazareth, Lynne; Sodergren, Erica; Weinstock, George M; Wheeler, David A; Yakub, Imtaz; Gabriel, Stacey B; Onofrio, Robert C; Richter, Daniel J; Ziaugra, Liuda; Birren, Bruce W; Daly, Mark J; Altshuler, David; Wilson, Richard K; Fulton, Lucinda L; Rogers, Jane; Burton, John; Carter, Nigel P; Clee, Christopher M; Griffiths, Mark; Jones, Matthew C; McLay, Kirsten; Plumb, Robert W; Ross, Mark T; Sims, Sarah K; Willey, David L; Chen, Zhu; Han, Hua; Kang, Le; Godbout, Martin; Wallenburg, John C; L'Archevêque, Paul; Bellemare, Guy; Saeki, Koji; Wang, Hongguang; An, Daochang; Fu, Hongbo; Li, Qing; Wang, Zhen; Wang, Renwu; Holden, Arthur L; Brooks, Lisa D; McEwen, Jean E; Guyer, Mark S; Wang, Vivian Ota; Peterson, Jane L; Shi, Michael; Spiegel, Jack; Sung, Lawrence M; Zacharia, Lynn F; Collins, Francis S; Kennedy, Karen; Jamieson, Ruth; Stewart, John

2007-10-18

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

A Framework for Collaborative Review of Candidate Events in High Data Rate Streams: the V-Fastr Experiment as a Case Study

NASA Astrophysics Data System (ADS)

Hart, Andrew F.; Cinquini, Luca; Khudikyan, Shakeh E.; Thompson, David R.; Mattmann, Chris A.; Wagstaff, Kiri; Lazio, Joseph; Jones, Dayton

2015-01-01

“Fast radio transients” are defined here as bright millisecond pulses of radio-frequency energy. These short-duration pulses can be produced by known objects such as pulsars or potentially by more exotic objects such as evaporating black holes. The identification and verification of such an event would be of great scientific value. This is one major goal of the Very Long Baseline Array (VLBA) Fast Transient Experiment (V-FASTR), a software-based detection system installed at the VLBA. V-FASTR uses a “commensal” (piggy-back) approach, analyzing all array data continually during routine VLBA observations and identifying candidate fast transient events. Raw data can be stored from a buffer memory, which enables a comprehensive off-line analysis. This is invaluable for validating the astrophysical origin of any detection. Candidates discovered by the automatic system must be reviewed each day by analysts to identify any promising signals that warrant a more in-depth investigation. To support the timely analysis of fast transient detection candidates by V-FASTR scientists, we have developed a metadata-driven, collaborative candidate review framework. The framework consists of a software pipeline for metadata processing composed of both open source software components and project-specific code written expressly to extract and catalog metadata from the incoming V-FASTR data products, and a web-based data portal that facilitates browsing and inspection of the available metadata for candidate events extracted from the VLBA radio data.

A Stratified Transcriptomics Analysis of Polygenic Fat and Lean Mouse Adipose Tissues Identifies Novel Candidate Obesity Genes

PubMed Central

Morton, Nicholas M.; Nelson, Yvonne B.; Michailidou, Zoi; Di Rollo, Emma M.; Ramage, Lynne; Hadoke, Patrick W. F.; Seckl, Jonathan R.; Bunger, Lutz; Horvat, Simon; Kenyon, Christopher J.; Dunbar, Donald R.

2011-01-01

Background Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain. Results To enrich for adipose tissue obesity genes a ‘snap-shot’ pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity. Conclusions A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity. PMID:21915269

A stratified transcriptomics analysis of polygenic fat and lean mouse adipose tissues identifies novel candidate obesity genes.

PubMed

Morton, Nicholas M; Nelson, Yvonne B; Michailidou, Zoi; Di Rollo, Emma M; Ramage, Lynne; Hadoke, Patrick W F; Seckl, Jonathan R; Bunger, Lutz; Horvat, Simon; Kenyon, Christopher J; Dunbar, Donald R

2011-01-01

Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain. To enrich for adipose tissue obesity genes a 'snap-shot' pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity. A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity.

Efficient implementation of the Metropolis-Hastings algorithm, with application to the Cormack?Jolly?Seber model

USGS Publications Warehouse

Link, W.A.; Barker, R.J.

2008-01-01

Judicious choice of candidate generating distributions improves efficiency of the Metropolis-Hastings algorithm. In Bayesian applications, it is sometimes possible to identify an approximation to the target posterior distribution; this approximate posterior distribution is a good choice for candidate generation. These observations are applied to analysis of the Cormack?Jolly?Seber model and its extensions.

Independence and Interdependence: An Analysis of Pre-Service Candidates' Use of Focused Assignments on an Electronic Discussion Forum during the Initial Field Experience

ERIC Educational Resources Information Center

Fisch, Audrey A.; Bennett, Deborah J.

2011-01-01

This article describes a case study using an electronic learning platform for creating an interactive learning community through asynchronous discussion to enhance the initial field experience of secondary math and English teacher candidates enrolled in Field Experience. We identified three problems with the field experience course--lack of…

Development of Diagnostic Biomarkers for Detecting Diabetic Retinopathy at Early Stages Using Quantitative Proteomics

PubMed Central

Min, Hophil; Kim, Sang Jin; Oh, Sohee; Kim, Kyunggon; Yu, Hyeong Gon; Park, Taesung; Kim, Youngsoo

2016-01-01

Diabetic retinopathy (DR) is a common microvascular complication caused by diabetes mellitus (DM) and is a leading cause of vision impairment and loss among adults. Here, we performed a comprehensive proteomic analysis to discover biomarkers for DR. First, to identify biomarker candidates that are specifically expressed in human vitreous, we performed data-mining on both previously published DR-related studies and our experimental data; 96 proteins were then selected. To confirm and validate the selected biomarker candidates, candidates were selected, confirmed, and validated using plasma from diabetic patients without DR (No DR) and diabetics with mild or moderate nonproliferative diabetic retinopathy (Mi or Mo NPDR) using semiquantitative multiple reaction monitoring (SQ-MRM) and stable-isotope dilution multiple reaction monitoring (SID-MRM). Additionally, we performed a multiplex assay using 15 biomarker candidates identified in the SID-MRM analysis, which resulted in merged AUC values of 0.99 (No DR versus Mo NPDR) and 0.93 (No DR versus Mi and Mo NPDR). Although further validation with a larger sample size is needed, the 4-protein marker panel (APO4, C7, CLU, and ITIH2) could represent a useful multibiomarker model for detecting the early stages of DR. PMID:26665153

Proteomics analysis of tissue samples from patients with squamous cell carcinoma of the penis and positive to human papillomavirus.

PubMed

Koifman, Leandro; Ornellas, Paulo; Ornellas, Antonio Augusto; Pereira, Denise de Abreu; Zingali, Benedeta Russolina; Cavalcanti, Silvia Maria Baeta; Afonso, Larissa Alves; Sandim, Vanessa; Alves, Gilda

2015-01-01

The aim of this study was to identify possible protein biomarkers and/or candidates for therapeutic targets in tissues of patients with SCCP, infected by HPV, applying one dimensional electrophoresis (1DE), followed by direct mass spectrometry (MS) analysis. Tissues from 10 HPV positive patients with SCCP and from 10 patients with HPV negative non-tumorous penile foreskins were analyzed applying 1D electrophoresis, followed by analysis with direct mass spectrometry (MS). Sixty-three different proteins were identified in the first group and 50 in the second group. Recognition was possible for 28 proteins exclusively detected in Group 1 and 21 proteins presented only in Group 2. Some proteins in the first group are directly involved in the development of other types of cancer, and therefore, suitable for analysis. Complement C3 protein is a strong candidate for evaluating SCCP patients.

Photoreceptor dysplasia (pd) in miniature schnauzer dogs: evaluation of candidate genes by molecular genetic analysis.

PubMed

Zhang, Q; Baldwin, V J; Acland, G M; Parshall, C J; Haskel, J; Aguirre, G D; Ray, K

1999-01-01

Photoreceptor dysplasia (pd) is one of a group of at least six distinct autosomal and one X-linked retinal disorders identified in dogs which are collectively known as progressive retinal atrophy (PRA). It is an early onset retinal disease identified in miniature schnauzer dogs, and pedigree analysis and breeding studies have established autosomal recessive inheritance of the disease. Using a gene-based approach, a number of retina-expressed genes, including some members of the phototransduction pathway, have been causally implicated in retinal diseases of humans and other animals. Here we examined seven such potential candidate genes (opsin, RDS/peripherin, ROM1, rod cGMP-gated cation channel alpha-subunit, and three subunits of transducin) for their causal association with the pd locus by testing segregation of intragenic markers with the disease locus, or, in the absence of informative polymorphisms, sequencing of the coding regions of the genes. Based on these results, we have conclusively excluded four photoreceptor-specific genes as candidates for pd by linkage analysis. For three other photoreceptor-specific genes, we did not find any mutation in the coding sequences of the genes and have excluded them provisionally. Formal exclusion would require investigation of the levels of expression of the candidate genes in pd-affected dogs relative to age-matched controls. At present we are building suitable informative pedigrees for the disease locus with a sufficient number of meiosis to be useful for genomewide screening. This should identify markers linked to the disease locus and eventually permit progress toward the identification of the photoreceptor dysplasia gene and the disease-causing mutation.

PLANET HUNTERS: NEW KEPLER PLANET CANDIDATES FROM ANALYSIS OF QUARTER 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lintott, Chris J.; Schwamb, Megan E.; Schwainski, Kevin, E-mail: cjl@astro.ox.ac.uk

2013-06-15

We present new planet candidates identified in NASA Kepler Quarter 2 public release data by volunteers engaged in the Planet Hunters citizen science project. The two candidates presented here survive checks for false positives, including examination of the pixel offset to constrain the possibility of a background eclipsing binary. The orbital periods of the planet candidates are 97.46 days (KIC 4552729) and 284.03 (KIC 10005758) days and the modeled planet radii are 5.3 and 3.8 R{sub Circled-Plus }. The latter star has an additional known planet candidate with a radius of 5.05 R{sub Circled-Plus} and a period of 134.49 days,more » which was detected by the Kepler pipeline. The discovery of these candidates illustrates the value of massively distributed volunteer review of the Kepler database to recover candidates which were otherwise uncataloged.« less

Identifying candidate genes for Type 2 Diabetes Mellitus and obesity through gene expression profiling in multiple tissues or cells.

PubMed

Chen, Junhui; Meng, Yuhuan; Zhou, Jinghui; Zhuo, Min; Ling, Fei; Zhang, Yu; Du, Hongli; Wang, Xiaoning

2013-01-01

Type 2 Diabetes Mellitus (T2DM) and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL) within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying high percentages of differential expression were filtered out. Specifically, DENND1B, LYN, MRPL30, POC1B, PRKCB, RP4-655J12.3, HIBADH, and TMBIM4 were identified from the T2DM-control study, and BCAT1, BMP2K, CSRNP2, MYNN, NCKAP5L, SAP30BP, SLC35B4, SP1, BAP1, GRB14, HSP90AB1, ITGA5, and TOMM5 were identified from the obesity-control study. The majority of these genes are known to be involved in T2DM and obesity. Therefore, analysis of gene expression in various tissues using GEO datasets may be an effective and feasible method to determine novel or causal genes associated with T2DM and obesity.

Transcriptomic Analysis Using Olive Varieties and Breeding Progenies Identifies Candidate Genes Involved in Plant Architecture

PubMed Central

González-Plaza, Juan J.; Ortiz-Martín, Inmaculada; Muñoz-Mérida, Antonio; García-López, Carmen; Sánchez-Sevilla, José F.; Luque, Francisco; Trelles, Oswaldo; Bejarano, Eduardo R.; De La Rosa, Raúl; Valpuesta, Victoriano; Beuzón, Carmen R.

2016-01-01

Plant architecture is a critical trait in fruit crops that can significantly influence yield, pruning, planting density and harvesting. Little is known about how plant architecture is genetically determined in olive, were most of the existing varieties are traditional with an architecture poorly suited for modern growing and harvesting systems. In the present study, we have carried out microarray analysis of meristematic tissue to compare expression profiles of olive varieties displaying differences in architecture, as well as seedlings from their cross pooled on the basis of their sharing architecture-related phenotypes. The microarray used, previously developed by our group has already been applied to identify candidates genes involved in regulating juvenile to adult transition in the shoot apex of seedlings. Varieties with distinct architecture phenotypes and individuals from segregating progenies displaying opposite architecture features were used to link phenotype to expression. Here, we identify 2252 differentially expressed genes (DEGs) associated to differences in plant architecture. Microarray results were validated by quantitative RT-PCR carried out on genes with functional annotation likely related to plant architecture. Twelve of these genes were further analyzed in individual seedlings of the corresponding pool. We also examined Arabidopsis mutants in putative orthologs of these targeted candidate genes, finding altered architecture for most of them. This supports a functional conservation between species and potential biological relevance of the candidate genes identified. This study is the first to identify genes associated to plant architecture in olive, and the results obtained could be of great help in future programs aimed at selecting phenotypes adapted to modern cultivation practices in this species. PMID:26973682

RNA-Seq analysis and annotation of a draft blueberry genome assembly identifies candidate genes involved in fruit ripening, biosynthesis of bioactive compounds, and stage-specific alternative splicing.

PubMed

Gupta, Vikas; Estrada, April D; Blakley, Ivory; Reid, Rob; Patel, Ketan; Meyer, Mason D; Andersen, Stig Uggerhøj; Brown, Allan F; Lila, Mary Ann; Loraine, Ann E

2015-01-01

Blueberries are a rich source of antioxidants and other beneficial compounds that can protect against disease. Identifying genes involved in synthesis of bioactive compounds could enable the breeding of berry varieties with enhanced health benefits. Toward this end, we annotated a previously sequenced draft blueberry genome assembly using RNA-Seq data from five stages of berry fruit development and ripening. Genome-guided assembly of RNA-Seq read alignments combined with output from ab initio gene finders produced around 60,000 gene models, of which more than half were similar to proteins from other species, typically the grape Vitis vinifera. Comparison of gene models to the PlantCyc database of metabolic pathway enzymes identified candidate genes involved in synthesis of bioactive compounds, including bixin, an apocarotenoid with potential disease-fighting properties, and defense-related cyanogenic glycosides, which are toxic. Cyanogenic glycoside (CG) biosynthetic enzymes were highly expressed in green fruit, and a candidate CG detoxification enzyme was up-regulated during fruit ripening. Candidate genes for ethylene, anthocyanin, and 400 other biosynthetic pathways were also identified. Homology-based annotation using Blast2GO and InterPro assigned Gene Ontology terms to around 15,000 genes. RNA-Seq expression profiling showed that blueberry growth, maturation, and ripening involve dynamic gene expression changes, including coordinated up- and down-regulation of metabolic pathway enzymes and transcriptional regulators. Analysis of RNA-seq alignments identified developmentally regulated alternative splicing, promoter use, and 3' end formation. We report genome sequence, gene models, functional annotations, and RNA-Seq expression data that provide an important new resource enabling high throughput studies in blueberry.

Dissecting Vancomycin-Intermediate Resistance in Staphylococcus aureus Using Genome-Wide Association

PubMed Central

Alam, Md Tauqeer; Petit, Robert A.; Crispell, Emily K.; Thornton, Timothy A.; Conneely, Karen N.; Jiang, Yunxuan; Satola, Sarah W.; Read, Timothy D.

2014-01-01

Vancomycin-intermediate Staphylococcus aureus (VISA) is currently defined as having minimal inhibitory concentration (MIC) of 4–8 µg/ml. VISA evolves through changes in multiple genetic loci with at least 16 candidate genes identified in clinical and in vitro-selected VISA strains. We report a whole-genome comparative analysis of 49 vancomycin-sensitive S. aureus and 26 VISA strains. Resistance to vancomycin was determined by broth microdilution, Etest, and population analysis profile-area under the curve (PAP-AUC). Genome-wide association studies (GWAS) of 55,977 single-nucleotide polymorphisms identified in one or more strains found one highly significant association (P = 8.78E-08) between a nonsynonymous mutation at codon 481 (H481) of the rpoB gene and increased vancomycin MIC. Additionally, we used a database of public S. aureus genome sequences to identify rare mutations in candidate genes associated with VISA. On the basis of these data, we proposed a preliminary model called ECM+RMCG for the VISA phenotype as a benchmark for future efforts. The model predicted VISA based on the presence of a rare mutation in a set of candidate genes (walKR, vraSR, graSR, and agrA) and/or three previously experimentally verified mutations (including the rpoB H481 locus) with an accuracy of 81% and a sensitivity of 73%. Further, the level of resistance measured by both Etest and PAP-AUC regressed positively with the number of mutations present in a strain. This study demonstrated 1) the power of GWAS for identifying common genetic variants associated with antibiotic resistance in bacteria and 2) that rare mutations in candidate gene, identified using large genomic data sets, can also be associated with resistance phenotypes. PMID:24787619

Replacement of ozone depleting and toxic chemicals in gravimetric analysis of non-volatile residue

NASA Technical Reports Server (NTRS)

Arnold, G. S.; Uht, J. C.; Sinsheimer, F. B.

1995-01-01

The standard tests for determining nonvolatile residue accretion on spacecraft surfaces and in clean processing facilities rely on the use of halogenated solvents that are targeted for elimination because of their toxic or ozone-depleting natures. This paper presents a literature-based screening survey for candidate replacement solvents. Potential replacements were evaluated for their vapor pressure, toxicity, and solvent properties. Three likely candidates were identified: ethyl acetate, methyl acetate, and acetone. Laboratory tests are presented that evaluate the suitability of these candidate replacement solvents.

Fine-mapping of qGW4.05, a major QTL for kernel weight and size in maize.

PubMed

Chen, Lin; Li, Yong-xiang; Li, Chunhui; Wu, Xun; Qin, Weiwei; Li, Xin; Jiao, Fuchao; Zhang, Xiaojing; Zhang, Dengfeng; Shi, Yunsu; Song, Yanchun; Li, Yu; Wang, Tianyu

2016-04-12

Kernel weight and size are important components of grain yield in cereals. Although some information is available concerning the map positions of quantitative trait loci (QTL) for kernel weight and size in maize, little is known about the molecular mechanisms of these QTLs. qGW4.05 is a major QTL that is associated with kernel weight and size in maize. We combined linkage analysis and association mapping to fine-map and identify candidate gene(s) at qGW4.05. QTL qGW4.05 was fine-mapped to a 279.6-kb interval in a segregating population derived from a cross of Huangzaosi with LV28. By combining the results of regional association mapping and linkage analysis, we identified GRMZM2G039934 as a candidate gene responsible for qGW4.05. Candidate gene-based association mapping was conducted using a panel of 184 inbred lines with variable kernel weights and kernel sizes. Six polymorphic sites in the gene GRMZM2G039934 were significantly associated with kernel weight and kernel size. The results of linkage analysis and association mapping revealed that GRMZM2G039934 is the most likely candidate gene for qGW4.05. These results will improve our understanding of the genetic architecture and molecular mechanisms underlying kernel development in maize.

Walking the interactome for candidate prioritization in exome sequencing studies of Mendelian diseases

DOE PAGES

Smedley, Damian; Kohler, Sebastian; Czeschik, Johanna Christina; ...

2014-07-30

Here, whole-exome sequencing (WES) has opened up previously unheard of possibilities for identifying novel disease genes in Mendelian disorders, only about half of which have been elucidated to date. However, interpretation of WES data remains challenging. As a result, we analyze protein–protein association (PPA) networks to identify candidate genes in the vicinity of genes previously implicated in a disease. The analysis, using a random-walk with restart (RWR) method, is adapted to the setting of WES by developing a composite variant-gene relevance score based on the rarity, location and predicted pathogenicity of variants and the RWR evaluation of genes harboring themore » variants. Benchmarking using known disease variants from 88 disease-gene families reveals that the correct gene is ranked among the top 10 candidates in ≥50% of cases, a figure which we confirmed using a prospective study of disease genes identified in 2012 and PPA data produced before that date. In conclusion, we implement our method in a freely available Web server, ExomeWalker, that displays a ranked list of candidates together with information on PPAs, frequency and predicted pathogenicity of the variants to allow quick and effective searches for candidates that are likely to reward closer investigation.« less

Walking the interactome for candidate prioritization in exome sequencing studies of Mendelian diseases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smedley, Damian; Kohler, Sebastian; Czeschik, Johanna Christina

Here, whole-exome sequencing (WES) has opened up previously unheard of possibilities for identifying novel disease genes in Mendelian disorders, only about half of which have been elucidated to date. However, interpretation of WES data remains challenging. As a result, we analyze protein–protein association (PPA) networks to identify candidate genes in the vicinity of genes previously implicated in a disease. The analysis, using a random-walk with restart (RWR) method, is adapted to the setting of WES by developing a composite variant-gene relevance score based on the rarity, location and predicted pathogenicity of variants and the RWR evaluation of genes harboring themore » variants. Benchmarking using known disease variants from 88 disease-gene families reveals that the correct gene is ranked among the top 10 candidates in ≥50% of cases, a figure which we confirmed using a prospective study of disease genes identified in 2012 and PPA data produced before that date. In conclusion, we implement our method in a freely available Web server, ExomeWalker, that displays a ranked list of candidates together with information on PPAs, frequency and predicted pathogenicity of the variants to allow quick and effective searches for candidates that are likely to reward closer investigation.« less

Predonation screening of candidate donors and prevention of window period donations.

PubMed

Lieshout-Krikke, Ryanne W; Zaaijer, Hans L; van de Laar, Thijs J W

2015-02-01

Infectious window period donations slip through routine donor screening procedures. To explore the potential value of predonation screening of candidate donors, we compared the proportion of incident transfusion-transmissible infections in candidate donors, in first-time donors, and in repeat donors. A retrospective analysis was performed of all incident hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infections in candidate, first-time, and repeat donors in the Netherlands during the period 2009 to 2013. In total, 176,716 candidate donors, 144,226 first-time donations, and 4,143,455 repeat donations were screened for HBV, HCV, and HIV infection. Acute HBV infection was identified in the predonation sample of six candidate donors. One first-time donor, testing HIV-negative at predonation screening, tested positive for anti-HIV and HIV RNA in the first donation 29 days later. Among repeat donations we identified 15, one, and six incident HBV, HCV and HIV infections, respectively. The proportion of incident infections among candidate donors/first-time donations/repeat donations was for HBV, 3.40/0/0.36; for HCV, 0/0/0.02; and for HIV 0/0.69/0.14 per 100,000, respectively. Predonation screening of candidate donors very likely causes a loss of donations, but it might prevent undetected window period donations. Further studies are necessary to determine the value of predonation screening as an additional safety measure. © 2014 AABB.

Novel Sequence-Based Mapping of Recently Emerging H5NX Influenza Viruses Reveals Pandemic Vaccine Candidates

PubMed Central

Anderson, Christopher S.; DeDiego, Marta L.; Thakar, Juilee; Topham, David J.

2016-01-01

Recently, an avian influenza virus, H5NX subclade 2.3.4.4, emerged and spread to North America. This subclade has frequently reassorted, leading to multiple novel viruses capable of human infection. Four cases of human infections, three leading to death, have already occurred. Existing vaccine strains do not protect against these new viruses, raising a need to identify new vaccine candidate strains. We have developed a novel sequence-based mapping (SBM) tool capable of visualizing complex protein sequence data sets using a single intuitive map. We applied SBM on the complete set of avian H5 viruses in order to better understand hemagglutinin protein variance amongst H5 viruses and identify any patterns associated with this variation. The analysis successfully identified the original reassortments that lead to the emergence of this new subclade of H5 viruses, as well as their known unusual ability to re-assort among neuraminidase subtypes. In addition, our analysis revealed distinct clusters of 2.3.4.4 variants that would not be covered by existing strains in the H5 vaccine stockpile. The results suggest that our method may be useful for pandemic candidate vaccine virus selection. PMID:27494186

Genomic expression analysis of rat chromosome 4 for skeletal traits at femoral neck.

PubMed

Alam, Imranul; Sun, Qiwei; Liu, Lixiang; Koller, Daniel L; Liu, Yunlong; Edenberg, Howard J; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2008-10-08

Hip fracture is the most devastating osteoporotic fracture type with significant morbidity and mortality. Several studies in humans and animal models identified chromosomal regions linked to hip size and bone mass. Previously, we identified that the region of 4q21-q41 on rat chromosome (Chr) 4 harbors multiple femoral neck quantitative trait loci (QTLs) in inbred Fischer 344 (F344) and Lewis (LEW) rats. The purpose of this study is to identify the candidate genes for femoral neck structure and density by correlating gene expression in the proximal femur with the femoral neck phenotypes linked to the QTLs on Chr 4. RNA was extracted from proximal femora of 4-wk-old rats from F344 and LEW strains, and two other strains, Copenhagen 2331 and Dark Agouti, were used as a negative control. Microarray analysis was performed using Affymetrix Rat Genome 230 2.0 arrays. A total of 99 genes in the 4q21-q41 region were differentially expressed (P < 0.05) among all strains of rats with a false discovery rate <10%. These 99 genes were then ranked based on the strength of correlation between femoral neck phenotypes measured in F2 animals, homozygous for a particular strain's allele at the Chr 4 QTL and the expression level of the gene in that strain. A total of 18 candidate genes were strongly correlated (r(2) > 0.50) with femoral neck width and prioritized for further analysis. Quantitative PCR analysis confirmed 14 of 18 of the candidate genes. Ingenuity pathway analysis revealed several direct or indirect relationships among the candidate genes related to angiogenesis (VEGF), bone growth (FGF2), bone formation (IGF2 and IGF2BP3), and resorption (TNF). This study provides a shortened list of genetic determinants of skeletal traits at the hip and may lead to novel approaches for prevention and treatment of hip fracture.

Genomic expression analysis of rat chromosome 4 for skeletal traits at femoral neck

PubMed Central

Alam, Imranul; Sun, Qiwei; Liu, Lixiang; Koller, Daniel L.; Liu, Yunlong; Edenberg, Howard J.; Econs, Michael J.; Foroud, Tatiana; Turner, Charles H.

2008-01-01

Hip fracture is the most devastating osteoporotic fracture type with significant morbidity and mortality. Several studies in humans and animal models identified chromosomal regions linked to hip size and bone mass. Previously, we identified that the region of 4q21-q41 on rat chromosome (Chr) 4 harbors multiple femoral neck quantitative trait loci (QTLs) in inbred Fischer 344 (F344) and Lewis (LEW) rats. The purpose of this study is to identify the candidate genes for femoral neck structure and density by correlating gene expression in the proximal femur with the femoral neck phenotypes linked to the QTLs on Chr 4. RNA was extracted from proximal femora of 4-wk-old rats from F344 and LEW strains, and two other strains, Copenhagen 2331 and Dark Agouti, were used as a negative control. Microarray analysis was performed using Affymetrix Rat Genome 230 2.0 arrays. A total of 99 genes in the 4q21-q41 region were differentially expressed (P < 0.05) among all strains of rats with a false discovery rate <10%. These 99 genes were then ranked based on the strength of correlation between femoral neck phenotypes measured in F2 animals, homozygous for a particular strain's allele at the Chr 4 QTL and the expression level of the gene in that strain. A total of 18 candidate genes were strongly correlated (r2 > 0.50) with femoral neck width and prioritized for further analysis. Quantitative PCR analysis confirmed 14 of 18 of the candidate genes. Ingenuity pathway analysis revealed several direct or indirect relationships among the candidate genes related to angiogenesis (VEGF), bone growth (FGF2), bone formation (IGF2 and IGF2BP3), and resorption (TNF). This study provides a shortened list of genetic determinants of skeletal traits at the hip and may lead to novel approaches for prevention and treatment of hip fracture. PMID:18728226

Genome-Wide Prediction of the Polymorphic Ser Gene Family in Tetrahymena thermophila Based on Motif Analysis

PubMed Central

Ponsuwanna, Patrath; Kümpornsin, Krittikorn; Chookajorn, Thanat

2014-01-01

Even though antigenic variation is employed among parasitic protozoa for host immune evasion, Tetrahymena thermophila, a free-living ciliate, can also change its surface protein antigens. These cysteine-rich glycosylphosphatidylinositol (GPI)-linked surface proteins are encoded by a family of polymorphic Ser genes. Despite the availability of T. thermophila genome, a comprehensive analysis of the Ser family is limited by its high degree of polymorphism. In order to overcome this problem, a new approach was adopted by searching for Ser candidates with common motif sequences, namely length-specific repetitive cysteine pattern and GPI anchor site. The candidate genes were phylogenetically compared with the previously identified Ser genes and classified into subtypes. Ser candidates were often found to be located as tandem arrays of the same subtypes on several chromosomal scaffolds. Certain Ser candidates located in the same chromosomal arrays were transcriptionally expressed at specific T. thermophila developmental stages. These Ser candidates selected by the motif analysis approach can form the foundation for a systematic identification of the entire Ser gene family, which will contribute to the understanding of their function and the basis of T. thermophila antigenic variation. PMID:25133747

Association Analysis Suggests SOD2 as a Newly Identified Candidate Gene Associated With Leprosy Susceptibility.

PubMed

Ramos, Geovana Brotto; Salomão, Heloisa; Francio, Angela Schneider; Fava, Vinícius Medeiros; Werneck, Renata Iani; Mira, Marcelo Távora

2016-08-01

Genetic studies have identified several genes and genomic regions contributing to the control of host susceptibility to leprosy. Here, we test variants of the positional and functional candidate gene SOD2 for association with leprosy in 2 independent population samples. Family-based analysis revealed an association between leprosy and allele G of marker rs295340 (P = .042) and borderline evidence of an association between leprosy and alleles C and A of markers rs4880 (P = .077) and rs5746136 (P = .071), respectively. Findings were validated in an independent case-control sample for markers rs295340 (P = .049) and rs4880 (P = .038). These results suggest SOD2 as a newly identified gene conferring susceptibility to leprosy. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

An Integrative Genetics Approach to Identify Candidate Genes Regulating BMD: Combining Linkage, Gene Expression, and Association

PubMed Central

Farber, Charles R; van Nas, Atila; Ghazalpour, Anatole; Aten, Jason E; Doss, Sudheer; Sos, Brandon; Schadt, Eric E; Ingram-Drake, Leslie; Davis, Richard C; Horvath, Steve; Smith, Desmond J; Drake, Thomas A; Lusis, Aldons J

2009-01-01

Numerous quantitative trait loci (QTLs) affecting bone traits have been identified in the mouse; however, few of the underlying genes have been discovered. To improve the process of transitioning from QTL to gene, we describe an integrative genetics approach, which combines linkage analysis, expression QTL (eQTL) mapping, causality modeling, and genetic association in outbred mice. In C57BL/6J × C3H/HeJ (BXH) F2 mice, nine QTLs regulating femoral BMD were identified. To select candidate genes from within each QTL region, microarray gene expression profiles from individual F2 mice were used to identify 148 genes whose expression was correlated with BMD and regulated by local eQTLs. Many of the genes that were the most highly correlated with BMD have been previously shown to modulate bone mass or skeletal development. Candidates were further prioritized by determining whether their expression was predicted to underlie variation in BMD. Using network edge orienting (NEO), a causality modeling algorithm, 18 of the 148 candidates were predicted to be causally related to differences in BMD. To fine-map QTLs, markers in outbred MF1 mice were tested for association with BMD. Three chromosome 11 SNPs were identified that were associated with BMD within the Bmd11 QTL. Finally, our approach provides strong support for Wnt9a, Rasd1, or both underlying Bmd11. Integration of multiple genetic and genomic data sets can substantially improve the efficiency of QTL fine-mapping and candidate gene identification. PMID:18767929

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

PubMed

Anderson, Carl A; Boucher, Gabrielle; Lees, Charlie W; Franke, Andre; D'Amato, Mauro; Taylor, Kent D; Lee, James C; Goyette, Philippe; Imielinski, Marcin; Latiano, Anna; Lagacé, Caroline; Scott, Regan; Amininejad, Leila; Bumpstead, Suzannah; Baidoo, Leonard; Baldassano, Robert N; Barclay, Murray; Bayless, Theodore M; Brand, Stephan; Büning, Carsten; Colombel, Jean-Frédéric; Denson, Lee A; De Vos, Martine; Dubinsky, Marla; Edwards, Cathryn; Ellinghaus, David; Fehrmann, Rudolf S N; Floyd, James A B; Florin, Timothy; Franchimont, Denis; Franke, Lude; Georges, Michel; Glas, Jürgen; Glazer, Nicole L; Guthery, Stephen L; Haritunians, Talin; Hayward, Nicholas K; Hugot, Jean-Pierre; Jobin, Gilles; Laukens, Debby; Lawrance, Ian; Lémann, Marc; Levine, Arie; Libioulle, Cecile; Louis, Edouard; McGovern, Dermot P; Milla, Monica; Montgomery, Grant W; Morley, Katherine I; Mowat, Craig; Ng, Aylwin; Newman, William; Ophoff, Roel A; Papi, Laura; Palmieri, Orazio; Peyrin-Biroulet, Laurent; Panés, Julián; Phillips, Anne; Prescott, Natalie J; Proctor, Deborah D; Roberts, Rebecca; Russell, Richard; Rutgeerts, Paul; Sanderson, Jeremy; Sans, Miquel; Schumm, Philip; Seibold, Frank; Sharma, Yashoda; Simms, Lisa A; Seielstad, Mark; Steinhart, A Hillary; Targan, Stephan R; van den Berg, Leonard H; Vatn, Morten; Verspaget, Hein; Walters, Thomas; Wijmenga, Cisca; Wilson, David C; Westra, Harm-Jan; Xavier, Ramnik J; Zhao, Zhen Z; Ponsioen, Cyriel Y; Andersen, Vibeke; Torkvist, Leif; Gazouli, Maria; Anagnou, Nicholas P; Karlsen, Tom H; Kupcinskas, Limas; Sventoraityte, Jurgita; Mansfield, John C; Kugathasan, Subra; Silverberg, Mark S; Halfvarson, Jonas; Rotter, Jerome I; Mathew, Christopher G; Griffiths, Anne M; Gearry, Richard; Ahmad, Tariq; Brant, Steven R; Chamaillard, Mathias; Satsangi, Jack; Cho, Judy H; Schreiber, Stefan; Daly, Mark J; Barrett, Jeffrey C; Parkes, Miles; Annese, Vito; Hakonarson, Hakon; Radford-Smith, Graham; Duerr, Richard H; Vermeire, Séverine; Weersma, Rinse K; Rioux, John D

2011-03-01

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Immunoinformatic Analysis of Crimean Congo Hemorrhagic Fever Virus Glycoproteins and Epitope Prediction for Synthetic Peptide Vaccine.

PubMed

Tipu, Hamid Nawaz

2016-02-01

To determine the Crimean Congo Hemorrhagic Fever (CCHF) virus M segement glycoprotein's immunoinformatic parameters, and identify Human Leukocyte Antigen (HLA) class I binders as candidates for synthetic peptide vaccines. Cross-sectional study. Combined Military Hospital, Khuzdar Cantt, in May 2015. Data acquisition, antigenicity prediction, secondary and tertiary structure prediction, residue analysis were done using immunoinformatics tools. HLAclass I binders in glycoprotein's sequence were identified at nanomer length using NetMHC 3.4 and mapped onto tertiary structure. Docking was done for strongest binder against its corresponding allele with CABS-dock. HLAA*0101, 0201, 0301, 2402, 2601 and B*0702, 0801, 2705, 3901, 4001, 5801, 1501 were analyzed against two glycoprotein components of the virus. Atotal of 35 nanomers from GP1, and 3 from GP2 were identified. HLAB*0702 bound maximum number of peptides (6), while HLAB*4001 showed strongest binding affinity. HLAspecific glycoproteins epitope prediction can help identify synthetic peptide vaccine candidates.

A framework for collaborative review of candidate events in high data rate streams: The V-FASTR experiment as a case study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hart, Andrew F.; Cinquini, Luca; Khudikyan, Shakeh E.

2015-01-01

“Fast radio transients” are defined here as bright millisecond pulses of radio-frequency energy. These short-duration pulses can be produced by known objects such as pulsars or potentially by more exotic objects such as evaporating black holes. The identification and verification of such an event would be of great scientific value. This is one major goal of the Very Long Baseline Array (VLBA) Fast Transient Experiment (V-FASTR), a software-based detection system installed at the VLBA. V-FASTR uses a “commensal” (piggy-back) approach, analyzing all array data continually during routine VLBA observations and identifying candidate fast transient events. Raw data can be storedmore » from a buffer memory, which enables a comprehensive off-line analysis. This is invaluable for validating the astrophysical origin of any detection. Candidates discovered by the automatic system must be reviewed each day by analysts to identify any promising signals that warrant a more in-depth investigation. To support the timely analysis of fast transient detection candidates by V-FASTR scientists, we have developed a metadata-driven, collaborative candidate review framework. The framework consists of a software pipeline for metadata processing composed of both open source software components and project-specific code written expressly to extract and catalog metadata from the incoming V-FASTR data products, and a web-based data portal that facilitates browsing and inspection of the available metadata for candidate events extracted from the VLBA radio data.« less

Psychological aptitude evaluation of the special forces candidate.

PubMed

Genoni, Luca; Jelmini, F; Lang, M; Muggli, F

2017-02-01

Changes in recruitment procedures reduced early dismissal rates from Swiss military basic recruitment schools; however, such improvements were not reflected in premature discharge rates from the special forces (SF) (Grenadier) recruitment school. A six-item questionnaire designed to identify recruits likely to be subject to premature dismissal on psychological or psychiatric grounds was developed and prospectively validated. The questionnaire was based on an analysis of medical and psychiatric/psychological records of 26 recruits dismissed from a SF recruitment school. Six items were identified that appeared to have prognostic value for early discharge. These six questions were submitted to the remaining applicants in the recruitment school by a suitably qualified psychologist or psychiatrist and effectively identified candidates who would be discharged early. Based on these results a 0-6 scale was developed and applied prospectively to subsequent Grenadier recruitment courses. Statistical analysis showed that 75% of candidates with the lowest scores would eventually complete the course and that no candidates with highest scores would subsequently complete the recruitment course. Prospective studies in subsequent recruitment courses candidates with high scores were classified as not qualified to enter the course, and those with intermediate scores were subject to additional in-depth interviews with a psychologist or psychiatrist to determine their suitability. In the following courses a correlation was established between the questionnaire score and week of discharge for those discharged. Application of this method during subsequent recruitment courses has reduced early dismissal from Swiss SF recruitment schools. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Functional dissection of drought-responsive gene expression patterns in Cynodon dactylon L.

PubMed

Kim, Changsoo; Lemke, Cornelia; Paterson, Andrew H

2009-05-01

Water deficit is one of the main abiotic factors that affect plant productivity in subtropical regions. To identify genes induced during the water stress response in Bermudagrass (Cynodon dactylon), cDNA macroarrays were used. The macroarray analysis identified 189 drought-responsive candidate genes from C. dactylon, of which 120 were up-regulated and 69 were down-regulated. The candidate genes were classified into seven groups by cluster analysis of expression levels across two intensities and three durations of imposed stress. Annotation using BLASTX suggested that up-regulated genes may be involved in proline biosynthesis, signal transduction pathways, protein repair systems, and removal of toxins, while down-regulated genes were mostly related to basic plant metabolism such as photosynthesis and glycolysis. The functional classification of gene ontology (GO) was consistent with the BLASTX results, also suggesting some crosstalk between abiotic and biotic stress. Comparative analysis of cis-regulatory elements from the candidate genes implicated specific elements in drought response in Bermudagrass. Although only a subset of genes was studied, Bermudagrass shared many drought-responsive genes and cis-regulatory elements with other botanical models, supporting a strategy of cross-taxon application of drought-responsive genes, regulatory cues, and physiological-genetic information.

Identification of novel biomarker and therapeutic target candidates for acute intracerebral hemorrhage by quantitative plasma proteomics.

PubMed

Li, Guo-Chun; Zhang, Lina; Yu, Ming; Jia, Haiyu; Tian, Ting; Wang, Junqin; Wang, Fuqiang; Zhou, Ling

2017-01-01

The systematic mechanisms of acute intracerebral hemorrhage are still unknown and unverified, although many recent researches have indicated the secondary insults. This study was aimed to disclose the pathological mechanism and identify novel biomarker and therapeutic target candidates by plasma proteome. Patients with AICH (n = 8) who demographically matched healthy controls (n = 4) were prospectively enrolled, and their plasma samples were obtained. The TMT-LC-MS/MS-based proteomics approach was used to quantify the differential proteome across plasma samples, and the results were analyzed by Ingenuity Pathway Analysis to explore canonical pathways and the relationship involved in the uploaded data. Compared with healthy controls, there were 31 differentially expressed proteins in the ICH group ( P  < 0.05), of which 21 proteins increased while 10 proteins decreased in abundance. These proteins are involved in 21 canonical pathways. One network with high confidence level was selected by the function network analysis, in which 23 proteins, P38MAPK and NFκB signaling pathways participated. Upstream regulator analysis found two regulators, IL6 and TNF, with an activation z -score. Seven biomarker candidates: APCS, FGB, LBP, MGMT, IGFBP2, LYZ, and APOA4 were found. Six candidate proteins were selected to assess the validity of the results by subsequent Western blotting analysis. Our analysis provided several intriguing pathways involved in ICH, like LXR/RXR activation, acute phase response signaling, and production of NO and ROS in macrophages pathways. The three upstream regulators: IL-6, TNF, LPS, and seven biomarker candidates: APCS, APOA4, FGB, IGFBP2, LBP, LYZ, and MGMT were uncovered. LPS, APOA4, IGFBP2, LBP, LYZ, and MGMT are novel potential biomarkers in ICH development. The identified proteins and pathways provide new perspectives to the potential pathological mechanism and therapeutic targets underlying ICH.

Parkinson's disease candidate gene prioritization based on expression profile of midbrain dopaminergic neurons

PubMed Central

2010-01-01

Background Parkinson's disease is the second most common neurodegenerative disorder. The pathological hallmark of the disease is degeneration of midbrain dopaminergic neurons. Genetic association studies have linked 13 human chromosomal loci to Parkinson's disease. Identification of gene(s), as part of the etiology of Parkinson's disease, within the large number of genes residing in these loci can be achieved through several approaches, including screening methods, and considering appropriate criteria. Since several of the indentified Parkinson's disease genes are expressed in substantia nigra pars compact of the midbrain, expression within the neurons of this area could be a suitable criterion to limit the number of candidates and identify PD genes. Methods In this work we have used the combination of findings from six rodent transcriptome analysis studies on the gene expression profile of midbrain dopaminergic neurons and the PARK loci in OMIM (Online Mendelian Inheritance in Man) database, to identify new candidate genes for Parkinson's disease. Results Merging the two datasets, we identified 20 genes within PARK loci, 7 of which are located in an orphan Parkinson's disease locus and one, which had been identified as a disease gene. In addition to identifying a set of candidates for further genetic association studies, these results show that the criteria of expression in midbrain dopaminergic neurons may be used to narrow down the number of genes in PARK loci for such studies. PMID:20716345

Space Transportation Booster Engine (STBE) configuration study

NASA Technical Reports Server (NTRS)

1986-01-01

The overall objective of this Space Transportation Booster Engine (STBE) study is to identify candidate engine configurations which enhance vehicle performance and provide operational flexibility at low cost. The specific objectives are as follows: (1) to identify and evaluate candidate LOX/HC engine configurations for the Advanced Space Transportation System for an early 1995 IOC and a late 2000 IOC; (2) to select one optimum engine for each time period; 3) to prepare a conceptual design for each configuration; (4) to develop a technology plan for the 2000 IOC engine; and, (5) to prepare preliminary programmatic planning and analysis for the 1995 IOC engine.

Transcription map of Xq27: candidates for several X-linked diseases.

PubMed

Zucchi, I; Jones, J; Affer, M; Montagna, C; Redolfi, E; Susani, L; Vezzoni, P; Parvari, R; Schlessinger, D; Whyte, M P; Mumm, S

1999-04-15

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found. Copyright 1999 Academic Press.

Identification of high-mass X-ray binaries selected from XMM-Newton observations of the LMC★

NASA Astrophysics Data System (ADS)

van Jaarsveld, N.; Buckley, D. A. H.; McBride, V. A.; Haberl, F.; Vasilopoulos, G.; Maitra, C.; Udalski, A.; Miszalski, B.

2018-04-01

The Large Magellanic Cloud (LMC) currently hosts around 23 high-mass X-ray binaries (HMXBs) of which most are Be/X-ray binaries. The LMC XMM-Newton survey provided follow-up observations of previously known X-ray sources that were likely HMXBs, as well as identifying new HMXB candidates. In total, 19 candidate HMXBs were selected based on their X-ray hardness ratios. In this paper we present red and blue optical spectroscopy, obtained with Southern African Large Telescope and the South African Astronomical Observatory 1.9-m telescope, plus a timing analysis of the long-term optical light curves from OGLE to confirm the nature of these candidates. We find that nine of the candidates are new Be/X-ray binaries, substantially increasing the LMC Be/X-ray binary population. Furthermore, we present the optical properties of these new systems, both individually and as a group of all the BeXBs identified by the XMM-Newton survey of the LMC.

Candidacy for Kidney Transplantation of Older Adults

PubMed Central

Grams, Morgan E.; Kucirka, Lauren M.; Hanrahan, Colleen F.; Montgomery, Robert A.; Massie, Allan B.; Segev, Dorry L.

2013-01-01

OBJECTIVES To develop a prediction model for kidney transplantation (KT) outcomes specific to older adults with end-stage renal disease (ESRD) and to use this model to estimate the number of excellent older KT candidates who lack access to KT. DESIGN Secondary analysis of data collected by the United Network for Organ Sharing and U.S. Renal Disease System. SETTING Retrospective analysis of national registry data. PARTICIPANTS Model development: Medicare-primary older recipients (aged ≥ 65) of a first KT between 1999 and 2006 (N = 6,988). Model application: incident Medicare-primary older adults with ESRD between 1999 and 2006 without an absolute or relative contraindication to transplantation (N = 128,850). MEASUREMENTS Comorbid conditions were extracted from U.S. Renal Disease System Form 2728 data and Medicare claims. RESULTS The prediction model used 19 variables to estimate post-KT outcome and showed good calibration (Hosmer–Lemeshow P = .44) and better prediction than previous population-average models (P < .001). Application of the model to the population with incident ESRD identified 11,756 excellent older transplant candidates (defined as >87% predicted 3-year post-KT survival, corresponding to the top 20% of transplanted older adults used in model development), of whom 76.3% (n = 8,966) lacked access. It was estimated that 11% of these candidates would have identified a suitable live donor had they been referred for KT. CONCLUSION A risk-prediction model specific to older adults can identify excellent KT candidates. Appropriate referral could result in significantly greater rates of KT in older adults. PMID:22239290

Refining adverse drug reaction signals by incorporating interaction variables identified using emergent pattern mining.

PubMed

Reps, Jenna M; Aickelin, Uwe; Hubbard, Richard B

2016-02-01

To develop a framework for identifying and incorporating candidate confounding interaction terms into a regularised cox regression analysis to refine adverse drug reaction signals obtained via longitudinal observational data. We considered six drug families that are commonly associated with myocardial infarction in observational healthcare data, but where the causal relationship ground truth is known (adverse drug reaction or not). We applied emergent pattern mining to find itemsets of drugs and medical events that are associated with the development of myocardial infarction. These are the candidate confounding interaction terms. We then implemented a cohort study design using regularised cox regression that incorporated and accounted for the candidate confounding interaction terms. The methodology was able to account for signals generated due to confounding and a cox regression with elastic net regularisation correctly ranking the drug families known to be true adverse drug reactions above those that are not. This was not the case without the inclusion of the candidate confounding interaction terms, where confounding leads to a non-adverse drug reaction being ranked highest. The methodology is efficient, can identify high-order confounding interactions and does not require expert input to specify outcome specific confounders, so it can be applied for any outcome of interest to quickly refine its signals. The proposed method shows excellent potential to overcome some forms of confounding and therefore reduce the false positive rate for signal analysis using longitudinal data. Copyright © 2015 Elsevier Ltd. All rights reserved.

Meta-Analysis and Experimental Validation Identified FREM2 and SPRY1 as New Glioblastoma Marker Candidates.

PubMed

Vidak, Marko; Jovcevska, Ivana; Samec, Neja; Zottel, Alja; Liovic, Mirjana; Rozman, Damjana; Dzeroski, Saso; Juvan, Peter; Komel, Radovan

2018-05-04

Glioblastoma (GB) is the most aggressive brain malignancy. Although some potential glioblastoma biomarkers have already been identified, there is a lack of cell membrane-bound biomarkers capable of distinguishing brain tissue from glioblastoma and/or glioblastoma stem cells (GSC), which are responsible for the rapid post-operative tumor reoccurrence. In order to find new GB/GSC marker candidates that would be cell surface proteins (CSP), we have performed meta-analysis of genome-scale mRNA expression data from three data repositories (GEO, ArrayExpress and GLIOMASdb). The search yielded ten appropriate datasets, and three (GSE4290/GDS1962, GSE23806/GDS3885, and GLIOMASdb) were used for selection of new GB/GSC marker candidates, while the other seven (GSE4412/GDS1975, GSE4412/GDS1976, E-GEOD-52009, E-GEOD-68848, E-GEOD-16011, E-GEOD-4536, and E-GEOD-74571) were used for bioinformatic validation. The selection identified four new CSP-encoding candidate genes— CD276 , FREM2 , SPRY1 , and SLC47A1 —and the bioinformatic validation confirmed these findings. A review of the literature revealed that CD276 is not a novel candidate, while SLC47A1 had lower validation test scores than the other new candidates and was therefore not considered for experimental validation. This validation revealed that the expression of FREM2—but not SPRY1—is higher in glioblastoma cell lines when compared to non-malignant astrocytes. In addition, FREM2 gene and protein expression levels are higher in GB stem-like cell lines than in conventional glioblastoma cell lines. FREM2 is thus proposed as a novel GB biomarker and a putative biomarker of glioblastoma stem cells. Both FREM2 and SPRY1 are expressed on the surface of the GB cells, while SPRY1 alone was found overexpressed in the cytosol of non-malignant astrocytes.

Sarcoidosis Related Novel Candidate Genes Identified by Multi-Omics Integrative Analyses.

PubMed

Hočevar, Keli; Maver, Aleš; Kunej, Tanja; Peterlin, Borut

2018-05-01

Sarcoidosis is a multifactorial systemic disease characterized by granulomatous inflammation and greatly impacting on global public health. The etiology and mechanisms of sarcoidosis are not fully understood. Recent high-throughput biological research has generated vast amounts of multi-omics big data on sarcoidosis, but their significance remains to be determined. We sought to identify novel candidate regions, and genes consistently altered in heterogeneous omics studies so as to reveal the underlying molecular mechanisms. We conducted a comprehensive integrative literature analysis on global data on sarcoidosis, including genomic, transcriptomic, proteomic, and phenomic studies. We performed positional integration analysis of 38 eligible datasets originating from 17 different biological layers. Using the integration interval length of 50 kb, we identified 54 regions reaching significance value p ≤ 0.0001 and 15 regions with significance value p ≤ 0.00001, when applying more stringent criteria. Secondary literature analysis of the top 20 regions, with the most significant accumulation of signals, revealed several novel candidate genes for which associations with sarcoidosis have not yet been established, but have considerable support for their involvement based on omic data. These new plausible candidate genes include NELFE, CFB, EGFL7, AGPAT2, FKBPL, NRC3, and NEU1. Furthermore, annotated data were prepared to enable custom visualization and browsing of these sarcoidosis related omics evidence in the University of California Santa Cruz (UCSC) Genome Browser. Further multi-omics approaches are called for sarcoidosis biomarkers and diagnostic and therapeutic innovation. Our approach for harnessing multi-omics data and the findings presented herein reflect important steps toward understanding the etiology and underlying pathological mechanisms of sarcoidosis.

An Arrayed Genome-Scale Lentiviral-Enabled Short Hairpin RNA Screen Identifies Lethal and Rescuer Gene Candidates

PubMed Central

Bhinder, Bhavneet; Antczak, Christophe; Ramirez, Christina N.; Shum, David; Liu-Sullivan, Nancy; Radu, Constantin; Frattini, Mark G.

2013-01-01

Abstract RNA interference technology is becoming an integral tool for target discovery and validation.; With perhaps the exception of only few studies published using arrayed short hairpin RNA (shRNA) libraries, most of the reports have been either against pooled siRNA or shRNA, or arrayed siRNA libraries. For this purpose, we have developed a workflow and performed an arrayed genome-scale shRNA lethality screen against the TRC1 library in HeLa cells. The resulting targets would be a valuable resource of candidates toward a better understanding of cellular homeostasis. Using a high-stringency hit nomination method encompassing criteria of at least three active hairpins per gene and filtered for potential off-target effects (OTEs), referred to as the Bhinder–Djaballah analysis method, we identified 1,252 lethal and 6 rescuer gene candidates, knockdown of which resulted in severe cell death or enhanced growth, respectively. Cross referencing individual hairpins with the TRC1 validated clone database, 239 of the 1,252 candidates were deemed independently validated with at least three validated clones. Through our systematic OTE analysis, we have identified 31 microRNAs (miRNAs) in lethal and 2 in rescuer genes; all having a seed heptamer mimic in the corresponding shRNA hairpins and likely cause of the OTE observed in our screen, perhaps unraveling a previously unknown plausible essentiality of these miRNAs in cellular viability. Taken together, we report on a methodology for performing large-scale arrayed shRNA screens, a comprehensive analysis method to nominate high-confidence hits, and a performance assessment of the TRC1 library highlighting the intracellular inefficiencies of shRNA processing in general. PMID:23198867

Novel genes on rat chromosome 10 are linked to body fat mass, preadipocyte number and adipocyte size.

PubMed

Weingarten, A; Turchetti, L; Krohn, K; Klöting, I; Kern, M; Kovacs, P; Stumvoll, M; Blüher, M; Klöting, N

2016-12-01

The genetic architecture of obesity is multifactorial. We have previously identified a quantitative trait locus (QTL) on rat chromosome 10 in a F2 cross of Wistar Ottawa Karlsburg (WOKW) and Dark Agouti (DA) rats responsible for obesity-related traits. The QTL was confirmed in congenic DA.WOKW10 rats. To pinpoint the region carrying causal genes, we established two new subcongenic lines, L1 and L2, with smaller refined segments of chromosome 10 to identify novel candidate genes. All lines were extensively characterized under different diet conditions. We employed transcriptome analysis in visceral adipose tissue (VAT) by RNA-Seq technology to identify potential underlying genes in the segregating regions. Three candidate genes were measured in human paired samples of VAT and subcutaneous (SC) AT (SAT) (N=304) individuals with a wide range of body weight and glucose homeostasis parameters. DA.WOKW and L1 subcongenic lines were protected against body fat gain under high-fat diet (HFD), whereas L2 and DA had significantly more body fat after high-fat feeding. Interestingly, adipocyte size distribution in SAT and epigonadal AT of L1 subcongenic rats did not undergo typical ballooning under HFD and the number of preadipocytes in AT was significantly elevated in L2 compared with L1 and parental rats. Transcriptome analysis identified three candidate genes in VAT on rat chromosome 10. In humans, these candidate genes were differentially expressed between SAT and VAT. Moreover, HID1 mRNA significantly correlates with parameters of obesity and glucose metabolism. Our data suggest novel candidate genes for obesity that map on rat chromosome 10 in an interval 102.2-104.7 Mb and are strongly associated with body fat mass regulation, preadipocyte number and adipocyte size in rats. Among those genes, AT head involution defective (HID1) mRNA expression may be relevant for human fat distribution and glucose homeostasis.

Ancestry-based stratified analysis of Immunochip data identifies novel associations with celiac disease.

PubMed

Garcia-Etxebarria, Koldo; Jauregi-Miguel, Amaia; Romero-Garmendia, Irati; Plaza-Izurieta, Leticia; Legarda, Maria; Irastorza, Iñaki; Bilbao, Jose Ramon

2016-12-01

To identify candidate genes in celiac disease (CD), we reanalyzed the whole Immunochip CD cohort using a different approach that clusters individuals based on immunoancestry prior to disease association analysis, rather than by geographical origin. We detected 636 new associated SNPs (P<7.02 × 10 -07 ) and identified 5 novel genomic regions, extended 8 others previously identified and also detected 18 isolated signals defined by one or very few significant SNPs. To test whether we could identify putative candidate genes, we performed expression analyses of several genes from the top novel region (chr2:134533564-136169524), from a previously identified locus that is now extended, and a gene marked by an isolated SNP, in duodenum biopsies of active and treated CD patients, and non-celiac controls. In the largest novel region, CCNT2 and R3HDM1 were constitutively underexpressed in disease, even after gluten removal. Moreover, several genes within this region were coexpressed in patients, but not in controls. Other novel genes like KIF21B, REL and SORD also showed altered expression in active disease. Apart from the identification of novel CD loci, these results suggest that ancestry-based stratified analysis is an efficient strategy for association studies in complex diseases.

TRANSIT TIMING OBSERVATIONS FROM KEPLER. I. STATISTICAL ANALYSIS OF THE FIRST FOUR MONTHS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ford, Eric B.; Rowe, Jason F.; Caldwell, Douglas A.

The architectures of multiple planet systems can provide valuable constraints on models of planet formation, including orbital migration, and excitation of orbital eccentricities and inclinations. NASA's Kepler mission has identified 1235 transiting planet candidates. The method of transit timing variations (TTVs) has already confirmed seven planets in two planetary systems. We perform a transit timing analysis of the Kepler planet candidates. We find that at least {approx}11% of planet candidates currently suitable for TTV analysis show evidence suggestive of TTVs, representing at least {approx}65 TTV candidates. In all cases, the time span of observations must increase for TTVs to providemore » strong constraints on planet masses and/or orbits, as expected based on N-body integrations of multiple transiting planet candidate systems (assuming circular and coplanar orbits). We find the fraction of planet candidates showing TTVs in this data set does not vary significantly with the number of transiting planet candidates per star, suggesting significant mutual inclinations and that many stars with a single transiting planet should host additional non-transiting planets. We anticipate that Kepler could confirm (or reject) at least {approx}12 systems with multiple transiting planet candidates via TTVs. Thus, TTVs will provide a powerful tool for confirming transiting planets and characterizing the orbital dynamics of low-mass planets. If Kepler observations were extended to at least seven years, then TTVs would provide much more precise constraints on the dynamics of systems with multiple transiting planets and would become sensitive to planets with orbital periods extending into the habitable zone of solar-type stars.« less

Dissecting the organ specificity of insecticide resistance candidate genes in Anopheles gambiae: known and novel candidate genes.

PubMed

Ingham, Victoria A; Jones, Christopher M; Pignatelli, Patricia; Balabanidou, Vasileia; Vontas, John; Wagstaff, Simon C; Moore, Jonathan D; Ranson, Hilary

2014-11-25

The elevated expression of enzymes with insecticide metabolism activity can lead to high levels of insecticide resistance in the malaria vector, Anopheles gambiae. In this study, adult female mosquitoes from an insecticide susceptible and resistant strain were dissected into four different body parts. RNA from each of these samples was used in microarray analysis to determine the enrichment patterns of the key detoxification gene families within the mosquito and to identify additional candidate insecticide resistance genes that may have been overlooked in previous experiments on whole organisms. A general enrichment in the transcription of genes from the four major detoxification gene families (carboxylesterases, glutathione transferases, UDP glucornyltransferases and cytochrome P450s) was observed in the midgut and malpighian tubules. Yet the subset of P450 genes that have previously been implicated in insecticide resistance in An gambiae, show a surprisingly varied profile of tissue enrichment, confirmed by qPCR and, for three candidates, by immunostaining. A stringent selection process was used to define a list of 105 genes that are significantly (p ≤0.001) over expressed in body parts from the resistant versus susceptible strain. Over half of these, including all the cytochrome P450s on this list, were identified in previous whole organism comparisons between the strains, but several new candidates were detected, notably from comparisons of the transcriptomes from dissected abdomen integuments. The use of RNA extracted from the whole organism to identify candidate insecticide resistance genes has a risk of missing candidates if key genes responsible for the phenotype have restricted expression within the body and/or are over expression only in certain tissues. However, as transcription of genes implicated in metabolic resistance to insecticides is not enriched in any one single organ, comparison of the transcriptome of individual dissected body parts cannot be recommended as a preferred means to identify new candidate insecticide resistant genes. Instead the rich data set on in vivo sites of transcription should be consulted when designing follow up qPCR validation steps, or for screening known candidates in field populations.

Network-based Analysis of Genome Wide Association Data Provides Novel Candidate Genes for Lipid and Lipoprotein Traits*

PubMed Central

Sharma, Amitabh; Gulbahce, Natali; Pevzner, Samuel J.; Menche, Jörg; Ladenvall, Claes; Folkersen, Lasse; Eriksson, Per; Orho-Melander, Marju; Barabási, Albert-László

2013-01-01

Genome wide association studies (GWAS) identify susceptibility loci for complex traits, but do not identify particular genes of interest. Integration of functional and network information may help in overcoming this limitation and identifying new susceptibility loci. Using GWAS and comorbidity data, we present a network-based approach to predict candidate genes for lipid and lipoprotein traits. We apply a prediction pipeline incorporating interactome, co-expression, and comorbidity data to Global Lipids Genetics Consortium (GLGC) GWAS for four traits of interest, identifying phenotypically coherent modules. These modules provide insights regarding gene involvement in complex phenotypes with multiple susceptibility alleles and low effect sizes. To experimentally test our predictions, we selected four candidate genes and genotyped representative SNPs in the Malmö Diet and Cancer Cardiovascular Cohort. We found significant associations with LDL-C and total-cholesterol levels for a synonymous SNP (rs234706) in the cystathionine beta-synthase (CBS) gene (p = 1 × 10−5 and adjusted-p = 0.013, respectively). Further, liver samples taken from 206 patients revealed that patients with the minor allele of rs234706 had significant dysregulation of CBS (p = 0.04). Despite the known biological role of CBS in lipid metabolism, SNPs within the locus have not yet been identified in GWAS of lipoprotein traits. Thus, the GWAS-based Comorbidity Module (GCM) approach identifies candidate genes missed by GWAS studies, serving as a broadly applicable tool for the investigation of other complex disease phenotypes. PMID:23882023

H-alpha LEGUS: Insights into the Field OB Star Population in Nearby Galaxies

NASA Astrophysics Data System (ADS)

Lee, Janice; Thilker, David; Kayitesi, Bridget; Chandar, Rupali; Halpha LEGUS Team

2018-01-01

The question of whether O-stars can form in isolation, without attendant clusters or associations of lower mass stars, is a topic of interest because the answer to the question can distinguish between models of star formation. To begin to investigate whether such isolated O-stars can be identified in nearby galaxies beyond the Local Group, we identify candidate field OB-stars in NGC 1313, NGC 4395 and NGC 7793, the three nearest spiral galaxies in the HST Legacy ExtraGalactic Ultraviolet Survey (LEGUS). Candidates are selected using a technique based on: (1) a reddening-free Q parameter, adapted for photometry in HST filters covering the NUV, U, & B bands; (2) isolation based on projected distance from the nearest young cluster and candidate OB star, and (3) the presence of an HII region, identified based on HST H-alpha narrowband imaging. Our catalogs enable a range of follow-up studies on massive stars, and in particular provide targets for future spectroscopic observation and analysis. We describe the candidate OB star sample, the spatial distribution of the stars, and their HII region properties, with special focus on the most isolated objects in the sample.

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

PubMed Central

Shaheen, Ranad; Faqeih, Eissa; Alshammari, Muneera J; Swaid, Abdulrahman; Al-Gazali, Lihadh; Mardawi, Elham; Ansari, Shinu; Sogaty, Sameera; Seidahmed, Mohammed Z; AlMotairi, Muhammed I; Farra, Chantal; Kurdi, Wesam; Al-Rasheed, Shatha; Alkuraya, Fowzan S

2013-01-01

Meckel–Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n=12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis–van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population. PMID:23169490

Quantitative Trait Loci Mapping in Brassica rapa Revealed the Structural and Functional Conservation of Genetic Loci Governing Morphological and Yield Component Traits in the A, B, and C Subgenomes of Brassica Species

PubMed Central

Li, Xiaonan; Ramchiary, Nirala; Dhandapani, Vignesh; Choi, Su Ryun; Hur, Yoonkang; Nou, Ill-Sup; Yoon, Moo Kyoung; Lim, Yong Pyo

2013-01-01

Brassica rapa is an important crop species that produces vegetables, oilseed, and fodder. Although many studies reported quantitative trait loci (QTL) mapping, the genes governing most of its economically important traits are still unknown. In this study, we report QTL mapping for morphological and yield component traits in B. rapa and comparative map alignment between B. rapa, B. napus, B. juncea, and Arabidopsis thaliana to identify candidate genes and conserved QTL blocks between them. A total of 95 QTL were identified in different crucifer blocks of the B. rapa genome. Through synteny analysis with A. thaliana, B. rapa candidate genes and intronic and exonic single nucleotide polymorphisms in the parental lines were detected from whole genome resequenced data, a few of which were validated by mapping them to the QTL regions. Semi-quantitative reverse transcriptase PCR analysis showed differences in the expression levels of a few genes in parental lines. Comparative mapping identified five key major evolutionarily conserved crucifer blocks (R, J, F, E, and W) harbouring QTL for morphological and yield components traits between the A, B, and C subgenomes of B. rapa, B. juncea, and B. napus. The information of the identified candidate genes could be used for breeding B. rapa and other related Brassica species. PMID:23223793

Frequency and clinical predictors of coronary artery disease in chronic renal failure renal transplant candidates.

PubMed

de Albuquerque Seixas, Emerson; Carmello, Beatriz Leone; Kojima, Christiane Akemi; Contti, Mariana Moraes; Modeli de Andrade, Luiz Gustavo; Maiello, José Roberto; Almeida, Fernando Antonio; Martin, Luis Cuadrado

2015-05-01

Cardiovascular diseases are major causes of mortality in chronic renal failure patients before and after renal transplantation. Among them, coronary disease presents a particular risk; however, risk predictors have been used to diagnose coronary heart disease. This study evaluated the frequency and importance of clinical predictors of coronary artery disease in chronic renal failure patients undergoing dialysis who were renal transplant candidates, and assessed a previously developed scoring system. Coronary angiographies conducted between March 2008 and April 2013 from 99 candidates for renal transplantation from two transplant centers in São Paulo state were analyzed for associations between significant coronary artery diseases (≥70% stenosis in one or more epicardial coronary arteries or ≥50% in the left main coronary artery) and clinical parameters. Univariate logistic regression analysis identified diabetes, angina, and/or previous infarction, clinical peripheral arterial disease and dyslipidemia as predictors of coronary artery disease. Multiple logistic regression analysis identified only diabetes and angina and/or previous infarction as independent predictors. The results corroborate previous studies demonstrating the importance of these factors when selecting patients for coronary angiography in clinical pretransplant evaluation.

Identifying Candidate Chemical-Disease Linkages ...

EPA Pesticide Factsheets

Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This hazard information is combined with exposure models to inform risk assessment. Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This hazard information is combined with exposure models to inform risk assessment.

Immune Profiles to Predict Response to Desensitization Therapy in Highly HLA-Sensitized Kidney Transplant Candidates

PubMed Central

Yabu, Julie M.; Siebert, Janet C.; Maecker, Holden T.

2016-01-01

Background Kidney transplantation is the most effective treatment for end-stage kidney disease. Sensitization, the formation of human leukocyte antigen (HLA) antibodies, remains a major barrier to successful kidney transplantation. Despite the implementation of desensitization strategies, many candidates fail to respond. Current progress is hindered by the lack of biomarkers to predict response and to guide therapy. Our objective was to determine whether differences in immune and gene profiles may help identify which candidates will respond to desensitization therapy. Methods and Findings Single-cell mass cytometry by time-of-flight (CyTOF) phenotyping, gene arrays, and phosphoepitope flow cytometry were performed in a study of 20 highly sensitized kidney transplant candidates undergoing desensitization therapy. Responders to desensitization therapy were defined as 5% or greater decrease in cumulative calculated panel reactive antibody (cPRA) levels, and non-responders had 0% decrease in cPRA. Using a decision tree analysis, we found that a combination of transitional B cell and regulatory T cell (Treg) frequencies at baseline before initiation of desensitization therapy could distinguish responders from non-responders. Using a support vector machine (SVM) and longitudinal data, TRAF3IP3 transcripts and HLA-DR-CD38+CD4+ T cells could also distinguish responders from non-responders. Combining all assays in a multivariate analysis and elastic net regression model with 72 analytes, we identified seven that were highly interrelated and eleven that predicted response to desensitization therapy. Conclusions Measuring baseline and longitudinal immune and gene profiles could provide a useful strategy to distinguish responders from non-responders to desensitization therapy. This study presents the integration of novel translational studies including CyTOF immunophenotyping in a multivariate analysis model that has potential applications to predict response to desensitization, select candidates, and personalize medicine to ultimately improve overall outcomes in highly sensitized kidney transplant candidates. PMID:27078882

Immune Profiles to Predict Response to Desensitization Therapy in Highly HLA-Sensitized Kidney Transplant Candidates.

PubMed

Yabu, Julie M; Siebert, Janet C; Maecker, Holden T

2016-01-01

Kidney transplantation is the most effective treatment for end-stage kidney disease. Sensitization, the formation of human leukocyte antigen (HLA) antibodies, remains a major barrier to successful kidney transplantation. Despite the implementation of desensitization strategies, many candidates fail to respond. Current progress is hindered by the lack of biomarkers to predict response and to guide therapy. Our objective was to determine whether differences in immune and gene profiles may help identify which candidates will respond to desensitization therapy. Single-cell mass cytometry by time-of-flight (CyTOF) phenotyping, gene arrays, and phosphoepitope flow cytometry were performed in a study of 20 highly sensitized kidney transplant candidates undergoing desensitization therapy. Responders to desensitization therapy were defined as 5% or greater decrease in cumulative calculated panel reactive antibody (cPRA) levels, and non-responders had 0% decrease in cPRA. Using a decision tree analysis, we found that a combination of transitional B cell and regulatory T cell (Treg) frequencies at baseline before initiation of desensitization therapy could distinguish responders from non-responders. Using a support vector machine (SVM) and longitudinal data, TRAF3IP3 transcripts and HLA-DR-CD38+CD4+ T cells could also distinguish responders from non-responders. Combining all assays in a multivariate analysis and elastic net regression model with 72 analytes, we identified seven that were highly interrelated and eleven that predicted response to desensitization therapy. Measuring baseline and longitudinal immune and gene profiles could provide a useful strategy to distinguish responders from non-responders to desensitization therapy. This study presents the integration of novel translational studies including CyTOF immunophenotyping in a multivariate analysis model that has potential applications to predict response to desensitization, select candidates, and personalize medicine to ultimately improve overall outcomes in highly sensitized kidney transplant candidates.

Fine mapping of the genic male-sterile ms 1 gene in Capsicum annuum L.

PubMed

Jeong, Kyumi; Choi, Doil; Lee, Jundae

2018-01-01

The genomic region cosegregating with the genic male-sterile ms 1 gene of Capsicum annuum L. was delimited to a region of 869.9 kb on chromosome 5 through fine mapping analysis. A strong candidate gene, CA05g06780, a homolog of the Arabidopsis MALE STERILITY 1 gene that controls pollen development, was identified in this region. Genic male sterility caused by the ms 1 gene has been used for the economically efficient production of massive hybrid seeds in paprika (Capsicum annuum L.), a colored bell-type sweet pepper. Previously, a CAPS marker, PmsM1-CAPS, located about 2-3 cM from the ms 1 locus, was reported. In this study, we constructed a fine map near the ms 1 locus using high-resolution melting (HRM) markers in an F 2 population consisting of 1118 individual plants, which segregated into 867 male-fertile and 251 male-sterile plants. A total of 12 HRM markers linked to the ms 1 locus were developed from 53 primer sets targeting intraspecific SNPs derived by comparing genome-wide sequences obtained by next-generation resequencing analysis. Using this approach, we narrowed down the region cosegregating with the ms 1 gene to 869.9 kb of sequence. Gene prediction analysis revealed 11 open reading frames in this region. A strong candidate gene, CA05g06780, was identified; this gene is a homolog of the Arabidopsis MALE STERILITY 1 (MS1) gene, which encodes a PHD-type transcription factor that regulates pollen and tapetum development. Sequence comparison analysis suggested that the CA05g06780 gene is the strongest candidate for the ms 1 gene of paprika. To summarize, we developed a cosegregated marker, 32187928-HRM, for marker-assisted selection and identified a strong candidate for the ms 1 gene.

New Observations of Candidate Herbig Ae/Be Stars in the LMC and SMC

NASA Astrophysics Data System (ADS)

Bjorkman, K. S.; Wisniewski, J. P.; Bjorkman, J. E.; Hesselbach, E. N.

2005-12-01

Based on analysis of the EROS microlensing data set, Lamers, Beaulieu, & de Wit (1999) and de Wit, Beaulieu, & Lamers (2002) identified 21 candidate Herbig Ae/Be (HAeBe) stars in the Large Magellanic Cloud (LMC). They based the selection of candidates on the irregular photometric variability exhibited by these stars, which bore some resemblance to the variability exhibited by known Galactic HAeBe stars. The candidate stars identified were designated as EROS LMC HAeBe Candidates, or ELHCs. A smaller number (7) of candidate stars identified in the SMC (Beaulieu et al. 2001; de Wit et al. 2003) were similarly designated ESHCs. Using the CTIO 0.9m telescope and imaging camera, we obtained B, V, R, and Hα photometry of 2 fields in the LMC encompassing 12 of the ELHCs. We used the CTIO 4m Blanco telescope with the Hydra multi-object spectrograph to obtain optical spectroscopy of all the ELHC stars as well as the ESHC stars. Further observations included JHK photometry of both the ELHC and ESHC fields using the CTIO 4m plus the ISPI infrared imager. We will discuss the results from our observations, and comment on the implications for the tentative identification of these stars as candidate HAeBe stars. We will also compare our results with the recent findings of de Wit et al. (2005). This work has been supported in part by NASA LTSA grant (KSB) NAG5-8054 and NASA GSRP Fellowship (JPW) NGT5-5069 to the University of Toledo. We thank the NOAO TAC for providing observing time for this project, and for providing travel support for JPW.

Analysis of Craniocardiac Malformations in Xenopus using Optical Coherence Tomography

PubMed Central

Deniz, Engin; Jonas, Stephan; Hooper, Michael; N. Griffin, John; Choma, Michael A.; Khokha, Mustafa K.

2017-01-01

Birth defects affect 3% of children in the United States. Among the birth defects, congenital heart disease and craniofacial malformations are major causes of mortality and morbidity. Unfortunately, the genetic mechanisms underlying craniocardiac malformations remain largely uncharacterized. To address this, human genomic studies are identifying sequence variations in patients, resulting in numerous candidate genes. However, the molecular mechanisms of pathogenesis for most candidate genes are unknown. Therefore, there is a need for functional analyses in rapid and efficient animal models of human disease. Here, we coupled the frog Xenopus tropicalis with Optical Coherence Tomography (OCT) to create a fast and efficient system for testing craniocardiac candidate genes. OCT can image cross-sections of microscopic structures in vivo at resolutions approaching histology. Here, we identify optimal OCT imaging planes to visualize and quantitate Xenopus heart and facial structures establishing normative data. Next we evaluate known human congenital heart diseases: cardiomyopathy and heterotaxy. Finally, we examine craniofacial defects by a known human teratogen, cyclopamine. We recapitulate human phenotypes readily and quantify the functional and structural defects. Using this approach, we can quickly test human craniocardiac candidate genes for phenocopy as a critical first step towards understanding disease mechanisms of the candidate genes. PMID:28195132

Prediction of Human Disease Genes by Human-Mouse Conserved Coexpression Analysis

PubMed Central

Grassi, Elena; Damasco, Christian; Silengo, Lorenzo; Oti, Martin; Provero, Paolo; Di Cunto, Ferdinando

2008-01-01

Background Even in the post-genomic era, the identification of candidate genes within loci associated with human genetic diseases is a very demanding task, because the critical region may typically contain hundreds of positional candidates. Since genes implicated in similar phenotypes tend to share very similar expression profiles, high throughput gene expression data may represent a very important resource to identify the best candidates for sequencing. However, so far, gene coexpression has not been used very successfully to prioritize positional candidates. Methodology/Principal Findings We show that it is possible to reliably identify disease-relevant relationships among genes from massive microarray datasets by concentrating only on genes sharing similar expression profiles in both human and mouse. Moreover, we show systematically that the integration of human-mouse conserved coexpression with a phenotype similarity map allows the efficient identification of disease genes in large genomic regions. Finally, using this approach on 850 OMIM loci characterized by an unknown molecular basis, we propose high-probability candidates for 81 genetic diseases. Conclusion Our results demonstrate that conserved coexpression, even at the human-mouse phylogenetic distance, represents a very strong criterion to predict disease-relevant relationships among human genes. PMID:18369433

Genetic Basis of Variation in Rice Seed Storage Protein (Albumin, Globulin, Prolamin, and Glutelin) Content Revealed by Genome-Wide Association Analysis.

PubMed

Chen, Pingli; Shen, Zhikang; Ming, Luchang; Li, Yibo; Dan, Wenhan; Lou, Guangming; Peng, Bo; Wu, Bian; Li, Yanhua; Zhao, Da; Gao, Guanjun; Zhang, Qinglu; Xiao, Jinghua; Li, Xianghua; Wang, Gongwei; He, Yuqing

2018-01-01

Rice seed storage protein (SSP) is an important source of nutrition and energy. Understanding the genetic basis of SSP content and mining favorable alleles that control it will be helpful for breeding new improved cultivars. An association analysis for SSP content was performed to identify underlying genes using 527 diverse Oryza sativa accessions grown in two environments. We identified more than 107 associations for five different traits, including the contents of albumin (Alb), globulin (Glo), prolamin (Pro), glutelin (Glu), and total SSP (Total). A total of 28 associations were located at previously reported QTLs or intervals. A lead SNP sf0709447538, associated for Glu content in the indica subpopulation in 2015, was further validated in near isogenic lines NIL(Zhenshan97) and NIL(Delong208), and the Glu phenotype had significantly difference between two NILs. The association region could be target for map-based cloning of the candidate genes. There were 13 associations in regions close to grain-quality-related genes; five lead single nucleotide polymorphisms (SNPs) were located less than 20 kb upstream from grain-quality-related genes ( PG5a , Wx , AGPS2a , RP6 , and, RM1 ). Several starch-metabolism-related genes ( AGPS2a , OsACS6 , PUL , GBSSII , and ISA2 ) were also associated with SSP content. We identified favorable alleles of functional candidate genes, such as RP6 , RM1 , Wx , and other four candidate genes by haplotype analysis and expression pattern. Genotypes of RP6 and RM1 with higher Pro were not identified in japonica and exhibited much higher expression levels in indica group. The lead SNP sf0601764762, repeatedly detected for Alb content in 2 years in the whole association population, was located in the Wx locus that controls the synthesis of amylose. And Alb content was significantly and negatively correlated with amylose content and the level of 2.3 kb Wx pre-mRNA examined in this study. The associations or candidate genes identified would provide new insights into the genetic basis of SSP content that will help in developing rice cultivars with improved grain nutritional quality through marker-assisted breeding.

Pilot study on the use of data mining to identify cochlear implant candidates.

PubMed

Grisel, Jedidiah J; Schafer, Erin; Lam, Anne; Griffin, Terry

2018-05-01

The goal of this pilot study was to determine the clinical utility of data-mining software that screens for cochlear implant (CI) candidacy. The Auditory Implant Initiative developed a software module that screens for CI candidates via integration with a software system (Noah 4) that serves as a depository for hearing test data. To identify candidates, patient audiograms from one practice were exported into the screening module. Candidates were tracked to determine if any eventually underwent implantation. After loading 4836 audiograms from the Noah 4 system, the screening module identified 558 potential CI candidates. After reviewing the data for the potential candidates, 117 were targeted and invited to an educational event. Following the event, a total of six candidates were evaluated, and two were implanted. This objective approach to identifying candidates has the potential to address the gross underutilization of CIs by removing any bias or lack of knowledge regarding the management of severe to profound sensorineural hearing loss with CIs. The screening module was an effective tool for identifying potential CI candidates at one ENT practice. On a larger scale, the screening module has the potential to impact thousands of CI candidates worldwide.

Characterisation of the macrophage transcriptome in glomerulonephritis-susceptible and -resistant rat strains

PubMed Central

Maratou, Klio; Behmoaras, Jacques; Fewings, Chris; Srivastava, Prashant; D’Souza, Zelpha; Smith, Jennifer; Game, Laurence; Cook, Terence; Aitman, Tim

2010-01-01

Crescentic glomerulonephritis (CRGN) is a major cause of rapidly progressive renal failure for which the underlying genetic basis is unknown. WKY rats show marked susceptibility to CRGN, while Lewis rats are resistant. Glomerular injury and crescent formation are macrophage-dependent and mainly explained by seven quantitative trait loci (Crgn1-7). Here, we used microarray analysis in basal and lipopolysaccharide (LPS)-stimulated macrophages to identify genes that reside on pathways predisposing WKY rats to CRGN. We detected 97 novel positional candidates for the uncharacterised Crgn3-7. We identified 10 additional secondary effector genes with profound differences in expression between the two strains (>5-fold change, <1% False Discovery Rate) for basal and LPS-stimulated macrophages. Moreover, we identified 8 genes with differentially expressed alternatively spliced isoforms, by using an in depth analysis at probe-level that allowed us to discard false positives due to polymorphisms between the two rat strains. Pathway analysis identified several common linked pathways, enriched for differentially expressed genes, which affect macrophage activation. In summary, our results identify distinct macrophage transcriptome profiles between two rat strains that differ in susceptibility to glomerulonephritis, provide novel positional candidates for Crgn3-7, and define groups of genes that play a significant role in differential regulation of macrophage activity. PMID:21179115

Candidate gene biodosimetry markers of exposure to external ionizing radiation in human blood: A systematic review

PubMed Central

Sima, Chao; Amundson, Sally A.; Zenhausern, Frederic

2018-01-01

Purpose To compile a list of genes that have been reported to be affected by external ionizing radiation (IR) and to assess their performance as candidate biomarkers for individual human radiation dosimetry. Methods Eligible studies were identified through extensive searches of the online databases from 1978 to 2017. Original English-language publications of microarray studies assessing radiation-induced changes in gene expression levels in human blood after external IR were included. Genes identified in at least half of the selected studies were retained for bio-statistical analysis in order to evaluate their diagnostic ability. Results 24 studies met the criteria and were included in this study. Radiation-induced expression of 10,170 unique genes was identified and the 31 genes that have been identified in at least 50% of studies (12/24 studies) were selected for diagnostic power analysis. Twenty-seven genes showed a significant Spearman’s correlation with radiation dose. Individually, TNFSF4, FDXR, MYC, ZMAT3 and GADD45A provided the best discrimination of radiation dose < 2 Gy and dose ≥ 2 Gy according to according to their maximized Youden’s index (0.67, 0.55, 0.55, 0.55 and 0.53 respectively). Moreover, 12 combinations of three genes display an area under the Receiver Operating Curve (ROC) curve (AUC) = 1 reinforcing the concept of biomarker combinations instead of looking for an ideal and unique biomarker. Conclusion Gene expression is a promising approach for radiation dosimetry assessment. A list of robust candidate biomarkers has been identified from analysis of the studies published to date, confirming for example the potential of well-known genes such as FDXR and TNFSF4 or highlighting other promising gene such as ZMAT3. However, heterogeneity in protocols and analysis methods will require additional studies to confirm these results. PMID:29879226

Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits

PubMed Central

Benton, Miles C.; Lea, Rod A.; Macartney-Coxson, Donia; Carless, Melanie A.; Göring, Harald H.; Bellis, Claire; Hanna, Michelle; Eccles, David; Chambers, Geoffrey K.; Curran, Joanne E.; Harper, Jacquie L.; Blangero, John; Griffiths, Lyn R.

2013-01-01

Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10−7) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations. PMID:24314549

A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis

PubMed Central

Yu, Haiyang; Artomov, Mykyta; Brähler, Sebastian; Stander, M. Christine; Shamsan, Ghaidan; Sampson, Matthew G.; White, J. Michael; Kretzler, Matthias; Jain, Sanjay; Winkler, Cheryl A.; Mitra, Robi D.; Daly, Mark J.; Shaw, Andrey S.

2016-01-01

Focal segmental glomerulosclerosis (FSGS) is a syndrome that involves kidney podocyte dysfunction and causes chronic kidney disease. Multiple factors including chemical toxicity, inflammation, and infection underlie FSGS; however, highly penetrant disease genes have been identified in a small fraction of patients with a family history of FSGS. Variants of apolipoprotein L1 (APOL1) have been linked to FSGS in African Americans with HIV or hypertension, supporting the proposal that genetic factors enhance FSGS susceptibility. Here, we used sequencing to investigate whether genetics plays a role in the majority of FSGS cases that are identified as primary or sporadic FSGS and have no known cause. Given the limited number of biopsy-proven cases with ethnically matched controls, we devised an analytic strategy to identify and rank potential candidate genes and used an animal model for validation. Nine candidate FSGS susceptibility genes were identified in our patient cohort, and three were validated using a high-throughput mouse method that we developed. Specifically, we introduced a podocyte-specific, doxycycline-inducible transactivator into a murine embryonic stem cell line with an FSGS-susceptible genetic background that allows shRNA-mediated targeting of candidate genes in the adult kidney. Our analysis supports a broader role for genetic susceptibility of both sporadic and familial cases of FSGS and provides a tool to rapidly evaluate candidate FSGS-associated genes. PMID:26901816

SFRP1 is a possible candidate for epigenetic therapy in non-small cell lung cancer.

PubMed

Taguchi, Y-H; Iwadate, Mitsuo; Umeyama, Hideaki

2016-08-12

Non-small cell lung cancer (NSCLC) remains a lethal disease despite many proposed treatments. Recent studies have indicated that epigenetic therapy, which targets epigenetic effects, might be a new therapeutic methodology for NSCLC. However, it is not clear which objects (e.g., genes) this treatment specifically targets. Secreted frizzled-related proteins (SFRPs) are promising candidates for epigenetic therapy in many cancers, but there have been no reports of SFRPs targeted by epigenetic therapy for NSCLC. This study performed a meta-analysis of reprogrammed NSCLC cell lines instead of the direct examination of epigenetic therapy treatment to identify epigenetic therapy targets. In addition, mRNA expression/promoter methylation profiles were processed by recently proposed principal component analysis based unsupervised feature extraction and categorical regression analysis based feature extraction. The Wnt/β-catenin signalling pathway was extensively enriched among 32 genes identified by feature extraction. Among the genes identified, SFRP1 was specifically indicated to target β-catenin, and thus might be targeted by epigenetic therapy in NSCLC cell lines. A histone deacetylase inhibitor might reactivate SFRP1 based upon the re-analysis of a public domain data set. Numerical computation validated the binding of SFRP1 to WNT1 to suppress Wnt signalling pathway activation in NSCLC. The meta-analysis of reprogrammed NSCLC cell lines identified SFRP1 as a promising target of epigenetic therapy for NSCLC.

Searching for Wolf-Rayet Stars Beyond the Local Group

NASA Astrophysics Data System (ADS)

Bibby, J. L.; Shara, M. M.; Crowther, P. A.; Moffat, A. F. J.

2012-12-01

We present preliminary results from our HST/WFC3 F469N narrow-band imaging of the nearby star-forming galaxy M101 in which we search for Wolf-Rayet (WR) stars, possible progenitors of Type Ibc core-collapse supernovae (ccSNe). From analysis of the central pointing of M101 we identify ˜1000 WR candidates from photometric analysis and estimate ˜ 450 using the “blinking” method. From analysis of a sample region we find that 35% of our WR candidates would not be detected in ground-based surveys and 40% of sources are not detected in the HST F435W images, highlighting the importance of high spatial resolution narrow-band imaging.

Systematic analysis of copy number variation associated with congenital diaphragmatic hernia.

PubMed

Zhu, Qihui; High, Frances A; Zhang, Chengsheng; Cerveira, Eliza; Russell, Meaghan K; Longoni, Mauro; Joy, Maliackal P; Ryan, Mallory; Mil-Homens, Adam; Bellfy, Lauren; Coletti, Caroline M; Bhayani, Pooja; Hila, Regis; Wilson, Jay M; Donahoe, Patricia K; Lee, Charles

2018-05-15

Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX , LHX1 , and HNF1B We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects. Copyright © 2018 the Author(s). Published by PNAS.

Combining Genotype, Phenotype, and Environment to Infer Potential Candidate Genes.

PubMed

Talbot, Benoit; Chen, Ting-Wen; Zimmerman, Shawna; Joost, Stéphane; Eckert, Andrew J; Crow, Taylor M; Semizer-Cuming, Devrim; Seshadri, Chitra; Manel, Stéphanie

2017-03-01

Population genomic analysis can be an important tool in understanding local adaptation. Identification of potential adaptive loci in such analyses is usually based on the survey of a large genomic dataset in combination with environmental variables. Phenotypic data are less commonly incorporated into such studies, although combining a genome scan analysis with a phenotypic trait analysis can greatly improve the insights obtained from each analysis individually. Here, we aimed to identify loci potentially involved in adaptation to climate in 283 Loblolly pine (Pinus taeda) samples from throughout the species' range in the southeastern United States. We analyzed associations between phenotypic, molecular, and environmental variables from datasets of 3082 single nucleotide polymorphism (SNP) loci and 3 categories of phenotypic traits (gene expression, metabolites, and whole-plant traits). We found only 6 SNP loci that displayed potential signals of local adaptation. Five of the 6 identified SNPs are linked to gene expression traits for lignin development, and 1 is linked with whole-plant traits. We subsequently compared the 6 candidate genes with environmental variables and found a high correlation in only 3 of them (R2 > 0.2). Our study highlights the need for a combination of genotypes, phenotypes, and environmental variables, and for an appropriate sampling scheme and study design, to improve confidence in the identification of potential candidate genes. © The American Genetic Association 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Transcriptional profiling of Medicago truncatula meristematic root cells

PubMed Central

Holmes, Peta; Goffard, Nicolas; Weiller, Georg F; Rolfe, Barry G; Imin, Nijat

2008-01-01

Background The root apical meristem of crop and model legume Medicago truncatula is a significantly different stem cell system to that of the widely studied model plant species Arabidopsis thaliana. In this study we used the Affymetrix Medicago GeneChip® to compare the transcriptomes of meristem and non-meristematic root to identify root meristem specific candidate genes. Results Using mRNA from root meristem and non-meristem we were able to identify 324 and 363 transcripts differentially expressed from the two regions. With bioinformatics tools developed to functionally annotate the Medicago genome array we could identify significant changes in metabolism, signalling and the differentially expression of 55 transcription factors in meristematic and non-meristematic roots. Conclusion This is the first comprehensive analysis of M. truncatula root meristem cells using this genome array. This data will facilitate the mapping of regulatory and metabolic networks involved in the open root meristem of M. truncatula and provides candidates for functional analysis. PMID:18302802

Comparative analysis of transcriptome in two wheat genotypes with contrasting levels of drought tolerance

USDA-ARS?s Scientific Manuscript database

Drought tolerance is a complex trait that is governed by multiple genes. To identify the potential candidate genes, comparative analysis of drought stress-responsive transcriptome between drought-tolerant (Triticum aestivum Cv. C306) and drought-sensitive (Triticum aestivum Cv. WL711) genotypes was ...

Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone-sensitive prostate cancer.

PubMed

Cheng, Heather H; Plets, Melissa; Li, Hongli; Higano, Celestia S; Tangen, Catherine M; Agarwal, Neeraj; Vogelzang, Nicholas J; Hussain, Maha; Thompson, Ian M; Tewari, Muneesh; Yu, Evan Y

2018-02-01

Previous studies suggest circulating, blood-based microRNAs (miRNAs) may serve as minimally invasive prostate cancer biomarkers, however there is limited data from prospective clinical trials. Here, we explore the role of candidate plasma miRNAs as potential biomarkers in the SWOG 0925 randomized phase II study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone-sensitive prostate cancer. Correlative biospecimens, including circulating tumor cells (CTCs) and plasma for miRNA analysis, were collected at baseline and after 12 weeks on treatment from 50 patients enrolled on SWOG 0925. Circulating microRNAs were quantified using real-time RT-PCR microRNA array that allowed specific analysis of previously identified candidate miRNAs (miR-141, miR-200a, miR-200b, miR-210, and miR-375) as well as discovery analysis to identify new candidate miRNAs. MiRNA levels were correlated to previously reported CTC counts using CellSearch® (Veridex) and with the primary study outcome of 28-week PSA response (≤0.2, 0.2 to ≤4.0, or >4.0 ng/mL), previously shown to correlate with overall survival. We observed a correlation between baseline circulating miR-141, miR-200a, and miR-375 levels with baseline CTCs. Baseline miR-375 levels were associated with 28-week PSA response (≤0.2, 0.2 to ≤4.0, or >4.0 ng/mL, P = 0.007). Using ROC curve analysis, there was no significant difference between baseline miR-375 and baseline CTC in predicting 28-week PSA response (≤0.2 vs >0.2 ng/mL). To discover novel candidate miRNAs, we analyzed 365 miRNAs for association with the 28-week PSA response endpoint and identified new candidate miRNAs along with the existing candidates miR-375 and miR-200b (P = 0.0012, P = 0.0046, respectively. Baseline plasma miR-141, miR-200a, and miR-375 levels are associated with baseline CTC count. Baseline miR-375 was also associated with the trial endpoint of 28-week PSA response. Our results provide evidence that circulating miRNA biomarkers may have value as prognostic biomarkers and warrant further study in larger prospective clinical trials. © 2017 Wiley Periodicals, Inc.

Project on Elite Athlete Commitment (PEAK): IV. identification of new candidate commitment sources in the sport commitment model.

PubMed

Scanlan, Tara K; Russell, David G; Scanlan, Larry A; Klunchoo, Tatiana J; Chow, Graig M

2013-10-01

Following a thorough review of the current updated Sport Commitment Model, new candidate commitment sources for possible future inclusion in the model are presented. They were derived from data obtained using the Scanlan Collaborative Interview Method. Three elite New Zealand teams participated: amateur All Black rugby players, amateur Silver Fern netball players, and professional All Black rugby players. An inductive content analysis of these players' open-ended descriptions of their sources of commitment identified four unique new candidate commitment sources: Desire to Excel, Team Tradition, Elite Team Membership, and Worthy of Team Membership. A detailed definition of each candidate source is included along with example quotes from participants. Using a mixed-methods approach, these candidate sources provide a basis for future investigations to test their viability and generalizability for possible expansion of the Sport Commitment Model.

A New Way to Confirm Planet Candidates

NASA Astrophysics Data System (ADS)

Kohler, Susanna

2016-05-01

What was the big deal behind the Kepler news conference yesterday? Its not just that the number of confirmed planets found by Kepler has more than doubled (though thats certainly exciting news!). Whats especially interesting is the way in which these new planets were confirmed.Number of planet discoveries by year since 1995, including previous non-Kepler discoveries (blue), previous Kepler discoveries (light blue) and the newly validated Kepler planets (orange). [NASA Ames/W. Stenzel; Princeton University/T. Morton]No Need for Follow-UpBefore Kepler, the way we confirmed planet candidates was with follow-up observations. The candidate could be validated either by directly imaging (which is rare) or obtaining a large number radial-velocity measurements of the wobble of the planets host star due to the planets orbit. But once Kepler started producing planet candidates, these approaches to validation became less feasible. A lot of Kepler candidates are small and orbit faint stars, making follow-up observations difficult or impossible.This problem is what inspired the development of whats known as probabilistic validation, an analysis technique that involves assessing the likelihood that the candidates signal is caused by various false-positive scenarios. Using this technique allows astronomers to estimate the likelihood of a candidate signal being a true planet detection; if that likelihood is high enough, the planet candidate can be confirmed without the need for follow-up observations.A breakdown of the catalog of Kepler Objects of Interest. Just over half had previously been identified as false positives or confirmed as candidates. 1284 are newly validated, and another 455 have FPP of1090%. [Morton et al. 2016]Probabilistic validation has been used in the past to confirm individual planet candidates in Kepler data, but now Timothy Morton (Princeton University) and collaborators have taken this to a new level: they developed the first code thats designed to do fully automated batch processing of a large number of candidates.In a recently published study the results of which were announced yesterday the teamapplied their code to the entire catalog of 7,470 Kepler objects of interest.New Planets and False PositivesThe teams code was able to successfully evaluate the total false-positive probability (FPP) for 7,056 of the objects of interest. Of these, 428 objects previously identified as candidates were found to have FPP of more than 90%, suggesting that they are most likely false positives.Periods and radii of candidate and confirmed planets in the Kepler Objects of Interest catalog. Blue circles have previously been identified as confirmed planets. Candidates (orange) are shaded by false positive probability; more transparent means more likely to be a false positive. [Morton et al. 2016]In contrast, 1,935 candidates were found to have FPP of less than 1%, and were therefore declared validated planets. Of these confirmations, 1,284 were previously unconfirmed, more than doubling Keplers previous catalog of 1,041 confirmed planets. Morton and collaborators believe that 9 of these newly confirmed planets may fall within the habitable zone of their host stars.While the announcement of 1,284 newly confirmed planets is huge, the analysis presented in this study is the real news. The code used is publicly available and can be applied to any transiting exoplanet candidate. This means that this analysis technique can be used to find batches of exoplanets in data from the extended Kepler mission (K2) or from the future TESS and PLATO transit missions.CitationTimothy D. Morton et al 2016 ApJ 822 86. doi:10.3847/0004-637X/822/2/86

PEACE: pulsar evaluation algorithm for candidate extraction - a software package for post-analysis processing of pulsar survey candidates

NASA Astrophysics Data System (ADS)

Lee, K. J.; Stovall, K.; Jenet, F. A.; Martinez, J.; Dartez, L. P.; Mata, A.; Lunsford, G.; Cohen, S.; Biwer, C. M.; Rohr, M.; Flanigan, J.; Walker, A.; Banaszak, S.; Allen, B.; Barr, E. D.; Bhat, N. D. R.; Bogdanov, S.; Brazier, A.; Camilo, F.; Champion, D. J.; Chatterjee, S.; Cordes, J.; Crawford, F.; Deneva, J.; Desvignes, G.; Ferdman, R. D.; Freire, P.; Hessels, J. W. T.; Karuppusamy, R.; Kaspi, V. M.; Knispel, B.; Kramer, M.; Lazarus, P.; Lynch, R.; Lyne, A.; McLaughlin, M.; Ransom, S.; Scholz, P.; Siemens, X.; Spitler, L.; Stairs, I.; Tan, M.; van Leeuwen, J.; Zhu, W. W.

2013-07-01

Modern radio pulsar surveys produce a large volume of prospective candidates, the majority of which are polluted by human-created radio frequency interference or other forms of noise. Typically, large numbers of candidates need to be visually inspected in order to determine if they are real pulsars. This process can be labour intensive. In this paper, we introduce an algorithm called Pulsar Evaluation Algorithm for Candidate Extraction (PEACE) which improves the efficiency of identifying pulsar signals. The algorithm ranks the candidates based on a score function. Unlike popular machine-learning-based algorithms, no prior training data sets are required. This algorithm has been applied to data from several large-scale radio pulsar surveys. Using the human-based ranking results generated by students in the Arecibo Remote Command Center programme, the statistical performance of PEACE was evaluated. It was found that PEACE ranked 68 per cent of the student-identified pulsars within the top 0.17 per cent of sorted candidates, 95 per cent within the top 0.34 per cent and 100 per cent within the top 3.7 per cent. This clearly demonstrates that PEACE significantly increases the pulsar identification rate by a factor of about 50 to 1000. To date, PEACE has been directly responsible for the discovery of 47 new pulsars, 5 of which are millisecond pulsars that may be useful for pulsar timing based gravitational-wave detection projects.

Unsupervised, statistically-based systems biology approach for unraveling the genetics of complex traits: A demonstration with ethanol metabolism.

PubMed

Lusk, Ryan; Saba, Laura M; Vanderlinden, Lauren A; Zidek, Vaclav; Silhavy, Jan; Pravenec, Michal; Hoffman, Paula L; Tabakoff, Boris

2018-04-24

A statistical pipeline was developed and used for determining candidate genes and candidate gene co-expression networks involved in two alcohol (i.e., ethanol) metabolism phenotypes, namely alcohol clearance and acetate area under the curve (AUC) in a recombinant inbred (HXB/BXH) rat panel. The approach was also used to provide an indication of how ethanol metabolism can impact the normal function of the identified networks. RNA was extracted from alcohol-naïve liver tissue of 30 strains of HXB/BXH recombinant inbred rats. The reconstructed transcripts were quantitated and data was used to construct gene co-expression modules and networks. A separate group of rats, comprising the same 30 strains, were injected with ethanol (2 gm/kg) for measurement of blood ethanol and acetate levels. These data were used for QTL analysis of the rate of ethanol disappearance and circulating acetate levels. The analysis pipeline required calculation of the module eigengene values, the correction of these values with ethanol metabolism rates and acetate levels across the rat strains and the determination of the eigengene QTLs. For a module to be considered a candidate for determining phenotype, the module eigengene values had to have significant correlation with the strain phenotypic values and the module eigengene QTLs had to overlap the phenotypic QTLs. Of the 658 transcript co-expression modules generated from liver RNA sequencing data, a single module satisfied all criteria for being a candidate for determining the alcohol clearance trait. This module contained two alcohol dehydrogenase genes, including the gene whose product was previously shown to be responsible for the majority of alcohol elimination in the rat. This module was also the only module identified as a candidate for influencing circulating acetate levels. This module was also linked to the process of generation and utilization of retinoic acid as related to the autonomous immune response. We propose that our analytical pipeline can successfully identify genetic regions and transcripts which predispose a particular phenotype and our analysis provides functional context for co-expression module components. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes.

PubMed

Johnson, Emma C; Border, Richard; Melroy-Greif, Whitney E; de Leeuw, Christiaan A; Ehringer, Marissa A; Keller, Matthew C

2017-11-15

A recent analysis of 25 historical candidate gene polymorphisms for schizophrenia in the largest genome-wide association study conducted to date suggested that these commonly studied variants were no more associated with the disorder than would be expected by chance. However, the same study identified other variants within those candidate genes that demonstrated genome-wide significant associations with schizophrenia. As such, it is possible that variants within historic schizophrenia candidate genes are associated with schizophrenia at levels above those expected by chance, even if the most-studied specific polymorphisms are not. The present study used association statistics from the largest schizophrenia genome-wide association study conducted to date as input to a gene set analysis to investigate whether variants within schizophrenia candidate genes are enriched for association with schizophrenia. As a group, variants in the most-studied candidate genes were no more associated with schizophrenia than were variants in control sets of noncandidate genes. While a small subset of candidate genes did appear to be significantly associated with schizophrenia, these genes were not particularly noteworthy given the large number of more strongly associated noncandidate genes. The history of schizophrenia research should serve as a cautionary tale to candidate gene investigators examining other phenotypes: our findings indicate that the most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Haploinsufficiency of TAB2 Causes Congenital Heart Defects in Humans

PubMed Central

Thienpont, Bernard; Zhang, Litu; Postma, Alex V.; Breckpot, Jeroen; Tranchevent, Léon-Charles; Van Loo, Peter; Møllgård, Kjeld; Tommerup, Niels; Bache, Iben; Tümer, Zeynep; van Engelen, Klaartje; Menten, Björn; Mortier, Geert; Waggoner, Darrel; Gewillig, Marc; Moreau, Yves; Devriendt, Koen; Larsen, Lars Allan

2010-01-01

Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion on 6q delineated a critical 850 kb region on 6q25.1 harboring five genes. Bioinformatics prioritization of candidate genes in this locus for a role in CHDs identified the TGF-β-activated kinase 1/MAP3K7 binding protein 2 gene (TAB2) as the top-ranking candidate gene. A role for this candidate gene in cardiac development was further supported by its conserved expression in the developing human and zebrafish heart. Moreover, a critical, dosage-sensitive role during development was demonstrated by the cardiac defects observed upon titrated knockdown of tab2 expression in zebrafish embryos. To definitively confirm the role of this candidate gene in CHDs, we performed mutation analysis of TAB2 in 402 patients with a CHD, which revealed two evolutionarily conserved missense mutations. Finally, a balanced translocation was identified, cosegregating with familial CHD. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAB2 in human cardiac development. PMID:20493459

In situ trans ligands of CD22 identified by glycan-protein photocross-linking-enabled proteomics.

PubMed

Ramya, T N C; Weerapana, Eranthie; Liao, Lujian; Zeng, Ying; Tateno, Hiroaki; Liao, Liang; Yates, John R; Cravatt, Benjamin F; Paulson, James C

2010-06-01

CD22, a regulator of B-cell signaling, is a siglec that recognizes the sequence NeuAcalpha2-6Gal on glycoprotein glycans as ligands. CD22 interactions with glycoproteins on the same cell (in cis) and apposing cells (in trans) modulate its activity in B-cell receptor signaling. Although CD22 predominantly recognizes neighboring CD22 molecules as cis ligands on B-cells, little is known about the trans ligands on apposing cells. We conducted a proteomics scale study to identify candidate trans ligands of CD22 on B-cells by UV photocross-linking CD22-Fc chimera bound to B-cell glycoproteins engineered to carry sialic acids with a 9-aryl azide moiety. Using mass spectrometry-based quantitative proteomics to analyze the cross-linked products, 27 glycoproteins were identified as candidate trans ligands. Next, CD22 expressed on the surface of one cell was photocross-linked to glycoproteins on apposing B-cells followed by immunochemical analysis of the products with antibodies to the candidate ligands. Of the many candidate ligands, only the B-cell receptor IgM was found to be a major in situ trans ligand of CD22 that is selectively redistributed to the site of cell contact upon interaction with CD22 on the apposing cell.

A semi-automated method for rapid detection of ripple events on interictal voltage discharges in the scalp electroencephalogram.

PubMed

Chu, Catherine J; Chan, Arthur; Song, Dan; Staley, Kevin J; Stufflebeam, Steven M; Kramer, Mark A

2017-02-01

High frequency oscillations are emerging as a clinically important indicator of epileptic networks. However, manual detection of these high frequency oscillations is difficult, time consuming, and subjective, especially in the scalp EEG, thus hindering further clinical exploration and application. Semi-automated detection methods augment manual detection by reducing inspection to a subset of time intervals. We propose a new method to detect high frequency oscillations that co-occur with interictal epileptiform discharges. The new method proceeds in two steps. The first step identifies candidate time intervals during which high frequency activity is increased. The second step computes a set of seven features for each candidate interval. These features require that the candidate event contain a high frequency oscillation approximately sinusoidal in shape, with at least three cycles, that co-occurs with a large amplitude discharge. Candidate events that satisfy these features are stored for validation through visual analysis. We evaluate the detector performance in simulation and on ten examples of scalp EEG data, and show that the proposed method successfully detects spike-ripple events, with high positive predictive value, low false positive rate, and high intra-rater reliability. The proposed method is less sensitive than the existing method of visual inspection, but much faster and much more reliable. Accurate and rapid detection of high frequency activity increases the clinical viability of this rhythmic biomarker of epilepsy. The proposed spike-ripple detector rapidly identifies candidate spike-ripple events, thus making clinical analysis of prolonged, multielectrode scalp EEG recordings tractable. Copyright © 2016 Elsevier B.V. All rights reserved.

A semi-automated method for rapid detection of ripple events on interictal voltage discharges in the scalp electroencephalogram

PubMed Central

Chu, Catherine. J.; Chan, Arthur; Song, Dan; Staley, Kevin J.; Stufflebeam, Steven M.; Kramer, Mark A.

2017-01-01

Summary Background High frequency oscillations are emerging as a clinically important indicator of epileptic networks. However, manual detection of these high frequency oscillations is difficult, time consuming, and subjective, especially in the scalp EEG, thus hindering further clinical exploration and application. Semi-automated detection methods augment manual detection by reducing inspection to a subset of time intervals. We propose a new method to detect high frequency oscillations that co-occur with interictal epileptiform discharges. New Method The new method proceeds in two steps. The first step identifies candidate time intervals during which high frequency activity is increased. The second step computes a set of seven features for each candidate interval. These features require that the candidate event contain a high frequency oscillation approximately sinusoidal in shape, with at least three cycles, that co-occurs with a large amplitude discharge. Candidate events that satisfy these features are stored for validation through visual analysis. Results We evaluate the detector performance in simulation and on ten examples of scalp EEG data, and show that the proposed method successfully detects spike-ripple events, with high positive predictive value, low false positive rate, and high intra-rater reliability. Comparison with Existing Method The proposed method is less sensitive than the existing method of visual inspection, but much faster and much more reliable. Conclusions Accurate and rapid detection of high frequency activity increases the clinical viability of this rhythmic biomarker of epilepsy. The proposed spike-ripple detector rapidly identifies candidate spike-ripple events, thus making clinical analysis of prolonged, multielectrode scalp EEG recordings tractable. PMID:27988323

Pool-based genome-wide association study identified novel candidate regions on BTA9 and 14 for oleic acid percentage in Japanese Black cattle.

PubMed

Kawaguchi, Fuki; Kigoshi, Hiroto; Nakajima, Ayaka; Matsumoto, Yuta; Uemoto, Yoshinobu; Fukushima, Moriyuki; Yoshida, Emi; Iwamoto, Eiji; Akiyama, Takayuki; Kohama, Namiko; Kobayashi, Eiji; Honda, Takeshi; Oyama, Kenji; Mannen, Hideyuki; Sasazaki, Shinji

2018-05-17

Fatty acid composition is an important indicator of beef quality. The objective of this study was to search the potential candidate region for fatty acid composition. We performed pool-based genome-wide association studies (GWAS) for oleic acid percentage (C18:1) in a Japanese Black cattle population from the Hyogo prefecture. GWAS analysis revealed two novel candidate regions on BTA9 and BTA14. The most significant single nucleotide polymorphisms (SNPs) in each region were genotyped in a population (n = 899) to verify their effect on C18:1. Statistical analysis revealed that both SNPs were significantly associated with C18:1 (p = .0080 and .0003), validating the quantitative trait loci (QTLs) detected in GWAS. We subsequently selected VNN1 and LYPLA1 genes as candidate genes from each region on BTA9 and BTA14, respectively. We sequenced full-length coding sequence (CDS) of these genes in eight individuals and identified a nonsynonymous SNP T66M on VNN1 gene as a putative candidate polymorphism. The polymorphism was also significantly associated with C18:1, but the p value (p = .0162) was higher than the most significant SNP on BTA9, suggesting that it would not be responsible for the QTL. Although further investigation will be needed to determine the responsible gene and polymorphism, our findings would contribute to development of selective markers for fatty acid composition in the Japanese Black cattle of Hyogo. © 2018 Japanese Society of Animal Science.

Identifying Inefficient Single-Family Homes With Utility Bill Analysis: Preprint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Casey, S.; Krarti, M.; Bianchi, M.

2010-08-01

Differentiating between energy-efficient and inefficient single-family homes on a community scale helps identify and prioritize candidates for energy-efficiency upgrades. Prescreening diagnostic procedures can further retrofit efforts by providing efficiency information before a site-visit is conducted. We applied the prescreening diagnostic to a simulated community of homes in Boulder, Colorado and analyzed energy consumption data to identify energy-inefficient homes.

Comparative Transcriptome Analysis Identifies Putative Genes Involved in the Biosynthesis of Xanthanolides in Xanthium strumarium L.

PubMed

Li, Yuanjun; Gou, Junbo; Chen, Fangfang; Li, Changfu; Zhang, Yansheng

2016-01-01

Xanthium strumarium L. is a traditional Chinese herb belonging to the Asteraceae family. The major bioactive components of this plant are sesquiterpene lactones (STLs), which include the xanthanolides. To date, the biogenesis of xanthanolides, especially their downstream pathway, remains largely unknown. In X. strumarium, xanthanolides primarily accumulate in its glandular trichomes. To identify putative gene candidates involved in the biosynthesis of xanthanolides, three X. strumarium transcriptomes, which were derived from the young leaves of two different cultivars and the purified glandular trichomes from one of the cultivars, were constructed in this study. In total, 157 million clean reads were generated and assembled into 91,861 unigenes, of which 59,858 unigenes were successfully annotated. All the genes coding for known enzymes in the upstream pathway to the biosynthesis of xanthanolides were present in the X. strumarium transcriptomes. From a comparative analysis of the X. strumarium transcriptomes, this study identified a number of gene candidates that are putatively involved in the downstream pathway to the synthesis of xanthanolides, such as four unigenes encoding CYP71 P450s, 50 unigenes for dehydrogenases, and 27 genes for acetyltransferases. The possible functions of these four CYP71 candidates are extensively discussed. In addition, 116 transcription factors that are highly expressed in X. strumarium glandular trichomes were also identified. Their possible regulatory roles in the biosynthesis of STLs are discussed. The global transcriptomic data for X. strumarium should provide a valuable resource for further research into the biosynthesis of xanthanolides.

Identification of multiple novel protein biomarkers shed by human serous ovarian tumors into the blood of immunocompromised mice and verified in patient sera.

PubMed

Beer, Lynn A; Wang, Huan; Tang, Hsin-Yao; Cao, Zhijun; Chang-Wong, Tony; Tanyi, Janos L; Zhang, Rugang; Liu, Qin; Speicher, David W

2013-01-01

The most cancer-specific biomarkers in blood are likely to be proteins shed directly by the tumor rather than less specific inflammatory or other host responses. The use of xenograft mouse models together with in-depth proteome analysis for identification of human proteins in the mouse blood is an under-utilized strategy that can clearly identify proteins shed by the tumor. In the current study, 268 human proteins shed into mouse blood from human OVCAR-3 serous tumors were identified based upon human vs. mouse species differences using a four-dimensional plasma proteome fractionation strategy. A multi-step prioritization and verification strategy was subsequently developed to efficiently select some of the most promising biomarkers from this large number of candidates. A key step was parallel analysis of human proteins detected in the tumor supernatant, because substantially greater sequence coverage for many of the human proteins initially detected in the xenograft mouse plasma confirmed assignments as tumor-derived human proteins. Verification of candidate biomarkers in patient sera was facilitated by in-depth, label-free quantitative comparisons of serum pools from patients with ovarian cancer and benign ovarian tumors. The only proteins that advanced to multiple reaction monitoring (MRM) assay development were those that exhibited increases in ovarian cancer patients compared with benign tumor controls. MRM assays were facilely developed for all 11 novel biomarker candidates selected by this process and analysis of larger pools of patient sera suggested that all 11 proteins are promising candidate biomarkers that should be further evaluated on individual patient blood samples.

Participation of the NDC Austria at the NDC Preparedness Exercise 2012

NASA Astrophysics Data System (ADS)

Mitterbauer, Ulrike; Wotawa, Gerhard; Schraick, Irene

2013-04-01

NDC Preparedness Exercises (NPEs) are conducted annually by the National Data Centers (NDCs) of CTBT States Signatories to train the detection of a (hypothetical) nuclear test. During the NDC Preparedness Exercise 2012, a fictitious radionuclide scenario originating from a real seismic event (mining explosion) was calculated by the German NDC and distributed among all NDCs. For the scenario computation, it was assumed that the selected seismic event was the epicentre of an underground nuclear fission explosion. The scenario included detections of the Iodine isotopes I-131 and I-133 (both particulates), and the Radioxenon Isotopes Xe-133, Xe-133M, Xe-131M and Xe-135 (noble gas). By means of atmospheric transport modelling (ATM), concentrations of all these six isotopes which would result from the hypothetical explosion were calculated and interpolated to the IMS station locations. The participating NDCs received information about the concentration of the isotopes at the station locations without knowing the underlying seismic event. The aim of the exercise was to identify this event based on the detection scenario. The Austrian NDC performed the following analyses: • Atmospheric backtracking and data fusion to identify seismic candidate events, • Seismic analysis of candidate events within the possible source region, • Atmospheric transport modelling (forward mode) from identified candidate events, comparison between "measured" and simulated concentrations based on certain release assumptions. The main goal of the analysis was to identify the event selected by NDC Germany to calculate the radionuclide scenario, and to exclude other events. In the presentation, the analysis methodology as well as the final results and conclusions will be shown and discussed in detail.

Identification of candidate cerebrospinal fluid biomarkers in parkinsonism using quantitative proteomics.

PubMed

Magdalinou, N K; Noyce, A J; Pinto, R; Lindstrom, E; Holmén-Larsson, J; Holtta, M; Blennow, K; Morris, H R; Skillbäck, T; Warner, T T; Lees, A J; Pike, I; Ward, M; Zetterberg, H; Gobom, J

2017-04-01

Neurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than α-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive. To study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls. CSF was collected consecutively from 134 participants; Parkinson's disease (n = 26), atypical parkinsonian syndromes (n = 78, including progressive supranuclear palsy (n = 36), multiple system atrophy (n = 28), corticobasal syndrome (n = 14)), and elderly healthy controls (n = 30). Participants were divided into a discovery and a validation set for analysis. The samples were subjected to tryptic digestion, followed by liquid chromatography-mass spectrometry analysis for identification and relative quantification by isobaric labelling. Candidate protein biomarkers were identified based on the relative abundances of the identified tryptic peptides. Their predictive performance was evaluated by analysis of the validation set. 79 tryptic peptides, derived from 26 proteins were found to differ significantly between atypical parkinsonism patients and controls. They included acute phase/inflammatory markers and neuronal/synaptic markers, which were respectively increased or decreased in atypical parkinsonism, while their levels in PD subjects were intermediate between controls and atypical parkinsonism. Using an unbiased proteomic approach, proteins were identified that were able to differentiate atypical parkinsonian syndrome patients from healthy controls. Our study indicates that markers that may reflect neuronal function and/or plasticity, such as the amyloid precursor protein, and inflammatory markers may hold future promise as candidate biomarkers in parkinsonism. Copyright © 2017. Published by Elsevier Ltd.

Exome sequencing of oral squamous cell carcinoma in users of Arabian snuff reveals novel candidates for driver genes.

PubMed

Al-Hebshi, Nezar Noor; Li, Shiyong; Nasher, Akram Thabet; El-Setouhy, Maged; Alsanosi, Rashad; Blancato, Jan; Loffredo, Christopher

2016-07-15

The study sought to identify genetic aberrations driving oral squamous cell carcinoma (OSCC) development among users of shammah, an Arabian preparation of smokeless tobacco. Twenty archival OSCC samples, 15 of which with a history of shammah exposure, were whole-exome sequenced at an average depth of 127×. Somatic mutations were identified using a novel, matched controls-independent filtration algorithm. CODEX and Exomedepth coupled with a novel, Database of Genomic Variant-based filter were employed to call somatic gene-copy number variations. Significantly mutated genes were identified with Oncodrive FM and the Youn and Simon's method. Candidate driver genes were nominated based on Gene Set Enrichment Analysis. The observed mutational spectrum was similar to that reported by the TCGA project. In addition to confirming known genes of OSCC (TP53, CDKNA2, CASP8, PIK3CA, HRAS, FAT1, TP63, CCND1 and FADD) the analysis identified several candidate novel driver events including mutations of NOTCH3, CSMD3, CRB1, CLTCL1, OSMR and TRPM2, amplification of the proto-oncogenes FOSL1, RELA, TRAF6, MDM2, FRS2 and BAG1, and deletion of the recently described tumor suppressor SMARCC1. Analysis also revealed significantly altered pathways not previously implicated in OSCC including Oncostatin-M signalling pathway, AP-1 and C-MYB transcription networks and endocytosis. There was a trend for higher number of mutations, amplifications and driver events in samples with history of shammah exposure particularly those that tested EBV positive, suggesting an interaction between tobacco exposure and EBV. The work provides further evidence for the genetic heterogeneity of oral cancer and suggests shammah-associated OSCC is characterized by extensive amplification of oncogenes. © 2016 UICC.

Lack of specific alleles for the bovine chemokine (C-X-C) receptor type 4 (CXCR4) gene in West African cattle questions its role as a candidate for trypanotolerance.

PubMed

Álvarez, Isabel; Pérez-Pardal, Lucía; Traoré, Amadou; Fernández, Iván; Goyache, Félix

2016-08-01

A panel of 81 Asian, African and European cattle (Bos taurus and B. indicus) was analysed for the whole sequence of the CXCR4 gene (3844bp), a strong candidate for cattle trypanotolerance. Thirty-one polymorphic sites identified gave 31 different haplotypes. Neutrality tests rejected the hypothesis of either positive or purifying selection. Bayesian phylogenetic tree showed differentiation of haplotypes into two clades gathering genetic variability predating domestication. Related with clades definition, linkage disequilibrium analyses suggested the existence of one only linkage block on the CXCR4 gene. Two tag SNPs identified on exon 2 captured 50% of variability. Whatever the analysis carried out, no clear separation between cattle groups was identified. Most haplotypes identified in West African taurine cattle were also found in European cattle and in Asian and West African zebu. West African taurine samples did not carry unique variants on the CXCR4 gene sequence. The current analysis failed in identifying a causal mutation on the CXCR4 gene underlying a previously reported QTL for cattle trypanotolerance on BTA2. Copyright © 2016 Elsevier B.V. All rights reserved.

High-throughput discovery of mutations in tef semi-dwarfing genes by next-generation sequencing analysis.

PubMed

Zhu, Qihui; Smith, Shavannor M; Ayele, Mulu; Yang, Lixing; Jogi, Ansuya; Chaluvadi, Srinivasa R; Bennetzen, Jeffrey L

2012-11-01

Tef (Eragrostis tef) is a major cereal crop in Ethiopia. Lodging is the primary constraint to increasing productivity in this allotetraploid species, accounting for losses of ∼15-45% in yield each year. As a first step toward identifying semi-dwarf varieties that might have improved lodging resistance, an ∼6× fosmid library was constructed and used to identify both homeologues of the dw3 semi-dwarfing gene of Sorghum bicolor. An EMS mutagenized population, consisting of ∼21,210 tef plants, was planted and leaf materials were collected into 23 superpools. Two dwarfing candidate genes, homeologues of dw3 of sorghum and rht1 of wheat, were sequenced directly from each superpool with 454 technology, and 120 candidate mutations were identified. Out of 10 candidates tested, six independent mutations were validated by Sanger sequencing, including two predicted detrimental mutations in both dw3 homeologues with a potential to improve lodging resistance in tef through further breeding. This study demonstrates that high-throughput sequencing can identify potentially valuable mutations in under-studied plant species like tef and has provided mutant lines that can now be combined and tested in breeding programs for improved lodging resistance.

Multi-gene panel testing in Korean patients with common genetic generalized epilepsy syndromes.

PubMed

Lee, Cha Gon; Lee, Jeehun; Lee, Munhyang

2018-01-01

Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases. A total of 57 patients were enrolled, including 51 sporadic cases and 6 familial cases. Twenty-two pathogenic and likely pathogenic variants of 16 different genes were identified. CACNA1H was the most frequently observed single gene. Variants of voltage-gated Ca2+ channel genes, including CACNA1A, CACNA1G, and CACNA1H were observed in 32% of variants (n = 7/22). Analyses to identify susceptibility variants using case-control association analysis indicated that KCNMA1 c.400G>C was associated with common genetic generalized epilepsy syndromes. Only 1 family (family A) exhibited a candidate pathogenic variant p.(Arg788His) on CACNA1H, as determined via family analyses. This study identified candidate genetic variants in about a quarter of patients (n = 16/57) and an average of 2.8 variants was identified in each patient. The results reinforced the polygenic disorder with very high locus and allelic heterogeneity of common GGE syndromes. Further, voltage-gated Ca2+ channels are suggested as important contributors to common genetic generalized epilepsy syndromes. This study extends our comprehensive understanding of common genetic generalized epilepsy syndromes.

Computerized multiple image analysis on mammograms: performance improvement of nipple identification for registration of multiple views using texture convergence analyses

NASA Astrophysics Data System (ADS)

Zhou, Chuan; Chan, Heang-Ping; Sahiner, Berkman; Hadjiiski, Lubomir M.; Paramagul, Chintana

2004-05-01

Automated registration of multiple mammograms for CAD depends on accurate nipple identification. We developed two new image analysis techniques based on geometric and texture convergence analyses to improve the performance of our previously developed nipple identification method. A gradient-based algorithm is used to automatically track the breast boundary. The nipple search region along the boundary is then defined by geometric convergence analysis of the breast shape. Three nipple candidates are identified by detecting the changes along the gray level profiles inside and outside the boundary and the changes in the boundary direction. A texture orientation-field analysis method is developed to estimate the fourth nipple candidate based on the convergence of the tissue texture pattern towards the nipple. The final nipple location is determined from the four nipple candidates by a confidence analysis. Our training and test data sets consisted of 419 and 368 randomly selected mammograms, respectively. The nipple location identified on each image by an experienced radiologist was used as the ground truth. For 118 of the training and 70 of the test images, the radiologist could not positively identify the nipple, but provided an estimate of its location. These were referred to as invisible nipple images. In the training data set, 89.37% (269/301) of the visible nipples and 81.36% (96/118) of the invisible nipples could be detected within 1 cm of the truth. In the test data set, 92.28% (275/298) of the visible nipples and 67.14% (47/70) of the invisible nipples were identified within 1 cm of the truth. In comparison, our previous nipple identification method without using the two convergence analysis techniques detected 82.39% (248/301), 77.12% (91/118), 89.93% (268/298) and 54.29% (38/70) of the nipples within 1 cm of the truth for the visible and invisible nipples in the training and test sets, respectively. The results indicate that the nipple on mammograms can be detected accurately. This will be an important step towards automatic multiple image analysis for CAD techniques.

Integrated Systems Biology Analysis of Transcriptomes Reveals Candidate Genes for Acidity Control in Developing Fruits of Sweet Orange (Citrus sinensis L. Osbeck).

PubMed

Huang, Dingquan; Zhao, Yihong; Cao, Minghao; Qiao, Liang; Zheng, Zhi-Liang

2016-01-01

Organic acids, such as citrate and malate, are important contributors for the sensory traits of fleshy fruits. Although their biosynthesis has been illustrated, regulatory mechanisms of acid accumulation remain to be dissected. To provide transcriptional architecture and identify candidate genes for citrate accumulation in fruits, we have selected for transcriptome analysis four varieties of sweet orange (Citrus sinensis L. Osbeck) with varying fruit acidity, Succari (acidless), Bingtang (low acid), and Newhall and Xinhui (normal acid). Fruits of these varieties at 45 days post anthesis (DPA), which corresponds to Stage I (cell division), had similar acidity, but they displayed differential acid accumulation at 142 DPA (Stage II, cell expansion). Transcriptomes of fruits at 45 and 142 DPA were profiled using RNA sequencing and analyzed with three different algorithms (Pearson correlation, gene coexpression network and surrogate variable analysis). Our network analysis shows that the acid-correlated genes belong to three distinct network modules. Several of these candidate fruit acidity genes encode regulatory proteins involved in transport (such as AHA10), degradation (such as APD2) and transcription (such as AIL6) and act as hubs in the citrate accumulation gene networks. Taken together, our integrated systems biology analysis has provided new insights into the fruit citrate accumulation gene network and led to the identification of candidate genes likely associated with the fruit acidity control.

Integrated Systems Biology Analysis of Transcriptomes Reveals Candidate Genes for Acidity Control in Developing Fruits of Sweet Orange (Citrus sinensis L. Osbeck)

PubMed Central

Huang, Dingquan; Zhao, Yihong; Cao, Minghao; Qiao, Liang; Zheng, Zhi-Liang

2016-01-01

Organic acids, such as citrate and malate, are important contributors for the sensory traits of fleshy fruits. Although their biosynthesis has been illustrated, regulatory mechanisms of acid accumulation remain to be dissected. To provide transcriptional architecture and identify candidate genes for citrate accumulation in fruits, we have selected for transcriptome analysis four varieties of sweet orange (Citrus sinensis L. Osbeck) with varying fruit acidity, Succari (acidless), Bingtang (low acid), and Newhall and Xinhui (normal acid). Fruits of these varieties at 45 days post anthesis (DPA), which corresponds to Stage I (cell division), had similar acidity, but they displayed differential acid accumulation at 142 DPA (Stage II, cell expansion). Transcriptomes of fruits at 45 and 142 DPA were profiled using RNA sequencing and analyzed with three different algorithms (Pearson correlation, gene coexpression network and surrogate variable analysis). Our network analysis shows that the acid-correlated genes belong to three distinct network modules. Several of these candidate fruit acidity genes encode regulatory proteins involved in transport (such as AHA10), degradation (such as APD2) and transcription (such as AIL6) and act as hubs in the citrate accumulation gene networks. Taken together, our integrated systems biology analysis has provided new insights into the fruit citrate accumulation gene network and led to the identification of candidate genes likely associated with the fruit acidity control. PMID:27092171

Identifying Candidate Chemical-Disease Linkages (Environmental and Epigenetic Determinants of IBD)

EPA Science Inventory

Presentation at meeting on Environmental and Epigenetic Determinants of IBD in New York, NY on identifying candidate chemical-disease linkages by using AOPs to identify molecular initiating events and using relevant high throughput assays to screen for candidate chemicals. This h...

Fine mapping of Restorer-of-fertility in pepper (Capsicum annuum L.) identified a candidate gene encoding a pentatricopeptide repeat (PPR)-containing protein.

PubMed

Jo, Yeong Deuk; Ha, Yeaseong; Lee, Joung-Ho; Park, Minkyu; Bergsma, Alex C; Choi, Hong-Il; Goritschnig, Sandra; Kloosterman, Bjorn; van Dijk, Peter J; Choi, Doil; Kang, Byoung-Cheorl

2016-10-01

Using fine mapping techniques, the genomic region co-segregating with Restorer - of - fertility ( Rf ) in pepper was delimited to a region of 821 kb in length. A PPR gene in this region, CaPPR6 , was identified as a strong candidate for Rf based on expression pattern and characteristics of encoding sequence. Cytoplasmic-genic male sterility (CGMS) has been used for the efficient production of hybrid seeds in peppers (Capsicum annuum L.). Although the mitochondrial candidate genes that might be responsible for cytoplasmic male sterility (CMS) have been identified, the nuclear Restorer-of-fertility (Rf) gene has not been isolated. To identify the genomic region co-segregating with Rf in pepper, we performed fine mapping using an Rf-segregating population consisting of 1068 F2 individuals, based on BSA-AFLP and a comparative mapping approach. Through six cycles of chromosome walking, the co-segregating region harboring the Rf locus was delimited to be within 821 kb of sequence. Prediction of expressed genes in this region based on transcription analysis revealed four candidate genes. Among these, CaPPR6 encodes a pentatricopeptide repeat (PPR) protein with PPR motifs that are repeated 14 times. Characterization of the CaPPR6 protein sequence, based on alignment with other homologs, showed that CaPPR6 is a typical Rf-like (RFL) gene reported to have undergone diversifying selection during evolution. A marker developed from a sequence near CaPPR6 showed a higher prediction rate of the Rf phenotype than those of previously developed markers when applied to a panel of breeding lines of diverse origin. These results suggest that CaPPR6 is a strong candidate for the Rf gene in pepper.

Automation of the longwall mining system

NASA Technical Reports Server (NTRS)

Zimmerman, W.; Aster, R. W.; Harris, J.; High, J.

1982-01-01

Cost effective, safe, and technologically sound applications of automation technology to underground coal mining were identified. The longwall analysis commenced with a general search for government and industry experience of mining automation technology. A brief industry survey was conducted to identify longwall operational, safety, and design problems. The prime automation candidates resulting from the industry experience and survey were: (1) the shearer operation, (2) shield and conveyor pan line advance, (3) a management information system to allow improved mine logistics support, and (4) component fault isolation and diagnostics to reduce untimely maintenance delays. A system network analysis indicated that a 40% improvement in productivity was feasible if system delays associated with all of the above four areas were removed. A technology assessment and conceptual system design of each of the four automation candidate areas showed that state of the art digital computer, servomechanism, and actuator technologies could be applied to automate the longwall system.

Use of Six Sigma Worksheets for assessment of internal and external failure costs associated with candidate quality control rules for an ADVIA 120 hematology analyzer.

PubMed

Cian, Francesco; Villiers, Elisabeth; Archer, Joy; Pitorri, Francesca; Freeman, Kathleen

2014-06-01

Quality control (QC) validation is an essential tool in total quality management of a veterinary clinical pathology laboratory. Cost-analysis can be a valuable technique to help identify an appropriate QC procedure for the laboratory, although this has never been reported in veterinary medicine. The aim of this study was to determine the applicability of the Six Sigma Quality Cost Worksheets in the evaluation of possible candidate QC rules identified by QC validation. Three months of internal QC records were analyzed. EZ Rules 3 software was used to evaluate candidate QC procedures, and the costs associated with the application of different QC rules were calculated using the Six Sigma Quality Cost Worksheets. The costs associated with the current and the candidate QC rules were compared, and the amount of cost savings was calculated. There was a significant saving when the candidate 1-2.5s, n = 3 rule was applied instead of the currently utilized 1-2s, n = 3 rule. The savings were 75% per year (£ 8232.5) based on re-evaluating all of the patient samples in addition to the controls, and 72% per year (£ 822.4) based on re-analyzing only the control materials. The savings were also shown to change accordingly with the number of samples analyzed and with the number of daily QC procedures performed. These calculations demonstrated the importance of the selection of an appropriate QC procedure, and the usefulness of the Six Sigma Costs Worksheet in determining the most cost-effective rule(s) when several candidate rules are identified by QC validation. © 2014 American Society for Veterinary Clinical Pathology and European Society for Veterinary Clinical Pathology.

Thorium-based mixed oxide fuel in a pressurized water reactor: A feasibility analysis with MCNP

NASA Astrophysics Data System (ADS)

Tucker, Lucas Powelson

This dissertation investigates techniques for spent fuel monitoring, and assesses the feasibility of using a thorium-based mixed oxide fuel in a conventional pressurized water reactor for plutonium disposition. Both non-paralyzing and paralyzing dead-time calculations were performed for the Portable Spectroscopic Fast Neutron Probe (N-Probe), which can be used for spent fuel interrogation. Also, a Canberra 3He neutron detector's dead-time was estimated using a combination of subcritical assembly measurements and MCNP simulations. Next, a multitude of fission products were identified as candidates for burnup and spent fuel analysis of irradiated mixed oxide fuel. The best isotopes for these applications were identified by investigating half-life, photon energy, fission yield, branching ratios, production modes, thermal neutron absorption cross section and fuel matrix diffusivity. 132I and 97Nb were identified as good candidates for MOX fuel on-line burnup analysis. In the second, and most important, part of this work, the feasibility of utilizing ThMOX fuel in a pressurized water reactor (PWR) was first examined under steady-state, beginning of life conditions. Using a three-dimensional MCNP model of a Westinghouse-type 17x17 PWR, several fuel compositions and configurations of a one-third ThMOX core were compared to a 100% UO2 core. A blanket-type arrangement of 5.5 wt% PuO2 was determined to be the best candidate for further analysis. Next, the safety of the ThMOX configuration was evaluated through three cycles of burnup at several using the following metrics: axial and radial nuclear hot channel factors, moderator and fuel temperature coefficients, delayed neutron fraction, and shutdown margin. Additionally, the performance of the ThMOX configuration was assessed by tracking cycle length, plutonium destroyed, and fission product poison concentration.

Whole genome analysis using Bayesian models to identify candidate genes for immune response to vaccination

USDA-ARS?s Scientific Manuscript database

This study identified genome regions associated with variation in immune response to vaccination against bovine viral diarrhea virus type 2 (BVDV 2) in American Angus calves. Calves were born in the spring or fall of 2006-2008 (n = 620). Two doses of modified live vaccine were administered three wee...

Automated analysis of immunohistochemistry images identifies candidate location biomarkers for cancers.

PubMed

Kumar, Aparna; Rao, Arvind; Bhavani, Santosh; Newberg, Justin Y; Murphy, Robert F

2014-12-23

Molecular biomarkers are changes measured in biological samples that reflect disease states. Such markers can help clinicians identify types of cancer or stages of progression, and they can guide in tailoring specific therapies. Many efforts to identify biomarkers consider genes that mutate between normal and cancerous tissues or changes in protein or RNA expression levels. Here we define location biomarkers, proteins that undergo changes in subcellular location that are indicative of disease. To discover such biomarkers, we have developed an automated pipeline to compare the subcellular location of proteins between two sets of immunohistochemistry images. We used the pipeline to compare images of healthy and tumor tissue from the Human Protein Atlas, ranking hundreds of proteins in breast, liver, prostate, and bladder based on how much their location was estimated to have changed. The performance of the system was evaluated by determining whether proteins previously known to change location in tumors were ranked highly. We present a number of candidate location biomarkers for each tissue, and identify biochemical pathways that are enriched in proteins that change location. The analysis technology is anticipated to be useful not only for discovering new location biomarkers but also for enabling automated analysis of biomarker distributions as an aid to determining diagnosis.

Nurse manager succession planning: A cost-benefit analysis.

PubMed

Phillips, Tracy; Evans, Jennifer L; Tooley, Stephanie; Shirey, Maria R

2018-03-01

This commentary presents a cost-benefit analysis to advocate for the use of succession planning to mitigate the problems ensuing from nurse manager turnover. An estimated 75% of nurse managers will leave the workforce by 2020. Many benefits are associated with proactively identifying and developing internal candidates. Fewer than 7% of health care organisations have implemented formal leadership succession planning programmes. A cost-benefit analysis of a formal succession-planning programme from one hospital illustrates the benefits of the programme in their organisation and can be replicated easily. Assumptions of nursing manager succession planning cost-benefit analysis are identified and discussed. The succession planning exemplar demonstrates the integration of cost-benefit analysis principles. Comparing the costs of a formal nurse manager succession planning strategy with the status quo results in a positive cost-benefit ratio. The implementation of a formal nurse manager succession planning programme effectively reduces replacement costs and time to transition into the new role. This programme provides an internal pipeline of future leaders who will be more successful than external candidates. Using an actual cost-benefit analysis equips nurse managers with valuable evidence depicting succession planning as a viable business strategy. © 2017 John Wiley & Sons Ltd.

Archival Legacy Investigations of Circumstellar Environments (ALICE): Statistical assessment of point source detections

NASA Astrophysics Data System (ADS)

Choquet, Élodie; Pueyo, Laurent; Soummer, Rémi; Perrin, Marshall D.; Hagan, J. Brendan; Gofas-Salas, Elena; Rajan, Abhijith; Aguilar, Jonathan

2015-09-01

The ALICE program, for Archival Legacy Investigation of Circumstellar Environment, is currently conducting a virtual survey of about 400 stars, by re-analyzing the HST-NICMOS coronagraphic archive with advanced post-processing techniques. We present here the strategy that we adopted to identify detections and potential candidates for follow-up observations, and we give a preliminary overview of our detections. We present a statistical analysis conducted to evaluate the confidence level on these detection and the completeness of our candidate search.

Preliminary Design of a Manned Nuclear Electric Propulsion Vehicle Using Genetic Algorithms

NASA Technical Reports Server (NTRS)

Irwin, Ryan W.; Tinker, Michael L.

2005-01-01

Nuclear electric propulsion (NEP) vehicles will be needed for future manned missions to Mars and beyond. Candidate designs must be identified for further detailed design from a large array of possibilities. Genetic algorithms have proven their utility in conceptual design studies by effectively searching a large design space to pinpoint unique optimal designs. This research combined analysis codes for NEP subsystems with a genetic algorithm. The use of penalty functions with scaling ratios was investigated to increase computational efficiency. Also, the selection of design variables for optimization was considered to reduce computation time without losing beneficial design search space. Finally, trend analysis of a reference mission to the asteroids yielded a group of candidate designs for further analysis.

Integrated systems analysis reveals a molecular network underlying autism spectrum disorders

PubMed Central

Li, Jingjing; Shi, Minyi; Ma, Zhihai; Zhao, Shuchun; Euskirchen, Ghia; Ziskin, Jennifer; Urban, Alexander; Hallmayer, Joachim; Snyder, Michael

2014-01-01

Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology. PMID:25549968

Investigating a population of infrared-bright gamma-ray burst host galaxies

NASA Astrophysics Data System (ADS)

Chrimes, Ashley A.; Stanway, Elizabeth R.; Levan, Andrew J.; Davies, Luke J. M.; Angus, Charlotte R.; Greis, Stephanie M. L.

2018-07-01

We identify and explore the properties of an infrared-bright gamma-ray burst (GRB) host population. Candidate hosts are selected by coincidence with sources in WISE, with matching to random coordinates and a false alarm probability analysis showing that the contamination fraction is ˜0.5. This methodology has already identified the host galaxy of GRB 080517. We combine survey photometry from Pan-STARRS, SDSS, APASS, 2MASS, GALEX, and WISE with our own WHT/ACAM and VLT/X-shooter observations to classify the candidates and identify interlopers. Galaxy SED fitting is performed using MAGPHYS, in addition to stellar template fitting, yielding 13 possible IR-bright hosts. A further seven candidates are identified from the previously published work. We report a candidate host for GRB 061002, previously unidentified as such. The remainder of the galaxies have already been noted as potential hosts. Comparing the IR-bright population properties including redshift z, stellar mass M⋆, star formation rate SFR, and V-band attenuation AV to GRB host catalogues in the literature, we find that the infrared-bright population is biased towards low z, high M⋆, and high AV. This naturally arises from their initial selection - local and dusty galaxies are more likely to have the required IR flux to be detected in WISE. We conclude that while IR-bright GRB hosts are not a physically distinct class, they are useful for constraining existing GRB host populations, particularly for long GRBs.

Investigating a population of infrared-bright gamma-ray burst host galaxies

NASA Astrophysics Data System (ADS)

Chrimes, Ashley A.; Stanway, Elizabeth R.; Levan, Andrew J.; Davies, Luke J. M.; Angus, Charlotte R.; Greis, Stephanie M. L.

2018-04-01

We identify and explore the properties of an infrared-bright gamma-ray burst (GRB) host population. Candidate hosts are selected by coincidence with sources in WISE, with matching to random coordinates and a false alarm probability analysis showing that the contamination fraction is ˜ 0.5. This methodology has already identified the host galaxy of GRB 080517. We combine survey photometry from Pan-STARRS, SDSS, APASS, 2MASS, GALEX and WISE with our own WHT/ACAM and VLT/X-shooter observations to classify the candidates and identify interlopers. Galaxy SED fitting is performed using MAGPHYS, in addition to stellar template fitting, yielding 13 possible IR-bright hosts. A further 7 candidates are identified from previously published work. We report a candidate host for GRB 061002, previously unidentified as such. The remainder of the galaxies have already been noted as potential hosts. Comparing the IR-bright population properties including redshift z, stellar mass M⋆, star formation rate SFR and V-band attenuation AV to GRB host catalogues in the literature, we find that the infrared-bright population is biased toward low z, high M⋆ and high AV. This naturally arises from their initial selection - local and dusty galaxies are more likely to have the required IR flux to be detected in WISE. We conclude that while IR-bright GRB hosts are not a physically distinct class, they are useful for constraining existing GRB host populations, particularly for long GRBs.

Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era

PubMed Central

2014-01-01

Background Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings. Methods We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding. Results Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4. Conclusions These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci. PMID:24885462

In search of Nemesis

NASA Technical Reports Server (NTRS)

Carlson, S.; Culler, T.; Muller, R. A.; Tetreault, M.; Perlmutter, S.

1994-01-01

The parallax of all stars of visual magnitude greater than about 6.5 has already been measured. If Nemesis is a main-sequence star 1 parsec away, this requires Nemesis's mass to be less than about 0.4 solar masses. If it were less than about 0.05 solar masses its gravity would be too weak to trigger a comet storm. If Nemesis is on the main sequence, this mass range requires it to be a red dwarf. A red dwarf companion would probably have been missed by standard astronomical surveys. Nearby stars are usually found because they are bright or have high proper motion. However, Nemesis's proper motion would now be 0.01 arcsec/yr, and if it is a red dwarf its magnitude is about 10 - too dim to attract attention. Unfortunately, standard four-color photometry does not distinguish between red dwarfs and giants. So although surveys such as the Dearborn Red Star Catalog list stars by magnitude and spectral type, they do not identify the dwarfs. Every star of the correct spectral type and magnitude must be scrutinized. Our candidate list is a hybrid; candidate red stars are identified in the astrometrically poor Dearborn Red Star Catalog and their positions are corrected using the Hubble Guide Star Catalog. When errors in the Dearborn catalog make it impossible to identify the corresponding Hubble star, the fields are split so that we have one centering on each possible candidate. We are currently scrutinizing 3098 fields, which we believe contain all possible red dwarf candidates in the northern hemisphere. Since our last report the analysis and database software has been completely rebuilt to take advantage of updated hardware, to make the data more accessible, and to implement improved methods of data analysis. The software is now completed and we are eliminating stars every clear night.

Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa

PubMed Central

Marks, M. David; Tian, Li; Wenger, Jonathan P.; Omburo, Stephanie N.; Soto-Fuentes, Wilfredo; He, Ji; Gang, David R.; Weiblen, George D.; Dixon, Richard A.

2009-01-01

RNA isolated from the glands of a Δ9-tetrahydrocannabinolic acid (THCA)-producing strain of Cannabis sativa was used to generate a cDNA library containing over 100 000 expressed sequence tags (ESTs). Sequencing of over 2000 clones from the library resulted in the identification of over 1000 unigenes. Candidate genes for almost every step in the biochemical pathways leading from primary metabolites to THCA were identified. Quantitative PCR analysis suggested that many of the pathway genes are preferentially expressed in the glands. Hexanoyl-CoA, one of the metabolites required for THCA synthesis, could be made via either de novo fatty acids synthesis or via the breakdown of existing lipids. qPCR analysis supported the de novo pathway. Many of the ESTs encode transcription factors and two putative MYB genes were identified that were preferentially expressed in glands. Given the similarity of the Cannabis MYB genes to those in other species with known functions, these Cannabis MYBs may play roles in regulating gland development and THCA synthesis. Three candidates for the polyketide synthase (PKS) gene responsible for the first committed step in the pathway to THCA were characterized in more detail. One of these was identical to a previously reported chalcone synthase (CHS) and was found to have CHS activity. All three could use malonyl-CoA and hexanoyl-CoA as substrates, including the CHS, but reaction conditions were not identified that allowed for the production of olivetolic acid (the proposed product of the PKS activity needed for THCA synthesis). One of the PKS candidates was highly and specifically expressed in glands (relative to whole leaves) and, on the basis of these expression data, it is proposed to be the most likely PKS responsible for olivetolic acid synthesis in Cannabis glands. PMID:19581347

Rapid Classification and Identification of Multiple Microorganisms with Accurate Statistical Significance via High-Resolution Tandem Mass Spectrometry

NASA Astrophysics Data System (ADS)

Alves, Gelio; Wang, Guanghui; Ogurtsov, Aleksey Y.; Drake, Steven K.; Gucek, Marjan; Sacks, David B.; Yu, Yi-Kuo

2018-06-01

Rapid and accurate identification and classification of microorganisms is of paramount importance to public health and safety. With the advance of mass spectrometry (MS) technology, the speed of identification can be greatly improved. However, the increasing number of microbes sequenced is complicating correct microbial identification even in a simple sample due to the large number of candidates present. To properly untwine candidate microbes in samples containing one or more microbes, one needs to go beyond apparent morphology or simple "fingerprinting"; to correctly prioritize the candidate microbes, one needs to have accurate statistical significance in microbial identification. We meet these challenges by using peptide-centric representations of microbes to better separate them and by augmenting our earlier analysis method that yields accurate statistical significance. Here, we present an updated analysis workflow that uses tandem MS (MS/MS) spectra for microbial identification or classification. We have demonstrated, using 226 MS/MS publicly available data files (each containing from 2500 to nearly 100,000 MS/MS spectra) and 4000 additional MS/MS data files, that the updated workflow can correctly identify multiple microbes at the genus and often the species level for samples containing more than one microbe. We have also shown that the proposed workflow computes accurate statistical significances, i.e., E values for identified peptides and unified E values for identified microbes. Our updated analysis workflow MiCId, a freely available software for Microorganism Classification and Identification, is available for download at https://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads.html.

Rapid Classification and Identification of Multiple Microorganisms with Accurate Statistical Significance via High-Resolution Tandem Mass Spectrometry.

PubMed

Alves, Gelio; Wang, Guanghui; Ogurtsov, Aleksey Y; Drake, Steven K; Gucek, Marjan; Sacks, David B; Yu, Yi-Kuo

2018-06-05

Rapid and accurate identification and classification of microorganisms is of paramount importance to public health and safety. With the advance of mass spectrometry (MS) technology, the speed of identification can be greatly improved. However, the increasing number of microbes sequenced is complicating correct microbial identification even in a simple sample due to the large number of candidates present. To properly untwine candidate microbes in samples containing one or more microbes, one needs to go beyond apparent morphology or simple "fingerprinting"; to correctly prioritize the candidate microbes, one needs to have accurate statistical significance in microbial identification. We meet these challenges by using peptide-centric representations of microbes to better separate them and by augmenting our earlier analysis method that yields accurate statistical significance. Here, we present an updated analysis workflow that uses tandem MS (MS/MS) spectra for microbial identification or classification. We have demonstrated, using 226 MS/MS publicly available data files (each containing from 2500 to nearly 100,000 MS/MS spectra) and 4000 additional MS/MS data files, that the updated workflow can correctly identify multiple microbes at the genus and often the species level for samples containing more than one microbe. We have also shown that the proposed workflow computes accurate statistical significances, i.e., E values for identified peptides and unified E values for identified microbes. Our updated analysis workflow MiCId, a freely available software for Microorganism Classification and Identification, is available for download at https://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads.html . Graphical Abstract ᅟ.

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.

PubMed

Janse, Marcel; Lamberts, Laetitia E; Franke, Lude; Raychaudhuri, Soumya; Ellinghaus, Eva; Muri Boberg, Kirsten; Melum, Espen; Folseraas, Trine; Schrumpf, Erik; Bergquist, Annika; Björnsson, Einar; Fu, Jingyuan; Jan Westra, Harm; Groen, Harry J M; Fehrmann, Rudolf S N; Smolonska, Joanna; van den Berg, Leonard H; Ophoff, Roel A; Porte, Robert J; Weismüller, Tobias J; Wedemeyer, Jochen; Schramm, Christoph; Sterneck, Martina; Günther, Rainer; Braun, Felix; Vermeire, Severine; Henckaerts, Liesbet; Wijmenga, Cisca; Ponsioen, Cyriel Y; Schreiber, Stefan; Karlsen, Tom H; Franke, Andre; Weersma, Rinse K

2011-06-01

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10(-4) ), 4q27 (P-value 4.10 × 10(-5) ), and 9q34 (P-value 8.41 × 10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors. Copyright © 2011 American Association for the Study of Liver Diseases.

Digital transcriptome analysis of putative sex-determination genes in papaya (Carica papaya).

PubMed

Urasaki, Naoya; Tarora, Kazuhiko; Shudo, Ayano; Ueno, Hiroki; Tamaki, Moritoshi; Miyagi, Norimichi; Adaniya, Shinichi; Matsumura, Hideo

2012-01-01

Papaya (Carica papaya) is a trioecious plant species that has male, female and hermaphrodite flowers on different plants. The primitive sex chromosomes genetically determine the sex of the papaya. Although draft sequences of the papaya genome are already available, the genes for sex determination have not been identified, likely due to the complicated structure of its sex-chromosome sequences. To identify the candidate genes for sex determination, we conducted a transcriptome analysis of flower samples from male, female and hermaphrodite plants using high-throughput SuperSAGE for digital gene expression analysis. Among the short sequence tags obtained from the transcripts, 312 unique tags were specifically mapped to the primitive sex chromosome (X or Y(h)) sequences. An annotation analysis revealed that retroelements are the most abundant sequences observed in the genes corresponding to these tags. The majority of tags on the sex chromosomes were located on the X chromosome, and only 30 tags were commonly mapped to both the X and Y(h) chromosome, implying a loss of many genes on the Y(h) chromosome. Nevertheless, candidate Y(h) chromosome-specific female determination genes, including a MADS-box gene, were identified. Information on these sex chromosome-specific expressed genes will help elucidating sex determination in the papaya.

Digital Transcriptome Analysis of Putative Sex-Determination Genes in Papaya (Carica papaya)

PubMed Central

Urasaki, Naoya; Tarora, Kazuhiko; Shudo, Ayano; Ueno, Hiroki; Tamaki, Moritoshi; Miyagi, Norimichi; Adaniya, Shinichi; Matsumura, Hideo

2012-01-01

Papaya (Carica papaya) is a trioecious plant species that has male, female and hermaphrodite flowers on different plants. The primitive sex chromosomes genetically determine the sex of the papaya. Although draft sequences of the papaya genome are already available, the genes for sex determination have not been identified, likely due to the complicated structure of its sex-chromosome sequences. To identify the candidate genes for sex determination, we conducted a transcriptome analysis of flower samples from male, female and hermaphrodite plants using high-throughput SuperSAGE for digital gene expression analysis. Among the short sequence tags obtained from the transcripts, 312 unique tags were specifically mapped to the primitive sex chromosome (X or Yh) sequences. An annotation analysis revealed that retroelements are the most abundant sequences observed in the genes corresponding to these tags. The majority of tags on the sex chromosomes were located on the X chromosome, and only 30 tags were commonly mapped to both the X and Yh chromosome, implying a loss of many genes on the Yh chromosome. Nevertheless, candidate Yh chromosome-specific female determination genes, including a MADS-box gene, were identified. Information on these sex chromosome-specific expressed genes will help elucidating sex determination in the papaya. PMID:22815863

A Novel Strategy for Selection and Validation of Reference Genes in Dynamic Multidimensional Experimental Design in Yeast

PubMed Central

Cankorur-Cetinkaya, Ayca; Dereli, Elif; Eraslan, Serpil; Karabekmez, Erkan; Dikicioglu, Duygu; Kirdar, Betul

2012-01-01

Background Understanding the dynamic mechanism behind the transcriptional organization of genes in response to varying environmental conditions requires time-dependent data. The dynamic transcriptional response obtained by real-time RT-qPCR experiments could only be correctly interpreted if suitable reference genes are used in the analysis. The lack of available studies on the identification of candidate reference genes in dynamic gene expression studies necessitates the identification and the verification of a suitable gene set for the analysis of transient gene expression response. Principal Findings In this study, a candidate reference gene set for RT-qPCR analysis of dynamic transcriptional changes in Saccharomyces cerevisiae was determined using 31 different publicly available time series transcriptome datasets. Ten of the twelve candidates (TPI1, FBA1, CCW12, CDC19, ADH1, PGK1, GCN4, PDC1, RPS26A and ARF1) we identified were not previously reported as potential reference genes. Our method also identified the commonly used reference genes ACT1 and TDH3. The most stable reference genes from this pool were determined as TPI1, FBA1, CDC19 and ACT1 in response to a perturbation in the amount of available glucose and as FBA1, TDH3, CCW12 and ACT1 in response to a perturbation in the amount of available ammonium. The use of these newly proposed gene sets outperformed the use of common reference genes in the determination of dynamic transcriptional response of the target genes, HAP4 and MEP2, in response to relaxation from glucose and ammonium limitations, respectively. Conclusions A candidate reference gene set to be used in dynamic real-time RT-qPCR expression profiling in yeast was proposed for the first time in the present study. Suitable pools of stable reference genes to be used under different experimental conditions could be selected from this candidate set in order to successfully determine the expression profiles for the genes of interest. PMID:22675547

Genome-Wide Identification of Differentially Expressed Genes Associated with the High Yielding of Oleoresin in Secondary Xylem of Masson Pine (Pinus massoniana Lamb) by Transcriptomic Analysis

PubMed Central

Liu, Qinghua; Zhou, Zhichun; Wei, Yongcheng; Shen, Danyu; Feng, Zhongping; Hong, Shanping

2015-01-01

Masson pine is an important timber and resource for oleoresin in South China. Increasing yield of oleoresin in stems can raise economic benefits and enhance the resistance to bark beetles. However, the genetic mechanisms for regulating the yield of oleoresin were still unknown. Here, high-throughput sequencing technology was used to investigate the transcriptome and compare the gene expression profiles of high and low oleoresin-yielding genotypes. A total of 40,690,540 reads were obtained and assembled into 137,499 transcripts from the secondary xylem tissues. We identified 84,842 candidate unigenes based on sequence annotation using various databases and 96 unigenes were candidates for terpenoid backbone biosynthesis in pine. By comparing the expression profiles of high and low oleoresin-yielding genotypes, 649 differentially expressed genes (DEGs) were identified. GO enrichment analysis of DEGs revealed that multiple pathways were related to high yield of oleoresin. Nine candidate genes were validated by QPCR analysis. Among them, the candidate genes encoding geranylgeranyl diphosphate synthase (GGPS) and (-)-alpha/beta-pinene synthase were up-regulated in the high oleoresin-yielding genotype, while tricyclene synthase revealed lower expression level, which was in good agreement with the GC/MS result. In addition, DEG encoding ABC transporters, pathogenesis-related proteins (PR5 and PR9), phosphomethylpyrimidine synthase, non-specific lipid-transfer protein-like protein and ethylene responsive transcription factors (ERFs) were also confirmed to be critical for the biosynthesis of oleoresin. The next-generation sequencing strategy used in this study has proven to be a powerful means for analyzing transcriptome variation related to the yield of oleoresin in masson pine. The candidate genes encoding GGPS, (-)-alpha/beta-pinene, tricyclene synthase, ABC transporters, non-specific lipid-transfer protein-like protein, phosphomethylpyrimidine synthase, ERFs and pathogen responses may play important roles in regulating the yield of oleoresin. These DEGs are worthy of special attention in future studies. PMID:26167875

Linkage and association analysis of obesity traits reveals novel loci and interactions with dietary n-3 fatty acids in an Alaska Native (Yup’ik) population

PubMed Central

Vaughan, Laura Kelly; Wiener, Howard W.; Aslibekyan, Stella; Allison, David B.; Havel, Peter J.; Stanhope, Kimber L.; O’Brien, Diane M.; Hopkins, Scarlett E.; Lemas, Dominick J.; Boyer, Bert B.; Tiwari, Hemant K.

2015-01-01

Objective To identify novel genetic markers of obesity-related traits and to identify gene-diet interactions with n-3 polyunsaturated fatty acid (n-3 PUFA) intake in Yup’ik people. Material and Methods We measured body composition, plasma adipokines and ghrelin in 982 participants enrolled in the Center for Alaska Native Health Research (CANHR) Study. We conducted a genome-wide SNP linkage scan and targeted association analysis, fitting additional models to investigate putative gene-diet interactions. Finally, we performed bioinformatic analysis to uncover likely candidate genes within the identified linkage peaks. Results We observed evidence of linkage for all obesity-related traits, replicating previous results and identifying novel regions of interest for adiponectin (10q26.13-2) and thigh circumference (8q21.11-13). Bioinformatic analysis revealed DOCK1, PTPRE (10q26.13-2) and FABP4 (8q21.11-13) as putative candidate genes in the newly identified regions. Targeted SNP analysis under the linkage peaks identified associations between three SNPs and obesity-related traits: rs1007750 on chromosome 8 and thigh circumference (P=0.0005), rs878953 on chromosome 5 and thigh skinfold (P=0.0004), and rs1596854 on chromosome 11 for waist circumference (P=0.0003). Finally, we showed that n-3 PUFA modified the association between obesity related traits and two additional variants (rs2048417 on chromosome 3 for adiponectin, P for interaction=0.0006 and rs730414 on chromosome 11 for percentage body fat, P for interaction=0.0004). Conclusions This study presents evidence of novel genomic regions and gene-diet interactions that may contribute to the pathophysiology of obesity-related traits among Yup’ik people. PMID:25772781

Linkage and association analysis of obesity traits reveals novel loci and interactions with dietary n-3 fatty acids in an Alaska Native (Yup'ik) population.

PubMed

Vaughan, Laura Kelly; Wiener, Howard W; Aslibekyan, Stella; Allison, David B; Havel, Peter J; Stanhope, Kimber L; O'Brien, Diane M; Hopkins, Scarlett E; Lemas, Dominick J; Boyer, Bert B; Tiwari, Hemant K

2015-06-01

To identify novel genetic markers of obesity-related traits and to identify gene-diet interactions with n-3 polyunsaturated fatty acid (n-3 PUFA) intake in Yup'ik people. We measured body composition, plasma adipokines and ghrelin in 982 participants enrolled in the Center for Alaska Native Health Research (CANHR) Study. We conducted a genome-wide SNP linkage scan and targeted association analysis, fitting additional models to investigate putative gene-diet interactions. Finally, we performed bioinformatic analysis to uncover likely candidate genes within the identified linkage peaks. We observed evidence of linkage for all obesity-related traits, replicating previous results and identifying novel regions of interest for adiponectin (10q26.13-2) and thigh circumference (8q21.11-13). Bioinformatic analysis revealed DOCK1, PTPRE (10q26.13-2) and FABP4 (8q21.11-13) as putative candidate genes in the newly identified regions. Targeted SNP analysis under the linkage peaks identified associations between three SNPs and obesity-related traits: rs1007750 on chromosome 8 and thigh circumference (P=0.0005), rs878953 on chromosome 5 and thigh skinfold (P=0.0004), and rs1596854 on chromosome 11 for waist circumference (P=0.0003). Finally, we showed that n-3 PUFA modified the association between obesity related traits and two additional variants (rs2048417 on chromosome 3 for adiponectin, P for interaction=0.0006 and rs730414 on chromosome 11 for percentage body fat, P for interaction=0.0004). This study presents evidence of novel genomic regions and gene-diet interactions that may contribute to the pathophysiology of obesity-related traits among Yup'ik people. Copyright © 2015 Elsevier Inc. All rights reserved.

A genome-wide association study of corneal astigmatism: The CREAM Consortium.

PubMed

Shah, Rupal L; Li, Qing; Zhao, Wanting; Tedja, Milly S; Tideman, J Willem L; Khawaja, Anthony P; Fan, Qiao; Yazar, Seyhan; Williams, Katie M; Verhoeven, Virginie J M; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J; Pärssinen, Olavi; Wedenoja, Juho; Biino, Ginevra; Concas, Maria Pina; Uitterlinden, André; Rivadeneira, Fernando; Jaddoe, Vincent W V; Hysi, Pirro G; Sim, Xueling; Tan, Nicholas; Tham, Yih-Chung; Sensaki, Sonoko; Hofman, Albert; Vingerling, Johannes R; Jonas, Jost B; Mitchell, Paul; Hammond, Christopher J; Höhn, René; Baird, Paul N; Wong, Tien-Yin; Cheng, Chinfsg-Yu; Teo, Yik Ying; Mackey, David A; Williams, Cathy; Saw, Seang-Mei; Klaver, Caroline C W; Guggenheim, Jeremy A; Bailey-Wilson, Joan E

2018-01-01

To identify genes and genetic markers associated with corneal astigmatism. A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha ( PDGFRA ) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10 -9 . No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 ( CLDN7 ), acid phosphatase 2, lysosomal ( ACP2 ), and TNF alpha-induced protein 8 like 3 ( TNFAIP8L3 ). In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7 , ACP2 , and TNFAIP8L3 , that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Average Albedos of Close-in Super-Earths and Super-Neptunes from Statistical Analysis of Long-cadence Kepler Secondary Eclipse Data

NASA Astrophysics Data System (ADS)

Sheets, Holly A.; Deming, Drake

2017-10-01

We present the results of our work to determine the average albedo for small, close-in planets in the Kepler candidate catalog. We have adapted our method of averaging short-cadence light curves of multiple Kepler planet candidates to long-cadence data, in order to detect an average albedo for the group of candidates. Long-cadence data exist for many more candidates than the short-cadence data, and so we separate the candidates into smaller radius bins than in our previous work: 1-2 {R}\\oplus , 2-4 {R}\\oplus , and 4-6 {R}\\oplus . We find that, on average, all three groups appear darker than suggested by the short-cadence results, but not as dark as many hot Jupiters. The average geometric albedos for the three groups are 0.11 ± 0.06, 0.05 ± 0.04, and 0.23 ± 0.11, respectively, for the case where heat is uniformly distributed about the planet. If heat redistribution is inefficient, the albedos are even lower, since there will be a greater thermal contribution to the total light from the planet. We confirm that newly identified false-positive Kepler Object of Interest (KOI) 1662.01 is indeed an eclipsing binary at twice the period listed in the planet candidate catalog. We also newly identify planet candidate KOI 4351.01 as an eclipsing binary, and we report a secondary eclipse measurement for Kepler-4b (KOI 7.01) of ˜7.50 ppm at a phase of ˜0.7, indicating that the planet is on an eccentric orbit.

A challenge to identify an optical counterpart of the gravitational wave event GW151226 with Hyper Suprime-Cam†

NASA Astrophysics Data System (ADS)

Utsumi, Yousuke; Tominaga, Nozomu; Tanaka, Masaomi; Morokuma, Tomoki; Yoshida, Michitoshi; Asakura, Yuichiro; Finet, François; Furusawa, Hisanori; Kawabata, Koji S.; Liu, Wei; Matsubayashi, Kazuya; Moritani, Yuki; Motohara, Kentaro; Nakata, Fumiaki; Ohta, Kouji; Terai, Tsuyoshi; Uemura, Makoto; Yasuda, Naoki

2018-01-01

We present the results of detailed analysis of an optical imaging survey conducted using the Subaru/Hyper Suprime-Cam (HSC) that aimed to identify an optical counterpart to the gravitational wave event GW151226. In half a night, the i- and z-band imaging survey by HSC covered 63.5 deg2 of the error region, which contains about 7% of the LIGO localization probability, and the same field was observed in three different epochs. The detectable magnitude of the candidates in a differenced image is evaluated as i ˜ 23.2 mag for the requirement of at least two 5 σ detections, and 1744 candidates are discovered. Assuming a kilonova as an optical counterpart, we compare the optical properties of the candidates with model predictions. A red and rapidly declining light curve condition enables the discrimination of a kilonova from other transients, and a small number of candidates satisfy this condition. The presence of stellar-like counterparts in the reference frame suggests that the surviving candidates are likely to be flare stars. The fact that most of those candidates are in the galactic plane, |b| < 5°, supports this interpretation. We also check whether the candidates are associated with the nearby GLADE galaxies, which reduces the number of contaminants even with a looser color cut. When a better probability map (with localization accuracy of ˜50 deg2) is available, kilonova searches of up to approximately 200 Mpc will become feasible by conducting immediate follow-up observations with an interval of 3-6 d.

Candidate gene prioritization by network analysis of differential expression using machine learning approaches

PubMed Central

2010-01-01

Background Discovering novel disease genes is still challenging for diseases for which no prior knowledge - such as known disease genes or disease-related pathways - is available. Performing genetic studies frequently results in large lists of candidate genes of which only few can be followed up for further investigation. We have recently developed a computational method for constitutional genetic disorders that identifies the most promising candidate genes by replacing prior knowledge by experimental data of differential gene expression between affected and healthy individuals. To improve the performance of our prioritization strategy, we have extended our previous work by applying different machine learning approaches that identify promising candidate genes by determining whether a gene is surrounded by highly differentially expressed genes in a functional association or protein-protein interaction network. Results We have proposed three strategies scoring disease candidate genes relying on network-based machine learning approaches, such as kernel ridge regression, heat kernel, and Arnoldi kernel approximation. For comparison purposes, a local measure based on the expression of the direct neighbors is also computed. We have benchmarked these strategies on 40 publicly available knockout experiments in mice, and performance was assessed against results obtained using a standard procedure in genetics that ranks candidate genes based solely on their differential expression levels (Simple Expression Ranking). Our results showed that our four strategies could outperform this standard procedure and that the best results were obtained using the Heat Kernel Diffusion Ranking leading to an average ranking position of 8 out of 100 genes, an AUC value of 92.3% and an error reduction of 52.8% relative to the standard procedure approach which ranked the knockout gene on average at position 17 with an AUC value of 83.7%. Conclusion In this study we could identify promising candidate genes using network based machine learning approaches even if no knowledge is available about the disease or phenotype. PMID:20840752

Using a New Crustal Thickness Model to Test Previous Candidate Lunar Basins and to Search for New Candidates

NASA Technical Reports Server (NTRS)

Meyer, H. M.; Frey, H. V.

2012-01-01

A new crustal thickness model was used to test the viability of 110 candidate large lunar basins previously identified using older topographic and crustal thickness data as well as photogeologic data. The new model was also used to search for new candidate lunar basins greater than 300 km in diameter. We eliminated 11 of 27 candidates previously identified in the older crustal thickness model, and found strong evidence for at least 8 new candidates.

Proteomic Analysis of Mouse Oocytes Identifies PRMT7 as a Reprogramming Factor that Replaces SOX2 in the Induction of Pluripotent Stem Cells.

PubMed

Wang, Bingyuan; Pfeiffer, Martin J; Drexler, Hannes C A; Fuellen, Georg; Boiani, Michele

2016-08-05

The reprogramming process that leads to induced pluripotent stem cells (iPSCs) may benefit from adding oocyte factors to Yamanaka's reprogramming cocktail (OCT4, SOX2, KLF4, with or without MYC; OSK(M)). We previously searched for such facilitators of reprogramming (the reprogrammome) by applying label-free LC-MS/MS analysis to mouse oocytes, producing a catalog of 28 candidates that are (i) able to robustly access the cell nucleus and (ii) shared between mature mouse oocytes and pluripotent embryonic stem cells. In the present study, we hypothesized that our 28 reprogrammome candidates would also be (iii) abundant in mature oocytes, (iv) depleted after the oocyte-to-embryo transition, and (v) able to potentiate or replace the OSKM factors. Using LC-MS/MS and isotopic labeling methods, we found that the abundance profiles of the 28 proteins were below those of known oocyte-specific and housekeeping proteins. Of the 28 proteins, only arginine methyltransferase 7 (PRMT7) changed substantially during mouse embryogenesis and promoted the conversion of mouse fibroblasts into iPSCs. Specifically, PRMT7 replaced SOX2 in a factor-substitution assay, yielding iPSCs. These findings exemplify how proteomics can be used to prioritize the functional analysis of reprogrammome candidates. The LC-MS/MS data are available via ProteomeXchange with identifier PXD003093.

Deciphering the pharmacological mechanism of the Chinese formula Huanglian-Jie-Du decoction in the treatment of ischemic stroke using a systems biology-based strategy

PubMed Central

Zhang, Yan-qiong; Wang, Song-song; Zhu, Wei-liang; Ma, Yan; Zhang, Fang-bo; Liang, Ri-xin; Xu, Hai-yu; Yang, Hong-jun

2015-01-01

Aim: Huanglian-Jie-Du decoction (HLJDD) is an important multiherb remedy in TCM, which is recently demonstrated to be effective to treat ischemic stroke. Here, we aimed to investigate the pharmacological mechanisms of HLJDD in the treatment of ischemic stroke using systems biology approaches. Methods: Putative targets of HLJDD were predicted using MetaDrug. An interaction network of putative HLJDD targets and known therapeutic targets for the treatment of ischemic stroke was then constructed, and candidate HLJDD targets were identified by calculating topological features, including 'Degree', 'Node-betweenness', 'Closeness', and 'K-coreness'. The binding efficiencies of the candidate HLJDD targets with the corresponding compositive compounds were further validated by a molecular docking simulation. Results: A total of 809 putative targets were obtained for 168 compositive compounds in HLJDD. Additionally, 39 putative targets were common to all four herbs of HLJDD. Next, 49 major nodes were identified as candidate HLJDD targets due to their network topological importance. The enrichment analysis based on the Gene Ontology (GO) annotation system and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway demonstrated that candidate HLJDD targets were more frequently involved in G-protein-coupled receptor signaling pathways, neuroactive ligand-receptor interactions and gap junctions, which all played important roles in the progression of ischemic stroke. Finally, the molecular docking simulation showed that 170 pairs of chemical components and candidate HLJDD targets had strong binding efficiencies. Conclusion: This study has developed for the first time a comprehensive systems approach integrating drug target prediction, network analysis and molecular docking simulation to reveal the relationships between the herbs contained in HLJDD and their putative targets and ischemic stroke-related pathways. PMID:25937634

Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia

PubMed Central

Yamada, Kazuo; Gerber, David J.; Iwayama, Yoshimi; Ohnishi, Tetsuo; Ohba, Hisako; Toyota, Tomoko; Aruga, Jun; Minabe, Yoshio; Tonegawa, Susumu; Yoshikawa, Takeo

2007-01-01

The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes. To replicate and extend our previously reported association between the PPP3CC gene, encoding the calcineurin catalytic γ-subunit, and schizophrenia, we examined 84 SNPs from 14 calcineurin-related candidate genes for genetic association by using 124 Japanese schizophrenic pedigrees. Four of these genes (PPP3CC, EGR2, EGR3, and EGR4) showed nominally significant association with schizophrenia. In a postmortem brain study, EGR1, EGR2, and EGR3 transcripts were shown to be down-regulated in the prefrontal cortex of schizophrenic, but not bipolar, patients. These findings raise a potentially important role for EGR genes in schizophrenia pathogenesis. Because EGR3 is an attractive candidate gene based on its chromosomal location close to PPP3CC within 8p21.3 and its functional link to dopamine, glutamate, and neuregulin signaling, we extended our analysis by resequencing the entire EGR3 genomic interval and detected 15 SNPs. One of these, IVS1 + 607A→G SNP, displayed the strongest evidence for disease association, which was confirmed in 1,140 independent case-control samples. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify EGR3 as a compelling susceptibility gene. PMID:17360599

Identification of Candidate Genes Responsible for Stem Pith Production Using Expression Analysis in Solid-Stemmed Wheat.

PubMed

Oiestad, A J; Martin, J M; Cook, J; Varella, A C; Giroux, M J

2017-07-01

The wheat stem sawfly (WSS) is an economically important pest of wheat in the Northern Great Plains. The primary means of WSS control is resistance associated with the single quantitative trait locus (QTL) , which controls most stem solidness variation. The goal of this study was to identify stem solidness candidate genes via RNA-seq. This study made use of 28 single nucleotide polymorphism (SNP) makers derived from expressed sequence tags (ESTs) linked to contained within a 5.13 cM region. Allele specific expression of EST markers was examined in stem tissue for solid and hollow-stemmed pairs of two spring wheat near isogenic lines (NILs) differing for the QTL. Of the 28 ESTs, 13 were located within annotated genes and 10 had detectable stem expression. Annotated genes corresponding to four of the ESTs were differentially expressed between solid and hollow-stemmed NILs and represent possible stem solidness gene candidates. Further examination of the 5.13 cM region containing the 28 EST markers identified 260 annotated genes. Twenty of the 260 linked genes were up-regulated in hollow NIL stems, while only seven genes were up-regulated in solid NIL stems. An -methyltransferase within the region of interest was identified as a candidate based on differential expression between solid and hollow-stemmed NILs and putative function. Further study of these candidate genes may lead to the identification of the gene(s) controlling stem solidness and an increased ability to select for wheat stem solidness and manage WSS. Copyright © 2017 Crop Science Society of America.

Leishmania genome analysis and high-throughput immunological screening identifies tuzin as a novel vaccine candidate against visceral leishmaniasis.

PubMed

Lakshmi, Bhavana Sethu; Wang, Ruobing; Madhubala, Rentala

2014-06-24

Leishmaniasis is a neglected tropical disease caused by Leishmania species. It is a major health concern affecting 88 countries and threatening 350 million people globally. Unfortunately, there are no vaccines and there are limitations associated with the current therapeutic regimens for leishmaniasis. The emerging cases of drug-resistance further aggravate the situation, demanding rapid drug and vaccine development. The genome sequence of Leishmania, provides access to novel genes that hold potential as chemotherapeutic targets or vaccine candidates. In this study, we selected 19 antigenic genes from about 8000 common Leishmania genes based on the Leishmania major and Leishmania infantum genome information available in the pathogen databases. Potential vaccine candidates thus identified were screened using an in vitro high throughput immunological platform developed in the laboratory. Four candidate genes coding for tuzin, flagellar glycoprotein-like protein (FGP), phospholipase A1-like protein (PLA1) and potassium voltage-gated channel protein (K VOLT) showed a predominant protective Th1 response over disease exacerbating Th2. We report the immunogenic properties and protective efficacy of one of the four antigens, tuzin, as a DNA vaccine against Leishmania donovani challenge. Our results show that administration of tuzin DNA protected BALB/c mice against L. donovani challenge and that protective immunity was associated with higher levels of IFN-γ and IL-12 production in comparison to IL-4 and IL-10. Our study presents a simple approach to rapidly identify potential vaccine candidates using the exhaustive information stored in the genome and an in vitro high-throughput immunological platform. Copyright © 2014. Published by Elsevier Ltd.

“Soldier's Heart”: A Genetic Basis for Elevated Cardiovascular Disease Risk Associated with Post-traumatic Stress Disorder

PubMed Central

Pollard, Harvey B.; Shivakumar, Chittari; Starr, Joshua; Eidelman, Ofer; Jacobowitz, David M.; Dalgard, Clifton L.; Srivastava, Meera; Wilkerson, Matthew D.; Stein, Murray B.; Ursano, Robert J.

2016-01-01

“Soldier's Heart,” is an American Civil War term linking post-traumatic stress disorder (PTSD) with increased propensity for cardiovascular disease (CVD). We have hypothesized that there might be a quantifiable genetic basis for this linkage. To test this hypothesis we identified a comprehensive set of candidate risk genes for PTSD, and tested whether any were also independent risk genes for CVD. A functional analysis algorithm was used to identify associated signaling networks. We identified 106 PTSD studies that report one or more polymorphic variants in 87 candidate genes in 83,463 subjects and controls. The top upstream drivers for these PTSD risk genes are predicted to be the glucocorticoid receptor (NR3C1) and Tumor Necrosis Factor alpha (TNFA). We find that 37 of the PTSD candidate risk genes are also candidate independent risk genes for CVD. The association between PTSD and CVD is significant by Fisher's Exact Test (P = 3 × 10−54). We also find 15 PTSD risk genes that are independently associated with Type 2 Diabetes Mellitus (T2DM; also significant by Fisher's Exact Test (P = 1.8 × 10−16). Our findings offer quantitative evidence for a genetic link between post-traumatic stress and cardiovascular disease, Computationally, the common mechanism for this linkage between PTSD and CVD is innate immunity and NFκB-mediated inflammation. PMID:27721742

The Candidate Cancer Gene Database: a database of cancer driver genes from forward genetic screens in mice.

PubMed

Abbott, Kenneth L; Nyre, Erik T; Abrahante, Juan; Ho, Yen-Yi; Isaksson Vogel, Rachel; Starr, Timothy K

2015-01-01

Identification of cancer driver gene mutations is crucial for advancing cancer therapeutics. Due to the overwhelming number of passenger mutations in the human tumor genome, it is difficult to pinpoint causative driver genes. Using transposon mutagenesis in mice many laboratories have conducted forward genetic screens and identified thousands of candidate driver genes that are highly relevant to human cancer. Unfortunately, this information is difficult to access and utilize because it is scattered across multiple publications using different mouse genome builds and strength metrics. To improve access to these findings and facilitate meta-analyses, we developed the Candidate Cancer Gene Database (CCGD, http://ccgd-starrlab.oit.umn.edu/). The CCGD is a manually curated database containing a unified description of all identified candidate driver genes and the genomic location of transposon common insertion sites (CISs) from all currently published transposon-based screens. To demonstrate relevance to human cancer, we performed a modified gene set enrichment analysis using KEGG pathways and show that human cancer pathways are highly enriched in the database. We also used hierarchical clustering to identify pathways enriched in blood cancers compared to solid cancers. The CCGD is a novel resource available to scientists interested in the identification of genetic drivers of cancer. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

"Soldier's Heart": A Genetic Basis for Elevated Cardiovascular Disease Risk Associated with Post-traumatic Stress Disorder.

PubMed

Pollard, Harvey B; Shivakumar, Chittari; Starr, Joshua; Eidelman, Ofer; Jacobowitz, David M; Dalgard, Clifton L; Srivastava, Meera; Wilkerson, Matthew D; Stein, Murray B; Ursano, Robert J

2016-01-01

"Soldier's Heart," is an American Civil War term linking post-traumatic stress disorder (PTSD) with increased propensity for cardiovascular disease (CVD). We have hypothesized that there might be a quantifiable genetic basis for this linkage. To test this hypothesis we identified a comprehensive set of candidate risk genes for PTSD, and tested whether any were also independent risk genes for CVD. A functional analysis algorithm was used to identify associated signaling networks. We identified 106 PTSD studies that report one or more polymorphic variants in 87 candidate genes in 83,463 subjects and controls. The top upstream drivers for these PTSD risk genes are predicted to be the glucocorticoid receptor (NR3C1) and Tumor Necrosis Factor alpha (TNFA). We find that 37 of the PTSD candidate risk genes are also candidate independent risk genes for CVD. The association between PTSD and CVD is significant by Fisher's Exact Test ( P = 3 × 10 -54 ). We also find 15 PTSD risk genes that are independently associated with Type 2 Diabetes Mellitus (T2DM; also significant by Fisher's Exact Test ( P = 1.8 × 10 -16 ). Our findings offer quantitative evidence for a genetic link between post-traumatic stress and cardiovascular disease, Computationally, the common mechanism for this linkage between PTSD and CVD is innate immunity and NFκB-mediated inflammation.

Comparative Transcriptome Analysis Identifies Putative Genes Involved in the Biosynthesis of Xanthanolides in Xanthium strumarium L.

PubMed Central

Li, Yuanjun; Gou, Junbo; Chen, Fangfang; Li, Changfu; Zhang, Yansheng

2016-01-01

Xanthium strumarium L. is a traditional Chinese herb belonging to the Asteraceae family. The major bioactive components of this plant are sesquiterpene lactones (STLs), which include the xanthanolides. To date, the biogenesis of xanthanolides, especially their downstream pathway, remains largely unknown. In X. strumarium, xanthanolides primarily accumulate in its glandular trichomes. To identify putative gene candidates involved in the biosynthesis of xanthanolides, three X. strumarium transcriptomes, which were derived from the young leaves of two different cultivars and the purified glandular trichomes from one of the cultivars, were constructed in this study. In total, 157 million clean reads were generated and assembled into 91,861 unigenes, of which 59,858 unigenes were successfully annotated. All the genes coding for known enzymes in the upstream pathway to the biosynthesis of xanthanolides were present in the X. strumarium transcriptomes. From a comparative analysis of the X. strumarium transcriptomes, this study identified a number of gene candidates that are putatively involved in the downstream pathway to the synthesis of xanthanolides, such as four unigenes encoding CYP71 P450s, 50 unigenes for dehydrogenases, and 27 genes for acetyltransferases. The possible functions of these four CYP71 candidates are extensively discussed. In addition, 116 transcription factors that are highly expressed in X. strumarium glandular trichomes were also identified. Their possible regulatory roles in the biosynthesis of STLs are discussed. The global transcriptomic data for X. strumarium should provide a valuable resource for further research into the biosynthesis of xanthanolides. PMID:27625674

Identification of (R)-selective ω-aminotransferases by exploring evolutionary sequence space.

PubMed

Kim, Eun-Mi; Park, Joon Ho; Kim, Byung-Gee; Seo, Joo-Hyun

2018-03-01

Several (R)-selective ω-aminotransferases (R-ωATs) have been reported. The existence of additional R-ωATs having different sequence characteristics from previous ones is highly expected. In addition, it is generally accepted that R-ωATs are variants of aminotransferase group III. Based on these backgrounds, sequences in RefSeq database were scored using family profiles of branched-chain amino acid aminotransferase (BCAT) and d-alanine aminotransferase (DAT) to predict and identify putative R-ωATs. Sequences with two profile analysis scores were plotted on two-dimensional score space. Candidates with relatively similar scores in both BCAT and DAT profiles (i.e., profile analysis score using BCAT profile was similar to profile analysis score using DAT profile) were selected. Experimental results for selected candidates showed that putative R-ωATs from Saccharopolyspora erythraea (R-ωAT_Sery), Bacillus cellulosilyticus (R-ωAT_Bcel), and Bacillus thuringiensis (R-ωAT_Bthu) had R-ωAT activity. Additional experiments revealed that R-ωAT_Sery also possessed DAT activity while R-ωAT_Bcel and R-ωAT_Bthu had BCAT activity. Selecting putative R-ωATs from regions with similar profile analysis scores identified potential R-ωATs. Therefore, R-ωATs could be efficiently identified by using simple family profile analysis and exploring evolutionary sequence space. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of Multiple Novel Protein Biomarkers Shed by Human Serous Ovarian Tumors into the Blood of Immunocompromised Mice and Verified in Patient Sera

PubMed Central

Beer, Lynn A.; Wang, Huan; Tang, Hsin-Yao; Cao, Zhijun; Chang-Wong, Tony; Tanyi, Janos L.; Zhang, Rugang; Liu, Qin; Speicher, David W.

2013-01-01

The most cancer-specific biomarkers in blood are likely to be proteins shed directly by the tumor rather than less specific inflammatory or other host responses. The use of xenograft mouse models together with in-depth proteome analysis for identification of human proteins in the mouse blood is an under-utilized strategy that can clearly identify proteins shed by the tumor. In the current study, 268 human proteins shed into mouse blood from human OVCAR-3 serous tumors were identified based upon human vs. mouse species differences using a four-dimensional plasma proteome fractionation strategy. A multi-step prioritization and verification strategy was subsequently developed to efficiently select some of the most promising biomarkers from this large number of candidates. A key step was parallel analysis of human proteins detected in the tumor supernatant, because substantially greater sequence coverage for many of the human proteins initially detected in the xenograft mouse plasma confirmed assignments as tumor-derived human proteins. Verification of candidate biomarkers in patient sera was facilitated by in-depth, label-free quantitative comparisons of serum pools from patients with ovarian cancer and benign ovarian tumors. The only proteins that advanced to multiple reaction monitoring (MRM) assay development were those that exhibited increases in ovarian cancer patients compared with benign tumor controls. MRM assays were facilely developed for all 11 novel biomarker candidates selected by this process and analysis of larger pools of patient sera suggested that all 11 proteins are promising candidate biomarkers that should be further evaluated on individual patient blood samples. PMID:23544127

Non-coding cancer driver candidates identified with a sample- and position-specific model of the somatic mutation rate

PubMed Central

Juul, Malene; Bertl, Johanna; Guo, Qianyun; Nielsen, Morten Muhlig; Świtnicki, Michał; Hornshøj, Henrik; Madsen, Tobias; Hobolth, Asger; Pedersen, Jakob Skou

2017-01-01

Non-coding mutations may drive cancer development. Statistical detection of non-coding driver regions is challenged by a varying mutation rate and uncertainty of functional impact. Here, we develop a statistically founded non-coding driver-detection method, ncdDetect, which includes sample-specific mutational signatures, long-range mutation rate variation, and position-specific impact measures. Using ncdDetect, we screened non-coding regulatory regions of protein-coding genes across a pan-cancer set of whole-genomes (n = 505), which top-ranked known drivers and identified new candidates. For individual candidates, presence of non-coding mutations associates with altered expression or decreased patient survival across an independent pan-cancer sample set (n = 5454). This includes an antigen-presenting gene (CD1A), where 5’UTR mutations correlate significantly with decreased survival in melanoma. Additionally, mutations in a base-excision-repair gene (SMUG1) correlate with a C-to-T mutational-signature. Overall, we find that a rich model of mutational heterogeneity facilitates non-coding driver identification and integrative analysis points to candidates of potential clinical relevance. DOI: http://dx.doi.org/10.7554/eLife.21778.001 PMID:28362259

Variable Neighborhood Search Heuristics for Selecting a Subset of Variables in Principal Component Analysis

ERIC Educational Resources Information Center

Brusco, Michael J.; Singh, Renu; Steinley, Douglas

2009-01-01

The selection of a subset of variables from a pool of candidates is an important problem in several areas of multivariate statistics. Within the context of principal component analysis (PCA), a number of authors have argued that subset selection is crucial for identifying those variables that are required for correct interpretation of the…

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

PubMed

Phelan, Catherine M; Kuchenbaecker, Karoline B; Tyrer, Jonathan P; Kar, Siddhartha P; Lawrenson, Kate; Winham, Stacey J; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie J; Chornokur, Ganna; Earp, Madalene A; Lyra, Paulo C; Lee, Janet M; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M; Aben, Katja K H; Adams, Marcia; Adlard, Julian; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N; Barjhoux, Laure; Barkardottir, Rosa B; Bean, Yukie; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q; Birrer, Michael J; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R; Brenton, James D; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Cannioto, Rikki; Carney, Michael E; Cescon, Terence; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Conner, Thomas; Cook, Linda S; Cook, Jackie; Cramer, Daniel W; Cunningham, Julie M; D'Aloisio, Aimee A; Daly, Mary B; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H; Engel, Christoph; Evans, D Gareth; Fasching, Peter A; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M; Fogarty, Zachary C; Fortner, Renée T; Fostira, Florentia; Foulkes, William D; Fountzilas, George; Fridley, Brooke L; Friebel, Tara M; Friedman, Eitan; Frost, Debra; Ganz, Patricia A; Garber, Judy; García, María J; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Goranova, Teodora; Gore, Martin; Greene, Mark H; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V O; Harrington, Patricia A; Harris, Holly R; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A T; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K; Høgdall, Estrid; Hogervorst, Frans B L; Holland, Helene; Hooning, Maartje J; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J; Hung, Jillian; Hunter, David J; Huntsman, David G; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Iversen, Edwin S; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M; Johnatty, Sharon; Jones, Michael E; Kannisto, Päivi; Karlan, Beth Y; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J; Khusnutdinova, Elza; Kiemeney, Lambertus A; Kiiski, Johanna I; Kim, Sung-Won; Kjaer, Susanne K; Köbel, Martin; Kopperud, Reidun K; Kruse, Torben A; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C; Lazaro, Conxi; Le, Nhu D; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H; Lubinński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F A G; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N; McGuire, Valerie; McLaughlin, John R; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R; Merritt, Melissa A; Milne, Roger L; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L; Nedergaard, Lotte; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I; Olsson, Håkan; Olswold, Curtis; O'Malley, David M; Ong, Kai-Ren; Onland-Moret, N Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L; Pedersen, Inge Søkilde; Peeters, Petra H M; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M; Permuth, Jennifer B; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C; Piskorz, Anna M; Poblete, Samantha R; Pocza, Timea; Poole, Elizabeth M; Poppe, Bruce; Porteous, Mary E; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Salvesen, Helga B; Sandler, Dale P; Schoemaker, Minouk J; Senter, Leigha; Setiawan, V Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E; Sieh, Weiva; Singer, Christian F; Sobol, Hagay; Song, Honglin; Southey, Melissa C; Spurdle, Amanda B; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J; Szabo, Csilla I; Szafron, Lukasz; Tan, Yen Y; Taylor, Jack A; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L; Tihomirova, Laima; Tinker, Anna V; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S; van Altena, Anne M; Van Den Berg, David; van der Hout, Annemarie H; van der Luijt, Rob B; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Vega, Ana; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M; Weinberg, Clarice R; Weitzel, Jeffrey N; Wentzensen, Nicolas; Whittemore, Alice S; Wijnen, Juul T; Wilkens, Lynne R; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K; Narod, Steven A; Easton, Douglas F; Amos, Christopher I; Schildkraut, Joellen M; Ramus, Susan J; Ottini, Laura; Goodman, Marc T; Park, Sue K; Kelemen, Linda E; Risch, Harvey A; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N; Couch, Fergus J; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L; Sellers, Thomas A; Gayther, Simon A; Antoniou, Antonis C; Pharoah, Paul D P

2017-05-01

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Reverse Nearest Neighbor Search on a Protein-Protein Interaction Network to Infer Protein-Disease Associations.

PubMed

Suratanee, Apichat; Plaimas, Kitiporn

2017-01-01

The associations between proteins and diseases are crucial information for investigating pathological mechanisms. However, the number of known and reliable protein-disease associations is quite small. In this study, an analysis framework to infer associations between proteins and diseases was developed based on a large data set of a human protein-protein interaction network integrating an effective network search, namely, the reverse k -nearest neighbor (R k NN) search. The R k NN search was used to identify an impact of a protein on other proteins. Then, associations between proteins and diseases were inferred statistically. The method using the R k NN search yielded a much higher precision than a random selection, standard nearest neighbor search, or when applying the method to a random protein-protein interaction network. All protein-disease pair candidates were verified by a literature search. Supporting evidence for 596 pairs was identified. In addition, cluster analysis of these candidates revealed 10 promising groups of diseases to be further investigated experimentally. This method can be used to identify novel associations to better understand complex relationships between proteins and diseases.

Unexpected identification of a recurrent mutation in the DLX3 gene causing amelogenesis imperfecta.

PubMed

Kim, Y-J; Seymen, F; Koruyucu, M; Kasimoglu, Y; Gencay, K; Shin, T J; Hyun, H-K; Lee, Z H; Kim, J-W

2016-05-01

To identify the molecular genetic aetiology of a family with autosomal dominant amelogenesis imperfecta (AI). DNA samples were collected from a six-generation family, and the candidate gene approach was used to screen for the enamelin (ENAM) gene. Whole-exome sequencing and linkage analysis with SNP array data identified linked regions, and candidate gene screening was performed. Mutational analysis revealed a mutation (c.561_562delCT and p.Tyr188Glnfs*13) in the DLX3 gene. After finding a recurrent DLX3 mutation, the clinical phenotype of the family members was re-examined. The proband's mother had pulp elongation in the third molars. The proband had not hair phenotype, but her cousin had curly hair at birth. In this study, we identified a recurrent 2-bp deletional DLX3 mutation in a new family. The clinical phenotype was the mildest one associated with the DLX3 mutations. These results will advance the understanding of the functional role of DLX3 in developmental processes. © 2016 The Authors. Oral Diseases Published by John Wiley & Sons Ltd.

A search for H/ACA snoRNAs in yeast using MFE secondary structure prediction.

PubMed

Edvardsson, Sverker; Gardner, Paul P; Poole, Anthony M; Hendy, Michael D; Penny, David; Moulton, Vincent

2003-05-01

Noncoding RNA genes produce functional RNA molecules rather than coding for proteins. One such family is the H/ACA snoRNAs. Unlike the related C/D snoRNAs these have resisted automated detection to date. We develop an algorithm to screen the yeast genome for novel H/ACA snoRNAs. To achieve this, we introduce some new methods for facilitating the search for noncoding RNAs in genomic sequences which are based on properties of predicted minimum free-energy (MFE) secondary structures. The algorithm has been implemented and can be generalized to enable screening of other eukaryote genomes. We find that use of primary sequence alone is insufficient for identifying novel H/ACA snoRNAs. Only the use of secondary structure filters reduces the number of candidates to a manageable size. From genomic context, we identify three strong H/ACA snoRNA candidates. These together with a further 47 candidates obtained by our analysis are being experimentally screened.

An integrative, translational approach to understanding rare and orphan genetically based diseases

PubMed Central

Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

2013-01-01

PhenomeNet is an approach for integrating phenotypes across species and identifying candidate genes for genetic diseases based on the similarity between a disease and animal model phenotypes. In contrast to ‘guilt-by-association’ approaches, PhenomeNet relies exclusively on the comparison of phenotypes to suggest candidate genes, and can, therefore, be applied to study the molecular basis of rare and orphan diseases for which the molecular basis is unknown. In addition to disease phenotypes from the Online Mendelian Inheritance in Man (OMIM) database, we have now integrated the clinical signs from Orphanet into PhenomeNet. We demonstrate that our approach can efficiently identify known candidate genes for genetic diseases in Orphanet and OMIM. Furthermore, we find evidence that mutations in the HIP1 gene might cause Bassoe syndrome, a rare disorder with unknown genetic aetiology. Our results demonstrate that integration and computational analysis of human disease and animal model phenotypes using PhenomeNet has the potential to reveal novel insights into the pathobiology underlying genetic diseases. PMID:23853703

Integrative analysis of gene expression and DNA methylation using unsupervised feature extraction for detecting candidate cancer biomarkers.

PubMed

Moon, Myungjin; Nakai, Kenta

2018-04-01

Currently, cancer biomarker discovery is one of the important research topics worldwide. In particular, detecting significant genes related to cancer is an important task for early diagnosis and treatment of cancer. Conventional studies mostly focus on genes that are differentially expressed in different states of cancer; however, noise in gene expression datasets and insufficient information in limited datasets impede precise analysis of novel candidate biomarkers. In this study, we propose an integrative analysis of gene expression and DNA methylation using normalization and unsupervised feature extractions to identify candidate biomarkers of cancer using renal cell carcinoma RNA-seq datasets. Gene expression and DNA methylation datasets are normalized by Box-Cox transformation and integrated into a one-dimensional dataset that retains the major characteristics of the original datasets by unsupervised feature extraction methods, and differentially expressed genes are selected from the integrated dataset. Use of the integrated dataset demonstrated improved performance as compared with conventional approaches that utilize gene expression or DNA methylation datasets alone. Validation based on the literature showed that a considerable number of top-ranked genes from the integrated dataset have known relationships with cancer, implying that novel candidate biomarkers can also be acquired from the proposed analysis method. Furthermore, we expect that the proposed method can be expanded for applications involving various types of multi-omics datasets.

Proteomic analysis of Brucella abortus cell envelope and identification of immunogenic candidate proteins for vaccine development.

PubMed

Connolly, Joseph P; Comerci, Diego; Alefantis, Timothy G; Walz, Alexander; Quan, Marian; Chafin, Ryan; Grewal, Paul; Mujer, Cesar V; Ugalde, Rodolfo A; DelVecchio, Vito G

2006-07-01

Brucella abortus is the etiologic agent of bovine brucellosis and causes a chronic disease in humans known as undulant fever. In livestock the disease is characterized by abortion and sterility. Live, attenuated vaccines such as S19 and RB51 have been used to control the spread of the disease in animals; however, they are considered unsafe for human use and they induce abortion in pregnant cattle. For the development of a safer and equally efficacious vaccine, immunoproteomics was utilized to identify novel candidate proteins from B. abortus cell envelope (CE). A total of 163 proteins were identified using 2-DE with MALDI-TOF MS and LC-MS/MS. Some of the major protein components include outer-membrane protein (OMP) 25, OMP31, Omp2b porin, and 60 kDa chaperonin GroEL. 2-DE Western blot analyses probed with antiserum from bovine and a human patient infected with Brucella identified several new immunogenic proteins such as fumarate reductase flavoprotein subunit, F0F1-type ATP synthase alpha subunit, and cysteine synthase A. The elucidation of the immunome of B. abortus CE identified a number of candidate proteins for developing vaccines against Brucella infection in bovine and humans.

Multi-breed and multi-trait co-association analysis of meat tenderness and other meat quality traits in three French beef cattle breeds.

PubMed

Ramayo-Caldas, Yuliaxis; Renand, Gilles; Ballester, Maria; Saintilan, Romain; Rocha, Dominique

2016-04-23

Studies to identify markers associated with beef tenderness have focused on Warner-Bratzler shear force (WBSF) but the interplay between the genes associated with WBSF has not been explored. We used the association weight matrix (AWM), a systems biology approach, to identify a set of interacting genes that are co-associated with tenderness and other meat quality traits, and shared across the Charolaise, Limousine and Blonde d'Aquitaine beef cattle breeds. Genome-wide association studies were performed using ~500K single nucleotide polymorphisms (SNPs) and 17 phenotypes measured on more than 1000 animals for each breed. First, this multi-trait approach was applied separately for each breed across 17 phenotypes and second, between- and across-breed comparisons at the AWM and functional levels were performed. Genetic heterogeneity was observed, and most of the variants that were associated with WBSF segregated within rather than across breeds. We identified 206 common candidate genes associated with WBSF across the three breeds. SNPs in these common genes explained between 28 and 30 % of the phenotypic variance for WBSF. A reduced number of common SNPs mapping to the 206 common genes were identified, suggesting that different mutations may target the same genes in a breed-specific manner. Therefore, it is likely that, depending on allele frequencies and linkage disequilibrium patterns, a SNP that is identified for one breed may not be informative for another unrelated breed. Well-known candidate genes affecting beef tenderness were identified. In addition, some of the 206 common genes are located within previously reported quantitative trait loci for WBSF in several cattle breeds. Moreover, the multi-breed co-association analysis detected new candidate genes, regulators and metabolic pathways that are likely involved in the determination of meat tenderness and other meat quality traits in beef cattle. Our results suggest that systems biology approaches that explore associations of correlated traits increase statistical power to identify candidate genes beyond the one-dimensional approach. Further studies on the 206 common genes, their pathways, regulators and interactions will expand our knowledge on the molecular basis of meat tenderness and could lead to the discovery of functional mutations useful for genomic selection in a multi-breed beef cattle context.

Academic performance of ethnic minority candidates and discrimination in the MRCGP examinations between 2010 and 2012: analysis of data.

PubMed

Esmail, Aneez; Roberts, Chris

2013-09-26

To determine the difference in failure rates in the postgraduate examination of the Royal College of General Practitioners (MRCGP) by ethnic or national background, and to identify factors associated with pass rates in the clinical skills assessment component of the examination. Analysis of data provided by the Royal College of General Practitioners and the General Medical Council. Cohort of 5095 candidates sitting the applied knowledge test and clinical skills assessment components of the MRCGP examination between November 2010 and November 2012. A further analysis was carried out on 1175 candidates not trained in the United Kingdom, who sat an English language capability test (IELTS) and the Professional and Linguistic Assessment Board (PLAB) examination (as required for full medical registration), controlling for scores on these examinations and relating them to pass rates of the clinical skills assessment. United Kingdom. After controlling for age, sex, and performance in the applied knowledge test, significant differences persisted between white UK graduates and other candidate groups. Black and minority ethnic graduates trained in the UK were more likely to fail the clinical skills assessment at their first attempt than their white UK colleagues (odds ratio 3.536 (95% confidence interval 2.701 to 4.629), P<0.001; failure rate 17% v 4.5%). Black and minority ethnic candidates who trained abroad were also more likely to fail the clinical skills assessment than white UK candidates (14.741 (11.397 to 19.065), P<0.001; 65% v 4.5%). For candidates not trained in the UK, black or minority ethnic candidates were more likely to fail than white candidates, but this difference was no longer significant after controlling for scores in the applied knowledge test, IELTS, and PLAB examinations (adjusted odds ratio 1.580 (95% confidence interval 0.878 to 2.845), P=0.127). Subjective bias due to racial discrimination in the clinical skills assessment may be a cause of failure for UK trained candidates and international medical graduates. The difference between British black and minority ethnic candidates and British white candidates in the pass rates of the clinical skills assessment, despite controlling for prior attainment, suggests that subjective bias could also be a factor. Changes to the clinical skills assessment could improve the perception of the examination as being biased against black and minority ethnic candidates. The difference in training experience and other cultural factors between candidates trained in the UK and abroad could affect outcomes. Consideration should be given to strengthening postgraduate training for international medical graduates.

Diet and Colorectal Cancer: Analysis of a Candidate Pathway Using SNPS, Haplotypes, and Multi-Gene Assessment

PubMed Central

Slattery, Martha L.; Lundgreen, Abbie; Herrick, Jennifer S.; Caan, Bette J.; Potter, John D.; Wolff, Roger K.

2012-01-01

There is considerable biologic plausibility to the hypothesis that genetic variability in pathways involved in insulin signaling and energy homeostasis may modulate dietary risk associated with colorectal cancer. We utilized data from 2 population-based case-control studies of colon (n = 1,574 cases, 1,970 controls) and rectal (n = 791 cases, 999 controls) cancer to evaluate genetic variation in candidate SNPs identified from 9 genes in a candidate pathway: PDK1, RP6KA1, RPS6KA2, RPS6KB1, RPS6KB2, PTEN, FRAP1 (mTOR), TSC1, TSC2, Akt1, PIK3CA, and PRKAG2 with dietary intake of total energy, carbohydrates, fat, and fiber. We employed SNP, haplotype, and multiple-gene analysis to evaluate associations. PDK1 interacted with dietary fat for both colon and rectal cancer and with dietary carbohydrates for colon cancer. Statistically significant interaction with dietary carbohydrates and rectal cancer was detected by haplotype analysis of PDK1. Evaluation of dietary interactions with multiple genes in this candidate pathway showed several interactions with pairs of genes: Akt1 and PDK1, PDK1 and PTEN, PDK1 and TSC1, and PRKAG2 and PTEN. Analyses show that genetic variation influences risk of colorectal cancer associated with diet and illustrate the importance of evaluating dietary interactions beyond the level of single SNPs or haplotypes when a biologically relevant candidate pathway is examined. PMID:21999454

Architecture of Kepler's multi-transiting systems. II. New investigations with twice as many candidates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fabrycky, Daniel C.; Lissauer, Jack J.; Rowe, Jason F.

We report on the orbital architectures of Kepler systems having multiple-planet candidates identified in the analysis of data from the first six quarters of Kepler data and reported by Batalha et al. (2013). These data show 899 transiting planet candidates in 365 multiple-planet systems and provide a powerful means to study the statistical properties of planetary systems. Using a generic mass-radius relationship, we find that only two pairs of planets in these candidate systems (out of 761 pairs total) appear to be on Hill-unstable orbits, indicating ∼96% of the candidate planetary systems are correctly interpreted as true systems. We findmore » that planet pairs show little statistical preference to be near mean-motion resonances. We identify an asymmetry in the distribution of period ratios near first-order resonances (e.g., 2:1, 3:2), with an excess of planet pairs lying wide of resonance and relatively few lying narrow of resonance. Finally, based upon the transit duration ratios of adjacent planets in each system, we find that the interior planet tends to have a smaller transit impact parameter than the exterior planet does. This finding suggests that the mode of the mutual inclinations of planetary orbital planes is in the range 1.°0-2.°2, for the packed systems of small planets probed by these observations.« less

Protein profiles associated with survival in lung adenocarcinoma

PubMed Central

Chen, Guoan; Gharib, Tarek G; Wang, Hong; Huang, Chiang-Ching; Kuick, Rork; Thomas, Dafydd G.; Shedden, Kerby A.; Misek, David E.; Taylor, Jeremy M. G.; Giordano, Thomas J.; Kardia, Sharon L. R.; Iannettoni, Mark D.; Yee, John; Hogg, Philip J.; Orringer, Mark B.; Hanash, Samir M.; Beer, David G.

2003-01-01

Morphologic assessment of lung tumors is informative but insufficient to adequately predict patient outcome. We previously identified transcriptional profiles that predict patient survival, and here we identify proteins associated with patient survival in lung adenocarcinoma. A total of 682 individual protein spots were quantified in 90 lung adenocarcinomas by using quantitative two-dimensional polyacrylamide gel electrophoresis analysis. A leave-one-out cross-validation procedure using the top 20 survival-associated proteins identified by Cox modeling indicated that protein profiles as a whole can predict survival in stage I tumor patients (P = 0.01). Thirty-three of 46 survival-associated proteins were identified by using mass spectrometry. Expression of 12 candidate proteins was confirmed as tumor-derived with immunohistochemical analysis and tissue microarrays. Oligonucleotide microarray results from both the same tumors and from an independent study showed mRNAs associated with survival for 11 of 27 encoded genes. Combined analysis of protein and mRNA data revealed 11 components of the glycolysis pathway as associated with poor survival. Among these candidates, phosphoglycerate kinase 1 was associated with survival in the protein study, in both mRNA studies and in an independent validation set of 117 adenocarcinomas and squamous lung tumors using tissue microarrays. Elevated levels of phosphoglycerate kinase 1 in the serum were also significantly correlated with poor outcome in a validation set of 107 patients with lung adenocarcinomas using ELISA analysis. These studies identify new prognostic biomarkers and indicate that protein expression profiles can predict the outcome of patients with early-stage lung cancer. PMID:14573703

Analysis of PGY-1 Pharmacy Resident Candidate Letters of Recommendation at an Academically Affiliated Residency Program.

PubMed

McLaughlin, Milena M; Masic, Dalila; Gettig, Jacob P

2018-04-01

Letters of recommendation (LORs) are a critical component for differentiating among similarly qualified pharmacy residency candidates. These letters contain information that is difficult to ascertain from curricula vitae and pharmacy school transcripts. LOR writers may use any words or phrases appropriate for each candidate as there is no set framework for LORs. The objective of this study was to characterize descriptive themes in postgraduate year 1 (PGY-1) pharmacy residency candidates' LORs and to examine which themes of PGY-1 pharmacy residency candidates' LORs are predictive of an interview invitation at an academically affiliated residency program. LORs for candidates from the Pharmacy Online Residency Centralized Application System (PhORCAS) from 2013 and 2014 for the Midwestern University PGY-1 Pharmacy Residency were analyzed. LOR characteristics and descriptive themes were collected. All scores for candidate characteristics and overall PhORCAS recommendation were also recorded. A total of 351 LORs for 111 candidates from 2013 (n = 47 candidates) and 2014 (n = 64 candidates) were analyzed; 36 (32.4%) total candidates were offered an interview. Themes that were identified as predictors of an interview included a higher median (interquartile range) number of standout words (3 words [1.3-4] vs 3.8 words [2.5-5.5], P < .01) and teaching references (3.7 words [2.7-6] vs 5.7 words [3.7-7.8], P = .01). For this residency program, standout words and teaching references were important when offering interviews.

Identification of a duplication within the GDF9 gene and novel candidate genes for primary ovarian insufficiency (POI) by a customized high-resolution array comparative genomic hybridization platform.

PubMed

Norling, A; Hirschberg, A L; Rodriguez-Wallberg, K A; Iwarsson, E; Wedell, A; Barbaro, M

2014-08-01

Can high-resolution array comparative genomic hybridization (CGH) analysis of DNA samples from women with primary ovarian insufficiency (POI) improve the diagnosis of the condition and identify novel candidate genes for POI? A mutation affecting the regulatory region of growth differentiation factor 9 (GDF9) was identified for the first time together with several novel candidate genes for POI. Most patients with POI do not receive a molecular diagnosis despite a significant genetic component in the pathogenesis. We performed a case-control study. Twenty-six patients were analyzed by array CGH for identification of copy number variants. Novel changes were investigated in 95 controls and in a separate population of 28 additional patients with POI. The experimental procedures were performed during a 1-year period. DNA samples from 26 patients with POI were analyzed by a customized 1M array-CGH platform with whole genome coverage and probe enrichment targeting 78 genes in sex development. By PCR amplification and sequencing, the breakpoint of an identified partial GDF9 gene duplication was characterized. A multiplex ligation-dependent probe amplification (MLPA) probe set for specific identification of deletions/duplications affecting GDF9 was developed. An MLPA probe set for the identification of additional cases or controls carrying novel candidate regions identified by array-CGH was developed. Sequencing of three candidate genes was performed. Eleven unique copy number changes were identified in a total of 11 patients, including a tandem duplication of 475 bp, containing part of the GDF9 gene promoter region. The duplicated region contains three NOBOX-binding elements and an E-box, important for GDF9 gene regulation. This aberration is likely causative of POI. Fifty-four patients were investigated for copy number changes within GDF9, but no additional cases were found. Ten aberrations constituting novel candidate regions were detected, including a second DNAH6 deletion in a patient with POI. Other identified candidate genes were TSPYL6, SMARCC1, CSPG5 and ZFR2. This is a descriptive study and no functional experiments were performed. The study illustrates the importance of analyzing small copy number changes in addition to sequence alterations in the genetic investigation of patients with POI. Also, promoter regions should be included in the investigation. The study was supported by grants from the Swedish Research council (project no 12198 to A.W. and project no 20324 to A.L.H.), Stockholm County Council (E.I., A.W. and K.R.W.), Foundation Frimurare Barnhuset (A.N., A.W. and M.B.), Karolinska Institutet (A.N., A.L.H., E.I., A.W. and M.B.), Novo Nordic Foundation (A.W.) and Svenska Läkaresällskapet (M.B.). The funding sources had no involvement in the design or analysis of the study. The authors have no competing interests to declare. Not applicable. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Indel-seq: a fast-forward genetics approach for identification of trait-associated putative candidate genomic regions and its application in pigeonpea (Cajanus cajan).

PubMed

Singh, Vikas K; Khan, Aamir W; Saxena, Rachit K; Sinha, Pallavi; Kale, Sandip M; Parupalli, Swathi; Kumar, Vinay; Chitikineni, Annapurna; Vechalapu, Suryanarayana; Sameer Kumar, Chanda Venkata; Sharma, Mamta; Ghanta, Anuradha; Yamini, Kalinati Narasimhan; Muniswamy, Sonnappa; Varshney, Rajeev K

2017-07-01

Identification of candidate genomic regions associated with target traits using conventional mapping methods is challenging and time-consuming. In recent years, a number of single nucleotide polymorphism (SNP)-based mapping approaches have been developed and used for identification of candidate/putative genomic regions. However, in the majority of these studies, insertion-deletion (Indel) were largely ignored. For efficient use of Indels in mapping target traits, we propose Indel-seq approach, which is a combination of whole-genome resequencing (WGRS) and bulked segregant analysis (BSA) and relies on the Indel frequencies in extreme bulks. Deployment of Indel-seq approach for identification of candidate genomic regions associated with fusarium wilt (FW) and sterility mosaic disease (SMD) resistance in pigeonpea has identified 16 Indels affecting 26 putative candidate genes. Of these 26 affected putative candidate genes, 24 genes showed effect in the upstream/downstream of the genic region and two genes showed effect in the genes. Validation of these 16 candidate Indels in other FW- and SMD-resistant and FW- and SMD-susceptible genotypes revealed a significant association of five Indels (three for FW and two for SMD resistance). Comparative analysis of Indel-seq with other genetic mapping approaches highlighted the importance of the approach in identification of significant genomic regions associated with target traits. Therefore, the Indel-seq approach can be used for quick and precise identification of candidate genomic regions for any target traits in any crop species. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Power line identification of millimeter wave radar based on PCA-GS-SVM

NASA Astrophysics Data System (ADS)

Fang, Fang; Zhang, Guifeng; Cheng, Yansheng

2017-12-01

Aiming at the problem that the existing detection method can not effectively solve the security of UAV's ultra low altitude flight caused by power line, a power line recognition method based on grid search (GS) and the principal component analysis and support vector machine (PCA-SVM) is proposed. Firstly, the candidate line of Hough transform is reduced by PCA, and the main feature of candidate line is extracted. Then, upport vector machine (SVM is) optimized by grid search method (GS). Finally, using support vector machine classifier optimized parameters to classify the candidate line. MATLAB simulation results show that this method can effectively identify the power line and noise, and has high recognition accuracy and algorithm efficiency.

Transcriptome sequencing analysis of novel sRNAs of Kineococcus radiotolerans in response to ionizing radiation.

PubMed

Chen, Zhouwei; Li, Lufeng; Shan, Zhan; Huang, Hannian; Chen, Huan; Ding, Xianfeng; Guo, Jiangfeng; Liu, Lili

2016-11-01

Kineococcus radiotolerans is a Gram-positive, radio-resistant bacterium isolated from a radioactive environment. The small noncoding RNAs (sRNAs) in bacteria are reported to play roles in the immediate response to stress and/or the recovery from stress. The analysis of K. radiotolerans transcriptome sequencing results can identify these sRNAs in a genome-wide detection, using RNA sequencing (RNA-seq) by the deep sequencing technique. In this study, the raw data of radiation-exposed samples (RS) and control samples (CS) were acquired separately from the sequencing platform. There were 217 common sRNA candidates in the two samples screened in the genome-wide scale by bioinformatics analysis. There were 43 differentially expressed sRNA candidates, including 28 up-regulated and 15 down-regulated ones. The down-regulated sRNAs were selected for the sRNA target prediction, of which 12 sRNAs that may modulate the genes related to the transcription regulation and DNA repair were considered as the candidates involved in the radio-resistance regulation system. Copyright © 2016 Elsevier GmbH. All rights reserved.

M Dwarfs From The SDSS, 2MASS and WISE Surveys: Identification, Characterisation and Unresolved Ultracool Companionship

NASA Astrophysics Data System (ADS)

Cook, Neil James

2016-08-01

The aim of this thesis is to use a cross-match between WISE, 2MASS and SDSS to identify a large sample of M dwarfs. Through the careful characterisation and quality control of these M dwarfs I aim to identify rare systems (i.e. unresolved UCD companions, young M dwarfs, late M dwarfs and M dwarfs with common proper motion companions). Locating ultracool companions to M dwarfs is important for constraining low-mass formation models, the measurement of substellar dynamical masses and radii, and for testing ultracool evolutionary models. This is done by using an optimised method for identifying M dwarfs which may have unresolved ultracool companions. To do this I construct a catalogue of 440 694 M dwarf candidates, from WISE, 2MASS and SDSS, based on optical- and near-infrared colours and reduced proper motion. With strict reddening, photometric and quality constraints I isolate a sub-sample of 36 898 M dwarfs and search for possible mid-infrared M dwarf + ultracool dwarf candidates by comparing M dwarfs which have similar optical/near-infrared colours (chosen for their sensitivity to effective temperature and metallicity). I present 1 082 M dwarf + ultracool dwarf candidates for follow-up. Using simulated ultracool dwarf companions to M dwarfs, I estimate that the occurrence of unresolved ultracool companions amongst my M dwarf + ultracool dwarf candidates should be at least four times the average for my full M dwarf catalogue. I discuss yields of candidates based on my simulations. The possible contamination and bias from misidentified M dwarfs is then discussed, from chance alignments with other M dwarfs and UCDs, from chance alignments with giant stars, from chance alignments with galaxies, and from blended systems (via visual inspection). I then use optical spectra from LAMOST to spectral type a subset of my M dwarf + ultracool dwarf candidates. These candidates need confirming as true M dwarf + ultracool dwarf systems thus I present a new method I developed to use low resolution near-infrared spectra which relies on two colour similar objects (one an excess candidate, one not) having very similar spectra. A spectral difference of these two colour similar objects should leave the signature of a UCD in the residual of their differences, which I look for using the difference in two spectral bands designed to identify UCD spectral features. I then present the methods used to identify other rare systems from my full M dwarf catalogue. Young M dwarfs were identified by measuring equivalent widths of Hα from the LAMOST spectra, and by measuring rotation periods from Kepler 2 light curves. I identify late M dwarfs photometrically (using reduced proper motion and colour cuts) and spectroscopically (using the LAMOST spectra with spectral indices from the literature). Also I present common proper motion analysis aimed at finding Tycho-2 primaries for my M dwarfs and look for physically separated M dwarf + M dwarf pairs (internally within my full M dwarf catalogue).

Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

PubMed Central

2011-01-01

Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction. PMID:21999673

Evaluation of candidate geomagnetic field models for IGRF-11

NASA Astrophysics Data System (ADS)

Finlay, C. C.; Maus, S.; Beggan, C. D.; Hamoudi, M.; Lowes, F. J.; Olsen, N.; Thébault, E.

2010-10-01

The eleventh generation of the International Geomagnetic Reference Field (IGRF) was agreed in December 2009 by a task force appointed by the International Association of Geomagnetism and Aeronomy (IAGA) Division V Working Group V-MOD. New spherical harmonic main field models for epochs 2005.0 (DGRF-2005) and 2010.0 (IGRF-2010), and predictive linear secular variation for the interval 2010.0-2015.0 (SV-2010-2015) were derived from weighted averages of candidate models submitted by teams led by DTU Space, Denmark (team A); NOAA/NGDC, U.S.A. (team B); BGS, U.K. (team C); IZMIRAN, Russia (team D); EOST, France (team E); IPGP, France (team F); GFZ, Germany (team G) and NASA-GSFC, U.S.A. (team H). Here, we report the evaluations of candidate models carried out by the IGRF-11 task force during October/November 2009 and describe the weightings used to derive the new IGRF-11 model. The evaluations include calculations of root mean square vector field differences between the candidates, comparisons of the power spectra, and degree correlations between the candidates and a mean model. Coefficient by coefficient analysis including determination of weighting factors used in a robust estimation of mean coefficients is also reported. Maps of differences in the vertical field intensity at Earth's surface between the candidates and weighted mean models are presented. Candidates with anomalous aspects are identified and efforts made to pinpoint both troublesome coefficients and geographical regions where large variations between candidates originate. A retrospective analysis of IGRF-10 main field candidates for epoch 2005.0 and predictive secular variation candidates for 2005.0-2010.0 using the new IGRF-11 models as a reference is also reported. The high quality and consistency of main field models derived using vector satellite data is demonstrated; based on internal consistency DGRF-2005 has a formal root mean square vector field error over Earth's surface of 1.0 nT. Difficulties nevertheless remain in accurately forecasting field evolution only five years into the future.

Candidate Evaluation Using Targeted Construct Assessment in the Multiple Mini-Interview: A Multifaceted Rasch Model Analysis.

PubMed

McLaughlin, Jacqueline E; Singer, David; Cox, Wendy C

2017-01-01

Construct: A 7-station multiple mini-interview (MMI) circuit was implemented and assessed for 214 candidates rated by 37 interviewers (N = 1,498 ratings). The MMI stations were designed to assess 6 specific constructs (adaptability, empathy, integrity, critical thinking, teamwork [receiving instruction], teamwork [giving instruction]) and one open station about the candidate's interest in the school. Despite the apparent benefits of the MMI, construct-irrelevant variance continues to be a topic of study. Refining the MMI to more effectively measure candidate ability is critical to improving our ability to identify and select candidates that are equipped for success within health professions education and the workforce. Each station assessed a single construct and was rated by a single interviewer who was provided only the name of the candidate and no additional information about the candidate's background, application, or prior academic performance. All interviewers received online and in-person training in the fall prior to the MMI and the morning of the MMI. A 3-facet multifaceted Rasch measurement analysis was completed to determine interviewer severity, candidate ability, and MMI station difficulty and examine how the model performed overall (e.g., rating scale). Altogether, the Rasch measures explained 62.84% of the variance in the ratings. Differences in candidate ability explained 45.28% of the variance in the data, whereas differences in interviewer severity explained 16.09% of the variance in the data. None of the interviewers had Infit or Outfit mean-square scores greater than 1.7, and only 2 (5.4%) had mean-square scores less than 0.5. The data demonstrated acceptable fit to the multifaceted Rasch measurement model. This work is the first of its kind in pharmacy and provides insight into the development of an MMI that provides useful and meaningful candidate assessment ratings for institutional decision making.

Identification of MicroRNAs in Helicoverpa armigera and Spodoptera litura Based on Deep Sequencing and Homology Analysis

PubMed Central

Ge, Xie; Zhang, Yong; Jiang, Jianhao; Zhong, Yi; Yang, Xiaonan; Li, Zhiqian; Huang, Yongping; Tan, Anjiang

2013-01-01

The current identification of microRNAs (miRNAs) in insects is largely dependent on genome sequences. However, the lack of available genome sequences inhibits the identification of miRNAs in various insect species. In this study, we used a miRNA database of the silkworm Bombyx mori as a reference to identify miRNAs in Helicoverpa armigera and Spodoptera litura using deep sequencing and homology analysis. Because all three species belong to the Lepidoptera, the experiment produced reliable results. Our study identified 97 and 91 conserved miRNAs in H. armigera and S. litura, respectively. Using the genome of B. mori and BAC sequences of H. armigera as references, 1 novel miRNA and 8 novel miRNA candidates were identified in H. armigera, and 4 novel miRNA candidates were identified in S. litura. An evolutionary analysis revealed that most of the identified miRNAs were insect-specific, and more than 20 miRNAs were Lepidoptera-specific. The investigation of the expression patterns of miR-2a, miR-34, miR-2796-3p and miR-11 revealed their potential roles in insect development. miRNA target prediction revealed that conserved miRNA target sites exist in various genes in the 3 species. Conserved miRNA target sites for the Hsp90 gene among the 3 species were validated in the mammalian 293T cell line using a dual-luciferase reporter assay. Our study provides a new approach with which to identify miRNAs in insects lacking genome information and contributes to the functional analysis of insect miRNAs. PMID:23289012

Identifying potential selective fluorescent probes for cancer-associated protein carbonic anhydrase IX using a computational approach.

PubMed

Kamstra, Rhiannon L; Floriano, Wely B

2014-11-01

Carbonic anhydrase IX (CAIX) is a biomarker for tumor hypoxia. Fluorescent inhibitors of CAIX have been used to study hypoxic tumor cell lines. However, these inhibitor-based fluorescent probes may have a therapeutic effect that is not appropriate for monitoring treatment efficacy. In the search for novel fluorescent probes that are not based on known inhibitors, a database of 20,860 fluorescent compounds was virtually screened against CAIX using hierarchical virtual ligand screening (HierVLS). The screening database contained 14,862 compounds tagged with the ATTO680 fluorophore plus an additional 5998 intrinsically fluorescent compounds. Overall ranking of compounds to identify hit molecular probe candidates utilized a principal component analysis (PCA) approach. Four potential binding sites, including the catalytic site, were identified within the structure of the protein and targeted for virtual screening. Available sequence information for 23 carbonic anhydrase isoforms was used to prioritize the four sites based on the estimated "uniqueness" of each site in CAIX relative to the other isoforms. A database of 32 known inhibitors and 478 decoy compounds was used to validate the methodology. A receiver-operating characteristic (ROC) analysis using the first principal component (PC1) as predictive score for the validation database yielded an area under the curve (AUC) of 0.92. AUC is interpreted as the probability that a binder will have a better score than a non-binder. The use of first component analysis of binding energies for multiple sites is a novel approach for hit selection. The very high prediction power for this approach increases confidence in the outcome from the fluorescent library screening. Ten of the top scoring candidates for isoform-selective putative binding sites are suggested for future testing as fluorescent molecular probe candidates. Copyright © 2014 Elsevier Inc. All rights reserved.

Genome-Wide Association Studies of 11 Agronomic Traits in Cassava (Manihot esculenta Crantz)

PubMed Central

Zhang, Shengkui; Chen, Xin; Lu, Cheng; Ye, Jianqiu; Zou, Meiling; Lu, Kundian; Feng, Subin; Pei, Jinli; Liu, Chen; Zhou, Xincheng; Ma, Ping’an; Li, Zhaogui; Liu, Cuijuan; Liao, Qi; Xia, Zhiqiang; Wang, Wenquan

2018-01-01

Cassava (Manihot esculenta Crantz) is a major tuberous crop produced worldwide. In this study, we sequenced 158 diverse cassava varieties and identified 349,827 single-nucleotide polymorphisms (SNPs) and indels. In each chromosome, the number of SNPs and the physical length of the respective chromosome were in agreement. Population structure analysis indicated that this panel can be divided into three subgroups. Genetic diversity analysis indicated that the average nucleotide diversity of the panel was 1.21 × 10-4 for all sampled landraces. This average nucleotide diversity was 1.97 × 10-4, 1.01 × 10-4, and 1.89 × 10-4 for subgroups 1, 2, and 3, respectively. Genome-wide linkage disequilibrium (LD) analysis demonstrated that the average LD was about ∼8 kb. We evaluated 158 cassava varieties under 11 different environments. Finally, we identified 36 loci that were related to 11 agronomic traits by genome-wide association analyses. Four loci were associated with two traits, and 62 candidate genes were identified in the peak SNP sites. We found that 40 of these genes showed different expression profiles in different tissues. Of the candidate genes related to storage roots, Manes.13G023300, Manes.16G000800, Manes.02G154700, Manes.02G192500, and Manes.09G099100 had higher expression levels in storage roots than in leaf and stem; on the other hand, of the candidate genes related to leaves, Manes.05G164500, Manes.05G164600, Manes.04G057300, Manes.01G202000, and Manes.03G186500 had higher expression levels in leaves than in storage roots and stem. This study provides basis for research on genetics and the genetic improvement of cassava. PMID:29725343

Genome-Wide Association Studies of 11 Agronomic Traits in Cassava (Manihot esculenta Crantz).

PubMed

Zhang, Shengkui; Chen, Xin; Lu, Cheng; Ye, Jianqiu; Zou, Meiling; Lu, Kundian; Feng, Subin; Pei, Jinli; Liu, Chen; Zhou, Xincheng; Ma, Ping'an; Li, Zhaogui; Liu, Cuijuan; Liao, Qi; Xia, Zhiqiang; Wang, Wenquan

2018-01-01

Cassava ( Manihot esculenta Crantz) is a major tuberous crop produced worldwide. In this study, we sequenced 158 diverse cassava varieties and identified 349,827 single-nucleotide polymorphisms (SNPs) and indels. In each chromosome, the number of SNPs and the physical length of the respective chromosome were in agreement. Population structure analysis indicated that this panel can be divided into three subgroups. Genetic diversity analysis indicated that the average nucleotide diversity of the panel was 1.21 × 10 -4 for all sampled landraces. This average nucleotide diversity was 1.97 × 10 -4 , 1.01 × 10 -4 , and 1.89 × 10 -4 for subgroups 1, 2, and 3, respectively. Genome-wide linkage disequilibrium (LD) analysis demonstrated that the average LD was about ∼8 kb. We evaluated 158 cassava varieties under 11 different environments. Finally, we identified 36 loci that were related to 11 agronomic traits by genome-wide association analyses. Four loci were associated with two traits, and 62 candidate genes were identified in the peak SNP sites. We found that 40 of these genes showed different expression profiles in different tissues. Of the candidate genes related to storage roots, Manes.13G023300, Manes.16G000800, Manes.02G154700, Manes.02G192500, and Manes.09G099100 had higher expression levels in storage roots than in leaf and stem; on the other hand, of the candidate genes related to leaves, Manes.05G164500, Manes.05G164600, Manes.04G057300, Manes.01G202000, and Manes.03G186500 had higher expression levels in leaves than in storage roots and stem. This study provides basis for research on genetics and the genetic improvement of cassava.

Molecular dysexpression in gastric cancer revealed by integrated analysis of transcriptome data.

PubMed

Li, Xiaomei; Dong, Weiwei; Qu, Xueling; Zhao, Huixia; Wang, Shuo; Hao, Yixin; Li, Qiuwen; Zhu, Jianhua; Ye, Min; Xiao, Wenhua

2017-05-01

Gastric cancer (GC) is often diagnosed in the advanced stages and is associated with a poor prognosis. Obtaining an in depth understanding of the molecular mechanisms of GC has lagged behind compared with other cancers. This study aimed to identify candidate biomarkers for GC. An integrated analysis of microarray datasets was performed to identify differentially expressed genes (DEGs) between GC and normal tissues. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then performed to identify the functions of the DEGs. Furthermore, a protein-protein interaction (PPI) network of the DEGs was constructed. The expression levels of the DEGs were validated in human GC tissues using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A set of 689 DEGs were identified in GC tissues, as compared with normal tissues, including 202 upregulated DEGs and 487 downregulated DEGs. The KEGG pathway analysis suggested that various pathways may play important roles in the pathology of GC, including pathways related to protein digestion and absorption, extracellular matrix-receptor interaction, and the metabolism of xenobiotics by cytochrome P450. The PPI network analysis indicated that the significant hub proteins consisted of SPP1, TOP2A and ARPC1B. RT-qPCR validation indicated that the expression levels of the top 10 most significantly dysexpressed genes were consistent with the illustration of the integrated analysis. The present study yielded a reference list of reliable DEGs, which represents a robust pool of candidates for further evaluation of GC pathogenesis and treatment.

COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration.

PubMed

Southey, Melissa C; Park, Daniel J; Nguyen-Dumont, Tu; Campbell, Ian; Thompson, Ella; Trainer, Alison H; Chenevix-Trench, Georgia; Simard, Jacques; Dumont, Martine; Soucy, Penny; Thomassen, Mads; Jønson, Lars; Pedersen, Inge S; Hansen, Thomas Vo; Nevanlinna, Heli; Khan, Sofia; Sinilnikova, Olga; Mazoyer, Sylvie; Lesueur, Fabienne; Damiola, Francesca; Schmutzler, Rita; Meindl, Alfons; Hahnen, Eric; Dufault, Michael R; Chris Chan, Tl; Kwong, Ava; Barkardóttir, Rosa; Radice, Paolo; Peterlongo, Paolo; Devilee, Peter; Hilbers, Florentine; Benitez, Javier; Kvist, Anders; Törngren, Therese; Easton, Douglas; Hunter, David; Lindstrom, Sara; Kraft, Peter; Zheng, Wei; Gao, Yu-Tang; Long, Jirong; Ramus, Susan; Feng, Bing-Jian; Weitzel, Jeffrey N; Nathanson, Katherine; Offit, Kenneth; Joseph, Vijai; Robson, Mark; Schrader, Kasmintan; Wang, San; Kim, Yeong C; Lynch, Henry; Snyder, Carrie; Tavtigian, Sean; Neuhausen, Susan; Couch, Fergus J; Goldgar, David E

2013-06-21

Linkage analysis, positional cloning, candidate gene mutation scanning and genome-wide association study approaches have all contributed significantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identified genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered.

Exploring Valid Reference Genes for Quantitative Real-time PCR Analysis in Plutella xylostella (Lepidoptera: Plutellidae)

PubMed Central

Fu, Wei; Xie, Wen; Zhang, Zhuo; Wang, Shaoli; Wu, Qingjun; Liu, Yong; Zhou, Xiaomao; Zhou, Xuguo; Zhang, Youjun

2013-01-01

Abstract: Quantitative real-time PCR (qRT-PCR), a primary tool in gene expression analysis, requires an appropriate normalization strategy to control for variation among samples. The best option is to compare the mRNA level of a target gene with that of reference gene(s) whose expression level is stable across various experimental conditions. In this study, expression profiles of eight candidate reference genes from the diamondback moth, Plutella xylostella, were evaluated under diverse experimental conditions. RefFinder, a web-based analysis tool, integrates four major computational programs including geNorm, Normfinder, BestKeeper, and the comparative ΔCt method to comprehensively rank the tested candidate genes. Elongation factor 1 (EF1) was the most suited reference gene for the biotic factors (development stage, tissue, and strain). In contrast, although appropriate reference gene(s) do exist for several abiotic factors (temperature, photoperiod, insecticide, and mechanical injury), we were not able to identify a single universal reference gene. Nevertheless, a suite of candidate reference genes were specifically recommended for selected experimental conditions. Our finding is the first step toward establishing a standardized qRT-PCR analysis of this agriculturally important insect pest. PMID:23983612

Serum-circulating miRNAs predict neuroblastoma progression in mouse model of high-risk metastatic disease.

PubMed

Ramraj, Satish Kumar; Aravindan, Sheeja; Somasundaram, Dinesh Babu; Herman, Terence S; Natarajan, Mohan; Aravindan, Natarajan

2016-04-05

Circulating miRNAs have momentous clinical relevance as prognostic biomarkers and in the progression of solid tumors. Recognizing novel candidates of neuroblastoma-specific circulating miRNAs would allow us to identify potential prognostic biomarkers that could predict the switch from favorable to high-risk metastatic neuroblastoma (HR-NB). Utilizing mouse models of favorable and HR-NB and whole miRnome profiling, we identified high serum levels of 34 and low levels of 46 miRNAs in animals with HR-NB. Preferential sequence homology exclusion of mouse miRNAs identified 25 (11 increased; 14 decreased) human-specific prognostic marker candidates, of which, 21 were unique to HR-NB. miRNA QPCR validated miRnome profile. Target analysis defined the candidate miRNAs' signal transduction flow-through and demonstrated their converged roles in tumor progression. miRNA silencing studies verified the function of select miRNAs on the translation of at least 14 target proteins. Expressions of critical targets that correlate tumor progression in tissue of multifarious organs identify the orchestration of HR-NB. Significant (>10 fold) increase in serum levels of miR-381, miR-548h, and miR-580 identify them as potential prognostic markers for neuroblastoma progression. For the first time, we identified serum-circulating miRNAs that predict the switch from favorable to HR-NB and, further imply that these miRNAs could play a functional role in tumor progression.

Antennal transcriptome analysis of the piercing moth Oraesia emarginata (Lepidoptera: Noctuidae)

PubMed Central

Feng, Bo; Guo, Qianshuang; Zheng, Kaidi; Qin, Yuanxia; Du, Yongjun

2017-01-01

The piercing fruit moth Oraesia emarginata is an economically significant pest; however, our understanding of its olfactory mechanisms in infestation is limited. The present study conducted antennal transcriptome analysis of olfactory genes using real-time quantitative reverse transcription PCR analysis (RT-qPCR). We identified a total of 104 candidate chemosensory genes from several gene families, including 35 olfactory receptors (ORs), 41 odorant-binding proteins, 20 chemosensory proteins, 6 ionotropic receptors, and 2 sensory neuron membrane proteins. Seven candidate pheromone receptors (PRs) and 3 candidate pheromone-binding proteins (PBPs) for sex pheromone recognition were found. OemaOR29 and OemaPBP1 had the highest fragments per kb per million fragments (FPKM) values in all ORs and OBPs, respectively. Eighteen olfactory genes were upregulated in females, including 5 candidate PRs, and 20 olfactory genes were upregulated in males, including 2 candidate PRs (OemaOR29 and 4) and 2 PBPs (OemaPBP1 and 3). These genes may have roles in mediating sex-specific behaviors. Most candidate olfactory genes of sex pheromone recognition (except OemaOR29 and OemaPBP3) in O. emarginata were not clustered with those of studied noctuid species (type I pheromone). In addition, OemaOR29 was belonged to cluster PRIII, which comprise proteins that recognize type II pheromones instead of type I pheromones. The structure and function of olfactory genes that encode sex pheromones in O. emarginata might thus differ from those of other studied noctuids. The findings of the present study may help explain the molecular mechanism underlying olfaction and the evolution of olfactory genes encoding sex pheromones in O. emarginata. PMID:28614384

Fusible heat sink materials - An identification of alternate candidates. [for astronaut thermoregulation in EVA portable life support systems

NASA Technical Reports Server (NTRS)

Selvaduray, Guna; Lomax, Curtis

1991-01-01

Fusible heat sinks are a possible source for thermal regulation of space suited astronauts. An extensive database search was undertaken to identify candidate materials with liquid solid transformations over the temperature range of -18 C to 5 C; and 1215 candidates were identified. Based on available data, 59 candidate materials with thermal storage capability, DeltaH values higher than that of water were identified. This paper presents the methodology utilized in the study, including the decision process used for materials selection.

Identification of QTL with large effect on seed weight in a selective population of soybean with genome-wide association and fixation index analyses

USDA-ARS?s Scientific Manuscript database

Our objective was to identify candidate QTL that had a large effect on seed weight using a selective population through GWAS and fixation index analysis. A selective population was previously used for the identification of QTL in linkage analysis of bi-parental RIL populations in plant species, but ...

Identification of parental line specific effects of MLF2 on resistance to coccidiosis in chickens

PubMed Central

2011-01-01

Background MLF2 was the candidate gene associated with coccidiosis resistance in chickens. Although single marker analysis supported the association between MLF2 and coccidiosis resistance, causative mutation relevant to coccidiosis was not identified yet. Thus, this study suggested segregation analysis of MLF2 haplotype and the association test of the other candidate genes using improved data transformation. Results A haplotype probably originated from one parental line was found out of 4 major haplotypes of MLF2. Frequency of this haplotype was 0.2 in parental chickens and its offspring in 12 families. Allele substitution effect of the MLF2 haplotype originated from a specific line was associated with increased body weight and fecal egg count explaining coccidiosis resistance. Nevertheless Box-Cox transformation was able to improve normality; association test did not produce obvious different results compared with analysis with log transformed phenotype. Conclusion Allele substitution effect analysis and classification of MLF2 haplotype identified the segregation of haplotype associated with coccidiosis resistance. The haplotype originated from a specific parental line was associated with improving disease resistance. Estimating effect of MLF2 haplotype on coccidiosis resistance will provide useful information for selecting animals or lines for future study. PMID:21645301

Identification and Evolutionary Analysis of Potential Candidate Genes in a Human Eating Disorder.

PubMed

Sabbagh, Ubadah; Mullegama, Saman; Wyckoff, Gerald J

2016-01-01

The purpose of this study was to find genes linked with eating disorders and associated with both metabolic and neural systems. Our operating hypothesis was that there are genetic factors underlying some eating disorders resting in both those pathways. Specifically, we are interested in disorders that may rest in both sleep and metabolic function, generally called Night Eating Syndrome (NES). A meta-analysis of the Gene Expression Omnibus targeting the mammalian nervous system, sleep, and obesity studies was performed, yielding numerous genes of interest. Through a text-based analysis of the results, a number of potential candidate genes were identified. VGF, in particular, appeared to be relevant both to obesity and, broadly, to brain or neural development. VGF is a highly connected protein that interacts with numerous targets via proteolytically digested peptides. We examined VGF from an evolutionary perspective to determine whether other available evidence supported a role for the gene in human disease. We conclude that some of the already identified variants in VGF from human polymorphism studies may contribute to eating disorders and obesity. Our data suggest that there is enough evidence to warrant eGWAS and GWAS analysis of these genes in NES patients in a case-control study.

Hybridization-based antibody cDNA recovery for the production of recombinant antibodies identified by repertoire sequencing.

PubMed

Valdés-Alemán, Javier; Téllez-Sosa, Juan; Ovilla-Muñoz, Marbella; Godoy-Lozano, Elizabeth; Velázquez-Ramírez, Daniel; Valdovinos-Torres, Humberto; Gómez-Barreto, Rosa E; Martinez-Barnetche, Jesús

2014-01-01

High-throughput sequencing of the antibody repertoire is enabling a thorough analysis of B cell diversity and clonal selection, which may improve the novel antibody discovery process. Theoretically, an adequate bioinformatic analysis could allow identification of candidate antigen-specific antibodies, requiring their recombinant production for experimental validation of their specificity. Gene synthesis is commonly used for the generation of recombinant antibodies identified in silico. Novel strategies that bypass gene synthesis could offer more accessible antibody identification and validation alternatives. We developed a hybridization-based recovery strategy that targets the complementarity-determining region 3 (CDRH3) for the enrichment of cDNA of candidate antigen-specific antibody sequences. Ten clonal groups of interest were identified through bioinformatic analysis of the heavy chain antibody repertoire of mice immunized with hen egg white lysozyme (HEL). cDNA from eight of the targeted clonal groups was recovered efficiently, leading to the generation of recombinant antibodies. One representative heavy chain sequence from each clonal group recovered was paired with previously reported anti-HEL light chains to generate full antibodies, later tested for HEL-binding capacity. The recovery process proposed represents a simple and scalable molecular strategy that could enhance antibody identification and specificity assessment, enabling a more cost-efficient generation of recombinant antibodies.

[Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a mutation in TFG].

PubMed

Ishiura, Hiroyuki; Tsuji, Shoji

2013-01-01

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal dominant neurodegenerative disease characterized by proximal predominant weakness and muscle atrophy accompanied by distal sensory disturbance. Linkage analysis using 4 families identified a region on chromosome 3 showing a LOD score exceeding 4. Further refinement of candidate region was performed by haplotype analysis using high-density SNP data, resulting in a minimum candidate region spanning 3.3 Mb. Exome analysis of an HMSN-P patient revealed a mutation (c.854C>T, p.Pro285Leu) in TRK-fused gene (TFG). The identical mutation was found in the four families, which cosegregated with the disease. The mutation was neither found in Japanese control subjects nor public databases. Detailed haplotype analysis suggested two independent origins of the mutation. These findings indicate that the mutation in TFG causes HMSN-P.

A computational method for the identification of new candidate carcinogenic and non-carcinogenic chemicals.

PubMed

Chen, Lei; Chu, Chen; Lu, Jing; Kong, Xiangyin; Huang, Tao; Cai, Yu-Dong

2015-09-01

Cancer is one of the leading causes of human death. Based on current knowledge, one of the causes of cancer is exposure to toxic chemical compounds, including radioactive compounds, dioxin, and arsenic. The identification of new carcinogenic chemicals may warn us of potential danger and help to identify new ways to prevent cancer. In this study, a computational method was proposed to identify potential carcinogenic chemicals, as well as non-carcinogenic chemicals. According to the current validated carcinogenic and non-carcinogenic chemicals from the CPDB (Carcinogenic Potency Database), the candidate chemicals were searched in a weighted chemical network constructed according to chemical-chemical interactions. Then, the obtained candidate chemicals were further selected by a randomization test and information on chemical interactions and structures. The analyses identified several candidate carcinogenic chemicals, while those candidates identified as non-carcinogenic were supported by a literature search. In addition, several candidate carcinogenic/non-carcinogenic chemicals exhibit structural dissimilarity with validated carcinogenic/non-carcinogenic chemicals.

Genomic characteristics of cattle copy number variations

USDA-ARS?s Scientific Manuscript database

We performed a systematic analysis of cattle copy number variations (CNVs) using the Bovine HapMap SNP genotyping data, including 539 animals of 21 modern cattle breeds and 6 outgroups. After correcting genomic waves and considering the trio information, we identified 682 candidate CNV regions (CNVR...

Comparative proteome analysis reveals pathogen specific outer membrane proteins of Leptospira.

PubMed

Dhandapani, Gunasekaran; Sikha, Thoduvayil; Rana, Aarti; Brahma, Rahul; Akhter, Yusuf; Gopalakrishnan Madanan, Madathiparambil

2018-04-10

Proteomes of pathogenic Leptospira interrogans and L. borgpetersenii and the saprophytic L. biflexa were filtered through computational tools to identify Outer Membrane Proteins (OMPs) that satisfy the required biophysical parameters for their presence on the outer membrane. A total of 133, 130, and 144 OMPs were identified in L. interrogans, L. borgpetersenii, and L. biflexa, respectively, which forms approximately 4% of proteomes. A holistic analysis of transporting and pathogenic characteristics of OMPs together with Clusters of Orthologous Groups (COGs) among the OMPs and their distribution across 3 species was made and put forward a set of 21 candidate OMPs specific to pathogenic leptospires. It is also found that proteins homologous to the candidate OMPs were also present in other pathogenic species of leptospires. Six OMPs from L. interrogans and 2 from L. borgpetersenii observed to have similar COGs while those were not found in any intermediate or saprophytic forms. These OMPs appears to have role in infection and pathogenesis and useful for anti-leptospiral strategies. © 2018 Wiley Periodicals, Inc.

Differences in Brain Transcriptomes of Closely Related Baikal Coregonid Species

PubMed Central

Bychenko, Oksana S.; Sukhanova, Lyubov V.; Azhikina, Tatyana L.; Skvortsov, Timofey A.; Belomestnykh, Tuyana V.; Sverdlov, Eugene D.

2014-01-01

The aim of this work was to get deeper insight into genetic factors involved in the adaptive divergence of closely related species, specifically two representatives of Baikal coregonids—Baikal whitefish (Coregonus baicalensis Dybowski) and Baikal omul (Coregonus migratorius Georgi)—that diverged from a common ancestor as recently as 10–20 thousand years ago. Using the Serial Analysis of Gene Expression method, we obtained libraries of short representative cDNA sequences (tags) from the brains of Baikal whitefish and omul. A comparative analysis of the libraries revealed quantitative differences among ~4% tags of the fishes under study. Based on the similarity of these tags with cDNA of known organisms, we identified candidate genes taking part in adaptive divergence. The most important candidate genes related to the adaptation of Baikal whitefish and Baikal omul, identified in this work, belong to the genes of cell metabolism, nervous and immune systems, protein synthesis, and regulatory genes as well as to DTSsa4 Tc1-like transposons which are widespread among fishes. PMID:24719892

Detection of Significant Pneumococcal Meningitis Biomarkers by Ego Network.

PubMed

Wang, Qian; Lou, Zhifeng; Zhai, Liansuo; Zhao, Haibin

2017-06-01

To identify significant biomarkers for detection of pneumococcal meningitis based on ego network. Based on the gene expression data of pneumococcal meningitis and global protein-protein interactions (PPIs) data recruited from open access databases, the authors constructed a differential co-expression network (DCN) to identify pneumococcal meningitis biomarkers in a network view. Here EgoNet algorithm was employed to screen the significant ego networks that could accurately distinguish pneumococcal meningitis from healthy controls, by sequentially seeking ego genes, searching candidate ego networks, refinement of candidate ego networks and significance analysis to identify ego networks. Finally, the functional inference of the ego networks was performed to identify significant pathways for pneumococcal meningitis. By differential co-expression analysis, the authors constructed the DCN that covered 1809 genes and 3689 interactions. From the DCN, a total of 90 ego genes were identified. Starting from these ego genes, three significant ego networks (Module 19, Module 70 and Module 71) that could predict clinical outcomes for pneumococcal meningitis were identified by EgoNet algorithm, and the corresponding ego genes were GMNN, MAD2L1 and TPX2, respectively. Pathway analysis showed that these three ego networks were related to CDT1 association with the CDC6:ORC:origin complex, inactivation of APC/C via direct inhibition of the APC/C complex pathway, and DNA strand elongation, respectively. The authors successfully screened three significant ego modules which could accurately predict the clinical outcomes for pneumococcal meningitis and might play important roles in host response to pathogen infection in pneumococcal meningitis.

Evidence of linkage and association on chromosome 20 for late-onset Alzheimer disease.

PubMed

Goddard, Katrina A B; Olson, Jane M; Payami, Haydeh; van der Voet, Monique; Kuivaniemi, Helena; Tromp, Gerard

2004-06-01

Recently, we reported evidence of linkage on chromosome 20 for Alzheimer disease (AD) using a novel statistical approach to incorporate covariates (e.g., age, ApoE genotype) into the analysis. These results suggest that very elderly subjects (>85 years), and individuals who carry an epsilon2 allele at the ApoE locus are more likely to be linked to this candidate region. The region on chromosome 20 includes a strong candidate gene, cystatin C (CST3), which has previously been associated with AD in case-control studies. We investigated these findings further by genotyping additional markers to narrow the candidate region, and to identify evidence of linkage disequilibrium as additional support for a susceptibility locus on chromosome 20. We selected 43 elderly sibships (89 subjects) from the NIMH AD Genetics Initiative based on current age older than 84 years, and identified 129 unrelated control subjects who were older than 84 years from the Oregon Brain Aging Study to conduct linkage and association studies in this region. Fourteen additional markers were evaluated, including 4 markers located within or near CST3. We narrowed the candidate region on chromosome 20 to an 11.8-cM region between markers D20S174 and D20S471, which includes the CST3 candidate gene. In addition, we observed evidence of association for markers located near the CST3 candidate gene, with P values between 0.002 and 0.08 for two-locus haplotypes. These results support the presence of a susceptibility locus for AD in the vicinity of CST3 for very elderly subjects with AD.

An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits.

PubMed

Hsu, Yi-Hsiang; Zillikens, M Carola; Wilson, Scott G; Farber, Charles R; Demissie, Serkalem; Soranzo, Nicole; Bianchi, Estelle N; Grundberg, Elin; Liang, Liming; Richards, J Brent; Estrada, Karol; Zhou, Yanhua; van Nas, Atila; Moffatt, Miriam F; Zhai, Guangju; Hofman, Albert; van Meurs, Joyce B; Pols, Huibert A P; Price, Roger I; Nilsson, Olle; Pastinen, Tomi; Cupples, L Adrienne; Lusis, Aldons J; Schadt, Eric E; Ferrari, Serge; Uitterlinden, André G; Rivadeneira, Fernando; Spector, Timothy D; Karasik, David; Kiel, Douglas P

2010-06-10

Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6x10(-8)), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6x10(-13); SOX6, p = 6.4x10(-10)) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.

Mapping by sequencing in cotton (Gossypium hirsutum) line MD52ne identified candidate genes for fiber strength and its related quality attributes.

PubMed

Islam, Md S; Zeng, Linghe; Thyssen, Gregory N; Delhom, Christopher D; Kim, Hee Jin; Li, Ping; Fang, David D

2016-06-01

Three QTL regions controlling three fiber quality traits were validated and further fine-mapped with 27 new single nucleotide polymorphism (SNP) markers. Transcriptome analysis suggests that receptor-like kinases found within the validated QTLs are potential candidate genes responsible for superior fiber strength in cotton line MD52ne. Fiber strength, length, maturity and fineness determine the market value of cotton fibers and the quality of spun yarn. Cotton fiber strength has been recognized as a critical quality attribute in the modern textile industry. Fine mapping along with quantitative trait loci (QTL) validation and candidate gene prediction can uncover the genetic and molecular basis of fiber quality traits. Four previously-identified QTLs (qFBS-c3, qSFI-c14, qUHML-c14 and qUHML-c24) related to fiber bundle strength, short fiber index and fiber length, respectively, were validated using an F3 population that originated from a cross of MD90ne × MD52ne. A group of 27 new SNP markers generated from mapping-by-sequencing (MBS) were placed in QTL regions to improve and validate earlier maps. Our refined QTL regions spanned 4.4, 1.8 and 3.7 Mb of physical distance in the Gossypium raimondii reference genome. We performed RNA sequencing (RNA-seq) of 15 and 20 days post-anthesis fiber cells from MD52ne and MD90ne and aligned reads to the G. raimondii genome. The QTL regions contained 21 significantly differentially expressed genes (DEGs) between the two near-isogenic parental lines. SNPs that result in non-synonymous substitutions to amino acid sequences of annotated genes were identified within these DEGs, and mapped. Taken together, transcriptome and amino acid mutation analysis indicate that receptor-like kinase pathway genes are likely candidates for superior fiber strength and length in MD52ne. MBS along with RNA-seq demonstrated a powerful strategy to elucidate candidate genes for the QTLs that control complex traits in a complex genome like tetraploid upland cotton.

In silico analysis to identify vaccine candidates common to multiple serotypes of Shigella and evaluation of their immunogenicity.

PubMed

Pahil, Sapna; Taneja, Neelam; Ansari, Hifzur Rahman; Raghava, G P S

2017-01-01

Shigellosis or bacillary dysentery is an important cause of diarrhea, with the majority of the cases occurring in developing countries. Considering the high disease burden, increasing antibiotic resistance, serotype-specific immunity and the post-infectious sequelae associated with shigellosis, there is a pressing need of an effective vaccine against multiple serotypes of the pathogen. In the present study, we used bio-informatics approach to identify antigens shared among multiple serotypes of Shigella spp. This approach led to the identification of many immunogenic peptides. The five most promising peptides based on MHC binding efficiency were a putative lipoprotein (EL PGI I), a putative heat shock protein (EL PGI II), Spa32 (EL PGI III), IcsB (EL PGI IV) and a hypothetical protein (EL PGI V). These peptides were synthesized and the immunogenicity was evaluated in BALB/c mice by ELISA and cytokine assays. The putative heat shock protein (HSP) and the hypothetical protein elicited good humoral response, whereas putative lipoprotein, Spa32 and IcsB elicited good T-cell response as revealed by increased IFN-γ and TNF-α cytokine levels. The patient sera from confirmed cases of shigellosis were also evaluated for the presence of peptide specific antibodies with significant IgG and IgA antibodies against the HSP and the hypothetical protein, bestowing them as potential future vaccine candidates. The antigens reported in this study are novel and have not been tested as vaccine candidates against Shigella. This study offers time and cost-effective way of identifying unprecedented immunogenic antigens to be used as potential vaccine candidates. Moreover, this approach should easily be extendable to find new potential vaccine candidates for other pathogenic bacteria.

Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico

PubMed Central

Maga, A. Murat; Navarro, Nicolas; Cunningham, Michael L.; Cox, Timothy C.

2015-01-01

We describe the first application of high-resolution 3D micro-computed tomography, together with 3D landmarks and geometric morphometrics, to map QTL responsible for variation in skull shape and size using a backcross between C57BL/6J and A/J inbred strains. Using 433 animals, 53 3D landmarks, and 882 SNPs from autosomes, we identified seven QTL responsible for the skull size (SCS.qtl) and 30 QTL responsible for the skull shape (SSH.qtl). Size, sex, and direction-of-cross were all significant factors and included in the analysis as covariates. All autosomes harbored at least one SSH.qtl, sometimes up to three. Effect sizes of SSH.qtl appeared to be small, rarely exceeding 1% of the overall shape variation. However, they account for significant amount of variation in some specific directions of the shape space. Many QTL have stronger effect on the neurocranium than expected from a random vector that will parcellate uniformly across the four cranial regions. On the contrary, most of QTL have an effect on the palate weaker than expected. Combined interval length of 30 SSH.qtl was about 315 MB and contained 2476 known protein coding genes. We used a bioinformatics approach to filter these candidate genes and identified 16 high-priority candidates that are likely to play a role in the craniofacial development and disorders. Thus, coupling the QTL mapping approach in model organisms with candidate gene enrichment approaches appears to be a feasible way to identify high-priority candidates genes related to the structure or tissue of interest. PMID:25859222

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours.

PubMed

Barclay, Sarah F; Rand, Casey M; Borch, Lauren A; Nguyen, Lisa; Gray, Paul A; Gibson, William T; Wilson, Richard J A; Gordon, Paul M K; Aung, Zaw; Berry-Kravis, Elizabeth M; Ize-Ludlow, Diego; Weese-Mayer, Debra E; Bech-Hansen, N Torben

2015-08-25

Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients. We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons. The analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations. Clinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.

A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana.

PubMed

Lachowiec, Jennifer; Shen, Xia; Queitsch, Christine; Carlborg, Örjan

2015-01-01

Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance explains the insignificant narrow-sense and significant broad-sense heritability by using a combination of careful statistical epistatic analyses and functional genetic experiments.

QTL-seq for rapid identification of candidate genes for flowering time in broccoli × cabbage.

PubMed

Shu, Jinshuai; Liu, Yumei; Zhang, Lili; Li, Zhansheng; Fang, Zhiyuan; Yang, Limei; Zhuang, Mu; Zhang, Yangyong; Lv, Honghao

2018-04-01

A major QTL controlling early flowering in broccoli × cabbage was identified by marker analysis and next-generation sequencing, corresponding to GRF6 gene conditioning flowering time in Arabidopsis. Flowering is an important agronomic trait for hybrid production in broccoli and cabbage, but the genetic mechanism underlying this process is unknown. In this study, segregation analysis with BC 1 P1, BC 1 P2, F 2 , and F 2:3 populations derived from a cross between two inbred lines "195" (late-flowering) and "93219" (early flowering) suggested that flowering time is a quantitative trait. Next, employing a next-generation sequencing-based whole-genome QTL-seq strategy, we identified a major genomic region harboring a robust flowering time QTL using an F 2 mapping population, designated Ef2.1 on cabbage chromosome 2 for early flowering. Ef2.1 was further validated by indel (insertion or deletion) marker-based classical QTL mapping, explaining 51.5% (LOD = 37.67) and 54.0% (LOD = 40.5) of the phenotypic variation in F 2 and F 2:3 populations, respectively. Combined QTL-seq and classical QTL analysis narrowed down Ef1.1 to a 228-kb genomic region containing 29 genes. A cabbage gene, Bol024659, was identified in this region, which is a homolog of GRF6, a major gene regulating flowering in Arabidopsis, and was designated BolGRF6. qRT-PCR study of the expression level of BolGRF6 revealed significantly higher expression in the early flowering genotypes. Taken together, our results provide support for BolGRF6 as a possible candidate gene for early flowering in the broccoli line 93219. The identified candidate genomic regions and genes may be useful for molecular breeding to improve broccoli and cabbage flowering times.

Mutant Alleles of Photoperiod-1 in Wheat (Triticum aestivum L.) That Confer a Late Flowering Phenotype in Long Days

PubMed Central

Shaw, Lindsay M.; Turner, Adrian S.; Herry, Laurence; Griffiths, Simon; Laurie, David A.

2013-01-01

Flowering time in wheat and barley is known to be modified by mutations in the Photoperiod-1 (Ppd-1) gene. Semi-dominant Ppd-1a mutations conferring an early flowering phenotype are well documented in wheat but gene sequencing has also identified candidate loss of function mutations for Ppd-A1 and Ppd-D1. By analogy to the recessive ppd-H1 mutation in barley, loss of function mutations in wheat are predicted to delay flowering under long day conditions. To test this experimentally, introgression lines were developed in the spring wheat variety ‘Paragon’. Plants lacking a Ppd-B1 gene were identified from a gamma irradiated ‘Paragon’ population. These were crossed with the other introgression lines to generate plants with candidate loss of function mutations on one, two or three genomes. Lines lacking Ppd-B1 flowered 10 to 15 days later than controls under long days. Candidate loss of function Ppd-A1 alleles delayed flowering by 1 to 5 days while candidate loss of function Ppd-D1 alleles did not affect flowering time. Loss of Ppd-A1 gave an enhanced effect, and loss of Ppd-D1 became detectable in lines where Ppd-B1 was absent, indicating effects may be buffered by functional Ppd-1 alleles on other genomes. Expression analysis revealed that delayed flowering was associated with reduced expression of the TaFT1 gene and increased expression of TaCO1. A survey of the GEDIFLUX wheat collection grown in the UK and North Western Europe between the 1940s and 1980s and the A.E. Watkins global collection of landraces from the 1920s and 1930s showed that the identified candidate loss of function mutations for Ppd-D1 were common and widespread, while the identified candidate Ppd-A1 loss of function mutation was rare in countries around the Mediterranean and in the Far East but was common in North Western Europe. This may reflect a possible benefit of the latter in northern locations. PMID:24244507

Identification of possible genetic polymorphisms involved in cancer cachexia: a systematic review.

PubMed

Tan, Benjamin H L; Ross, James A; Kaasa, Stein; Skorpen, Frank; Fearon, Kenneth C H

2011-04-01

Cancer cachexia is a polygenic and complex syndrome. Genetic variations in regulation of the inflammatory response, muscle and fat metabolic pathways, and pathways in appetite regulation are likely to contribute to the susceptibility or resistance to developing cancer cachexia. A systematic search of Medline and EmBase databases, covering 1986-2008 was performed for potential candidate genes/genetic polymorphisms relating to cancer cachexia. Related genes were then identified using pathway functional analysis software. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Genes with variants which had functional or clinical associations with cachexia and replicated in at least one study were entered into pathway analysis software to reveal possible network associations between genes. A total of 184 polymorphisms with functional or clinical relevance to cancer cachexia were identified in 92 candidate genes. Of these, 42 polymorphisms (in 33 genes) were replicated in more than one study with 13 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Thirty-three genes were found to be significantly interconnected in two major networks with four genes (ADIPOQ, IL6, NFKB1 and TLR4) interlinking both networks. Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides an initial framework to select genes/polymorphisms for further study in cancer cachexia, and to develop their potential as susceptibility biomarkers of developing cachexia.

A Genomic Resource for the Development, Improvement, and Exploitation of Sorghum for Bioenergy

PubMed Central

Brenton, Zachary W.; Cooper, Elizabeth A.; Myers, Mathew T.; Boyles, Richard E.; Shakoor, Nadia; Zielinski, Kelsey J.; Rauh, Bradley L.; Bridges, William C.; Morris, Geoffrey P.; Kresovich, Stephen

2016-01-01

With high productivity and stress tolerance, numerous grass genera of the Andropogoneae have emerged as candidates for bioenergy production. To optimize these candidates, research examining the genetic architecture of yield, carbon partitioning, and composition is required to advance breeding objectives. Significant progress has been made developing genetic and genomic resources for Andropogoneae, and advances in comparative and computational genomics have enabled research examining the genetic basis of photosynthesis, carbon partitioning, composition, and sink strength. To provide a pivotal resource aimed at developing a comparative understanding of key bioenergy traits in the Andropogoneae, we have established and characterized an association panel of 390 racially, geographically, and phenotypically diverse Sorghum bicolor accessions with 232,303 genetic markers. Sorghum bicolor was selected because of its genomic simplicity, phenotypic diversity, significant genomic tools, and its agricultural productivity and resilience. We have demonstrated the value of sorghum as a functional model for candidate gene discovery for bioenergy Andropogoneae by performing genome-wide association analysis for two contrasting phenotypes representing key components of structural and non-structural carbohydrates. We identified potential genes, including a cellulase enzyme and a vacuolar transporter, associated with increased non-structural carbohydrates that could lead to bioenergy sorghum improvement. Although our analysis identified genes with potentially clear functions, other candidates did not have assigned functions, suggesting novel molecular mechanisms for carbon partitioning traits. These results, combined with our characterization of phenotypic and genetic diversity and the public accessibility of each accession and genomic data, demonstrate the value of this resource and provide a foundation for future improvement of sorghum and related grasses for bioenergy production. PMID:27356613

A population-specific uncommon variant in GRIN3A associated with schizophrenia.

PubMed

Takata, Atsushi; Iwayama, Yoshimi; Fukuo, Yasuhisa; Ikeda, Masashi; Okochi, Tomo; Maekawa, Motoko; Toyota, Tomoko; Yamada, Kazuo; Hattori, Eiji; Ohnishi, Tetsuo; Toyoshima, Manabu; Ujike, Hiroshi; Inada, Toshiya; Kunugi, Hiroshi; Ozaki, Norio; Nanko, Shinichiro; Nakamura, Kazuhiko; Mori, Norio; Kanba, Shigenobu; Iwata, Nakao; Kato, Tadafumi; Yoshikawa, Takeo

2013-03-15

Genome-wide association studies have successfully identified several common variants showing robust association with schizophrenia. However, individually, these variants only produce a weak effect. To identify genetic variants with larger effect sizes, increasing attention is now being paid to uncommon and rare variants. From the 1000 Genomes Project data, we selected 47 candidate single nucleotide variants (SNVs), which were: 1) uncommon (minor allele frequency < 5%); 2) Asian-specific; 3) missense, nonsense, or splice site variants predicted to be damaging; and 4) located in candidate genes for schizophrenia and bipolar disorder. We examined their association with schizophrenia, using a Japanese case-control cohort (2012 cases and 2781 control subjects). Additional meta-analysis was performed using genotyping data from independent Han-Chinese case-control (333 cases and 369 control subjects) and family samples (9 trios and 284 quads). We identified disease association of a missense variant in GRIN3A (p.R480G, rs149729514, p = .00042, odds ratio [OR] = 1.58), encoding a subunit of the N-methyl-D-aspartate type glutamate receptor, with study-wide significance (threshold p = .0012). This association was supported by meta-analysis (combined p = 3.3 × 10(-5), OR = 1.61). Nominally significant association was observed in missense variants from FAAH, DNMT1, MYO18B, and CFB, with ORs of risk alleles ranging from 1.41 to 2.35. The identified SNVs, particularly the GRIN3A R480G variant, are good candidates for further replication studies and functional evaluation. The results of this study indicate that association analyses focusing on uncommon and rare SNVs are a promising way to discover risk variants with larger effects. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies.

PubMed

Johns, N; Tan, B H; MacMillan, M; Solheim, T S; Ross, J A; Baracos, V E; Damaraju, S; Fearon, K C H

2014-12-01

Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986-2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and to develop their potential as susceptibility biomarkers of cachexia.

Stardust Interstellar Preliminary Examination VII: Synchrotron X-Ray Fluorescence Analysis of Six Stardust Interstellar Candidates Measured with the Advanced Photon Source 2-ID-D Microprobe

NASA Technical Reports Server (NTRS)

Allen, Carlton C.; Anderson, David; Bastien, Ron K.; Brenker, Frank E.; Flynn, George J.; Frank, David; Gainsforth, Zack; Sandford, Scott A.; Simionovici, Alexandre S.; Zolensky, Michael E.

2014-01-01

The NASA Stardust spacecraft exposed an aerogel collector to the interstellar dust passing through the solar system. We performed X-ray fluorescence element mapping and abundance measurements, for elements 19 < or = Z < or = 30, on six "interstellar candidates," potential interstellar impacts identified by Stardust@Home and extracted for analyses in picokeystones. One, I1044,3,33, showed no element hot-spots within the designated search area. However, we identified a nearby surface feature, consistent with the impact of a weak, high-speed particle having an approximately chondritic (CI) element abundance pattern, except for factor-of-ten enrichments in K and Zn and an S depletion. This hot-spot, containing approximately 10 fg of Fe, corresponds to an approximately 350 nm chondritic particle, small enough to be missed by Stardust@Home, indicating that other techniques may be necessary to identify all interstellar candidates. Only one interstellar candidate, I1004,1,2, showed a track. The terminal particle has large enrichments in S, Ti, Cr, Mn, Ni, Cu, and Zn relative to Fe-normalized CI values. It has high Al/Fe, but does not match the Ni/Fe range measured for samples of Al-deck material from the Stardust sample return capsule, which was within the field-of-view of the interstellar collector. A third interstellar candidate, I1075,1,25, showed an Al-rich surface feature that has a composition generally consistent with the Al-deck material, suggesting that it is a secondary particle. The other three interstellar candidates, I1001,1,16, I1001,2,17, and I1044,2,32, showed no impact features or tracks, but allowed assessment of submicron contamination in this aerogel, including Fe hot-spots having CI-like Ni/Fe ratios, complicating the search for CI-like interstellar/interplanetary dust.

Stardust Interstellar Preliminary Examination VII: Synchrotron X-ray fluorescence analysis of six Stardust interstellar candidates measured with the Advanced Photon Source 2-ID-D microprobe

NASA Astrophysics Data System (ADS)

Flynn, George J.; Sutton, Steven R.; Lai, Barry; Wirick, Sue; Allen, Carlton; Anderson, David; Ansari, Asna; Bajt, SašA.; Bastien, Ron K.; Bassim, Nabil; Bechtel, Hans A.; Borg, Janet; Brenker, Frank E.; Bridges, John; Brownlee, Donald E.; Burchell, Mark; Burghammer, Manfred; Butterworth, Anna L.; Changela, Hitesh; Cloetens, Peter; Davis, Andrew M.; Doll, Ryan; Floss, Christine; Frank, David; Gainsforth, Zack; Grün, Eberhard; Heck, Philipp R.; Hillier, Jon K.; Hoppe, Peter; Hudson, Bruce; Huth, Joachim; Hvide, Brit; Kearsley, Anton; King, Ashley J.; Leitner, Jan; Lemelle, Laurence; Leroux, Hugues; Leonard, Ariel; Lettieri, Robert; Marchant, William; Nittler, Larry R.; Ogliore, Ryan; Ong, Wei Ja; Postberg, Frank; Price, Mark C.; Sandford, Scott A.; Tresseras, Juan-Angel Sans; Schmitz, Sylvia; Schoonjans, Tom; Silversmit, Geert; Simionovici, Alexandre; Sol, Vicente A.; Srama, Ralf; Stadermann, Frank J.; Stephan, Thomas; Sterken, Veerle; Stodolna, Julien; Stroud, Rhonda M.; Trieloff, Mario; Tsou, Peter; Tsuchiyama, Akira; Tyliszczak, Tolek; Vekemans, Bart; Vincze, Laszlo; von Korff, Joshua; Westphal, Andrew J.; Wordsworth, Naomi; Zevin, Daniel; Zolensky, Michael E.

2014-09-01

The NASA Stardust spacecraft exposed an aerogel collector to the interstellar dust passing through the solar system. We performed X-ray fluorescence element mapping and abundance measurements, for elements 19 ≤ Z ≤ 30, on six "interstellar candidates," potential interstellar impacts identified by Stardust@Home and extracted for analyses in picokeystones. One, I1044,3,33, showed no element hot-spots within the designated search area. However, we identified a nearby surface feature, consistent with the impact of a weak, high-speed particle having an approximately chondritic (CI) element abundance pattern, except for factor-of-ten enrichments in K and Zn and an S depletion. This hot-spot, containing approximately 10 fg of Fe, corresponds to an approximately 350 nm chondritic particle, small enough to be missed by Stardust@Home, indicating that other techniques may be necessary to identify all interstellar candidates. Only one interstellar candidate, I1004,1,2, showed a track. The terminal particle has large enrichments in S, Ti, Cr, Mn, Ni, Cu, and Zn relative to Fe-normalized CI values. It has high Al/Fe, but does not match the Ni/Fe range measured for samples of Al-deck material from the Stardust sample return capsule, which was within the field-of-view of the interstellar collector. A third interstellar candidate, I1075,1,25, showed an Al-rich surface feature that has a composition generally consistent with the Al-deck material, suggesting that it is a secondary particle. The other three interstellar candidates, I1001,1,16, I1001,2,17, and I1044,2,32, showed no impact features or tracks, but allowed assessment of submicron contamination in this aerogel, including Fe hot-spots having CI-like Ni/Fe ratios, complicating the search for CI-like interstellar/interplanetary dust.

Association of candidate genes with drought tolerance traits in diverse perennial ryegrass accessions

PubMed Central

Jiang, Yiwei

2013-01-01

Drought is a major environmental stress limiting growth of perennial grasses in temperate regions. Plant drought tolerance is a complex trait that is controlled by multiple genes. Candidate gene association mapping provides a powerful tool for dissection of complex traits. Candidate gene association mapping of drought tolerance traits was conducted in 192 diverse perennial ryegrass (Lolium perenne L.) accessions from 43 countries. The panel showed significant variations in leaf wilting, leaf water content, canopy and air temperature difference, and chlorophyll fluorescence under well-watered and drought conditions across six environments. Analysis of 109 simple sequence repeat markers revealed five population structures in the mapping panel. A total of 2520 expression-based sequence readings were obtained for a set of candidate genes involved in antioxidant metabolism, dehydration, water movement across membranes, and signal transduction, from which 346 single nucleotide polymorphisms were identified. Significant associations were identified between a putative LpLEA3 encoding late embryogenesis abundant group 3 protein and a putative LpFeSOD encoding iron superoxide dismutase and leaf water content, as well as between a putative LpCyt Cu-ZnSOD encoding cytosolic copper-zinc superoxide dismutase and chlorophyll fluorescence under drought conditions. Four of these identified significantly associated single nucleotide polymorphisms from these three genes were also translated to amino acid substitutions in different genotypes. These results indicate that allelic variation in these genes may affect whole-plant response to drought stress in perennial ryegrass. PMID:23386684

Transcriptome-wide characterization of candidate genes for improving the water use efficiency of energy crops grown on semiarid land.

PubMed

Fan, Yangyang; Wang, Qian; Kang, Lifang; Liu, Wei; Xu, Qin; Xing, Shilai; Tao, Chengcheng; Song, Zhihong; Zhu, Caiyun; Lin, Cong; Yan, Juan; Li, Jianqiang; Sang, Tao

2015-10-01

Understanding the genetic basis of water use efficiency (WUE) and its roles in plant adaptation to a drought environment is essential for the production of second-generation energy crops in water-deficit marginal land. In this study, RNA-Seq and WUE measurements were performed for 78 individuals of Miscanthus lutarioriparius grown in two common gardens, one located in warm and wet Central China near the native habitats of the species and the other located in the semiarid Loess Plateau, the domestication site of the energy crop. The field measurements showed that WUE of M. lutarioriparius in the semiarid location was significantly higher than that in the wet location. A matrix correlation analysis was conducted between gene expression levels and WUE to identify candidate genes involved in the improvement of WUE from the native to the domestication site. A total of 48 candidate genes were identified and assigned to functional categories, including photosynthesis, stomatal regulation, protein metabolism, and abiotic stress responses. Of these genes, nearly 73% were up-regulated in the semiarid site. It was also found that the relatively high expression variation of the WUE-related genes was affected to a larger extent by environment than by genetic variation. The study demonstrates that transcriptome-wide correlation between physiological phenotypes and expression levels offers an effective means for identifying candidate genes involved in the adaptation to environmental changes. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

A novel truncation mutation in CRYBB1 associated with autosomal dominant congenital cataract with nystagmus.

PubMed

Rao, Yan; Dong, Sufang; Li, Zuhua; Yang, Guohua; Peng, Chunyan; Yan, Ming; Zheng, Fang

2017-01-01

To identify the potential candidate genes for a large Chinese family with autosomal dominant congenital cataract (ADCC) and nystagmus, and investigate the possible molecular mechanism underlying the role of the candidate genes in cataractogenesis. We combined the linkage analysis and direct sequencing for the candidate genes in the linkage regions to identify the causative mutation. The molecular and bio-functional properties of the proteins encoded by the candidate genes was further explored with biophysical and biochemical studies of the recombinant wild-type and mutant proteins. We identified a c. C749T (p.Q227X) transversion in exon 6 of CRYBB1 , a cataract-causative gene. This nonsense mutation changes a phylogenetically conserved glutamine to a stop codon and is predicted to truncate the C-terminus of the wild-type protein by 26 amino acids. Comparison of the biophysical and biochemical properties of the recombinant full-length and truncated βB1-crystallins revealed that the mutation led to the insolubility and the phase separation phenomenon of the truncated protein with a changed conformation. Meanwhile, the thermal stability of the truncated βB1-crystallin was significantly decreased, and the mutation diminished the chaperoning ability of αA-crystallin with the mutant under heating stress. Our findings highlight the importance of the C-terminus in βB1-crystallin in maintaining the crystalline function and stability, and provide a novel insight into the molecular mechanism underlying the pathogenesis of human autosomal dominant congenital cataract.

Comparative molecular analyses of select pH- and osmoregulatory genes in three freshwater crayfish Cherax quadricarinatus, C. destructor and C. cainii.

PubMed

Ali, Muhammad Y; Pavasovic, Ana; Dammannagoda, Lalith K; Mather, Peter B; Prentis, Peter J

2017-01-01

Systemic acid-base balance and osmotic/ionic regulation in decapod crustaceans are in part maintained by a set of transport-related enzymes such as carbonic anhydrase (CA), Na + /K + -ATPase (NKA), H + -ATPase (HAT), Na + /K + /2Cl - cotransporter (NKCC), Na + /Cl - /HCO[Formula: see text] cotransporter (NBC), Na + /H + exchanger (NHE), Arginine kinase (AK), Sarcoplasmic Ca +2 -ATPase (SERCA) and Calreticulin (CRT). We carried out a comparative molecular analysis of these genes in three commercially important yet eco-physiologically distinct freshwater crayfish , Cherax quadricarinatus, C. destructor and C. cainii , with the aim to identify mutations in these genes and determine if observed patterns of mutations were consistent with the action of natural selection. We also conducted a tissue-specific expression analysis of these genes across seven different organs, including gills, hepatopancreas, heart, kidney, liver, nerve and testes using NGS transcriptome data. The molecular analysis of the candidate genes revealed a high level of sequence conservation across the three Cherax sp. Hyphy analysis revealed that all candidate genes showed patterns of molecular variation consistent with neutral evolution. The tissue-specific expression analysis showed that 46% of candidate genes were expressed in all tissue types examined, while approximately 10% of candidate genes were only expressed in a single tissue type. The largest number of genes was observed in nerve (84%) and gills (78%) and the lowest in testes (66%). The tissue-specific expression analysis also revealed that most of the master genes regulating pH and osmoregulation (CA, NKA, HAT, NKCC, NBC, NHE) were expressed in all tissue types indicating an important physiological role for these genes outside of osmoregulation in other tissue types. The high level of sequence conservation observed in the candidate genes may be explained by the important role of these genes as well as potentially having a number of other basic physiological functions in different tissue types.

A novel integrated framework and improved methodology of computer-aided drug design.

PubMed

Chen, Calvin Yu-Chian

2013-01-01

Computer-aided drug design (CADD) is a critical initiating step of drug development, but a single model capable of covering all designing aspects remains to be elucidated. Hence, we developed a drug design modeling framework that integrates multiple approaches, including machine learning based quantitative structure-activity relationship (QSAR) analysis, 3D-QSAR, Bayesian network, pharmacophore modeling, and structure-based docking algorithm. Restrictions for each model were defined for improved individual and overall accuracy. An integration method was applied to join the results from each model to minimize bias and errors. In addition, the integrated model adopts both static and dynamic analysis to validate the intermolecular stabilities of the receptor-ligand conformation. The proposed protocol was applied to identifying HER2 inhibitors from traditional Chinese medicine (TCM) as an example for validating our new protocol. Eight potent leads were identified from six TCM sources. A joint validation system comprised of comparative molecular field analysis, comparative molecular similarity indices analysis, and molecular dynamics simulation further characterized the candidates into three potential binding conformations and validated the binding stability of each protein-ligand complex. The ligand pathway was also performed to predict the ligand "in" and "exit" from the binding site. In summary, we propose a novel systematic CADD methodology for the identification, analysis, and characterization of drug-like candidates.

Identifying Canadian Teacher Candidates' Needs for Training in the Use of Inclusive Classroom Assessment

ERIC Educational Resources Information Center

Lin, Pei-Ying; Lin, Yu-Cheng

2015-01-01

To identify teacher candidates' needs for training in inclusive classroom assessment, the present study investigated teacher candidates' beliefs about inclusive classroom assessments for all students educated in regular classrooms, including those with special needs and English language learners. An innovative theoretical assessment model,…

Genomic and evolutionary characteristics of cattle copy number variations

USDA-ARS?s Scientific Manuscript database

We performed a systematic analysis of cattle copy number variations (CNVs) using the Bovine HapMap SNP genotyping data, including 539 animals of 21 modern cattle breeds and 6 outgroups. After correcting genomic waves and considering the trio information, we identified 682 candidate CNV regions (CNVR...

Empowerment among Teachers in Leadership Positions Involving ICT Implementation in Schools

ERIC Educational Resources Information Center

Avidov-Ungar, Orit

2018-01-01

The study identifies motivational characteristics of empowerment among teachers in leadership positions involving information and communications technology (ICT) implementation in schools. The participants were 24 teachers who were candidates for an Information and Communications Technology Leadership Award. Analysis of the in-depth interviews…

Probiotic Candidates from Fish Pond Water in Central Java Indonesia

NASA Astrophysics Data System (ADS)

Harjuno Condro Haditomo, Alfabetian; Desrina; Sarjito; Budi Prayitno, S.

2018-02-01

Aeromonas hydrophilla is a major bacterial pathogen of intensive fresh water fish culture in Indonesia. An alternative method to control the pathogen is using probiotics. Probiotics is usually consist of live microorganisms which when administered in adequate amounts confer a health benefits on host. The aim of this research was to determine the probiotic candidates against A. hydrophilla which identified based on the 16S rDNA gene sequences. This research was started with field survey to obtained the probiotic candidate and continue with laboratory experiment. Probiotic candidates were isolated from fish pond water located in Boyolali, and Banjarnegara Regency, Central Java, Indonesia. A total of 133 isolates bacteria were isolated and cultured on to TSA, TSB and GSP medium. Out of 133 isolates only 30 isolates showed inhibition to A.hydrophilla activity. Three promising isolates were identified with PCR using primer for 16S rDNA. Based on 16S rDNA sequence analysis, all three isolates were belong to Bacillus genus. Isolate CKlA21, CKlA28, and CBA14 respectively were closely related to Bacillus sp. 13843 (GenBank accession no. JN874760.1 -100% homology), Bacillus subtilis strain H13 (GenBank accession no.KT907045.1 -- 99% homology), and Bacillus sp. strain 22-4 (GenBank accession no. KX816417.1 -- 97% homology).

Quantitative interaction screen of telomeric repeat-containing RNA reveals novel TERRA regulators

PubMed Central

Scheibe, Marion; Arnoult, Nausica; Kappei, Dennis; Buchholz, Frank; Decottignies, Anabelle; Butter, Falk; Mann, Matthias

2013-01-01

Telomeres are actively transcribed into telomeric repeat-containing RNA (TERRA), which has been implicated in the regulation of telomere length and heterochromatin formation. Here, we applied quantitative mass spectrometry (MS)–based proteomics to obtain a high-confidence interactome of TERRA. Using SILAC-labeled nuclear cell lysates in an RNA pull-down experiment and two different salt conditions, we distinguished 115 proteins binding specifically to TERRA out of a large set of background binders. While TERRA binders identified in two previous studies showed little overlap, using quantitative mass spectrometry we obtained many candidates reported in these two studies. To test whether novel candidates found here are involved in TERRA regulation, we performed an esiRNA-based interference analysis for 15 of them. Knockdown of 10 genes encoding candidate proteins significantly affected total cellular levels of TERRA, and RNAi of five candidates perturbed TERRA recruitment to telomeres. Notably, depletion of SRRT/ARS2, involved in miRNA processing, up-regulated both total and telomere-bound TERRA. Conversely, knockdown of MORF4L2, a component of the NuA4 histone acetyltransferase complex, reduced TERRA levels both globally and for telomere-bound TERRA. We thus identified new proteins involved in the homeostasis and telomeric abundance of TERRA, extending our knowledge of TERRA regulation. PMID:23921659

Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease.

PubMed

Brehm, John M; Hagiwara, Koichi; Tesfaigzi, Yohannes; Bruse, Shannon; Mariani, Thomas J; Bhattacharya, Soumyaroop; Boutaoui, Nadia; Ziniti, John P; Soto-Quiros, Manuel E; Avila, Lydiana; Cho, Michael H; Himes, Blanca; Litonjua, Augusto A; Jacobson, Francine; Bakke, Per; Gulsvik, Amund; Anderson, Wayne H; Lomas, David A; Forno, Erick; Datta, Soma; Silverman, Edwin K; Celedón, Juan C

2011-12-01

Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing. The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. Methods The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs). Weights were constructed based on the frequency of these RCHHs in case versus controls, and used to adjust the p values from a large collaborative GWAS of COPD. The authors identified 2318 RCHHs, of which 576 were significantly (p<0.05) over-represented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms (SNPs) in a novel gene (fibroblast growth factor-7 (FGF7)) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined p values of 7.9E-7 and 2.8E-6, respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function. Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.

GOLDRUSH. III. A systematic search for protoclusters at z ˜ 4 based on the >100 deg2 area

NASA Astrophysics Data System (ADS)

Toshikawa, Jun; Uchiyama, Hisakazu; Kashikawa, Nobunari; Ouchi, Masami; Overzier, Roderik; Ono, Yoshiaki; Harikane, Yuichi; Ishikawa, Shogo; Kodama, Tadayuki; Matsuda, Yuichi; Lin, Yen-Ting; Onoue, Masafusa; Tanaka, Masayuki; Nagao, Tohru; Akiyama, Masayuki; Komiyama, Yutaka; Goto, Tomotsugu; Lee, Chien-Hsiu

2018-01-01

We conduct a systematic search for galaxy protoclusters at z ˜ 3.8 based on the latest internal data release (S16A) of the Hyper Suprime-Cam Subaru strategic program (HSC-SSP). In the Wide layer of the HSC-SSP, we investigate the large-scale projected sky distribution of g-dropout galaxies over an area of 121 deg2, and identify 216 large-scale overdense regions (>4 σ overdensity significance) that are likely protocluster candidates. Of these, 37 are located within 8΄ (3.4 physical Mpc) of other protocluster candidates of higher overdensity, and are expected to merge into a single massive structure by z = 0. Therefore, we find 179 unique protocluster candidates in our survey. A cosmological simulation that includes projection effects predicts that more than 76% of these candidates will evolve into galaxy clusters with halo masses of at least 1014 M⊙ by z = 0. The unprecedented size of our protocluster candidate catalog allows us to perform, for the first time, an angular clustering analysis of the systematic sample of protocluster candidates. We find a correlation length of 35.0 h-1 Mpc. The relation between correlation length and number density of z ˜ 3.8 protocluster candidates is consistent with the prediction of the ΛCDM model, and the correlation length is similar to that of rich clusters in the local universe. This result suggests that our protocluster candidates are tracing similar spatial structures to those expected from the progenitors of rich clusters, and enhances the confidence that our method for identifying protoclusters at high redshifts is robust. In years to come, our protocluster search will be extended to the entire HSC-SSP Wide sky coverage of ˜ 1400 deg2 to probe cluster formation over a wide redshift range of z ˜ 2-6.

The American Board of Radiology Holman Research Pathway: 10-year retrospective review of the program and participant performance.

PubMed

Wallner, Paul E; Ang, K Kian; Zietman, Anthony L; Harris, Jay R; Ibbott, Geoffrey S; Mahoney, Mary C; Mezwa, Duane G; Wilson, Lynn D; Becker, Gary J

2013-01-01

In 1999, the American Board of Radiology (ABR) implemented an innovative training program track in diagnostic radiology (DR) and radiation oncology (RO) designed to stimulate development of a cadre of future academic researchers and educators in the 2 disciplines. The program was designated the Holman Research Pathway (HRP). An in-depth retrospective review of initial certification examination performance, post-training career choices, and academic productivity has not been written. This report represents a 10-year retrospective review of post-training performance of a cohort of trainees who have had sufficient time to complete their training and initial certification process and to enter practice. All pertinent proceedings of the ABR and Accreditation Council for Graduate Medical Education (ACGME) Residency Review Committees for DR and RO between 1997 and May 2011 were reviewed. Thirty-four HRP candidates who fulfilled the established evaluation criteria were identified, and their ABR data files were analyzed regarding performance on the qualifying and certifying examinations. All candidates were contacted directly to obtain a current curriculum vitae. Twenty candidates in RO and 14 candidates in DR were identifiable for review. All candidates attained initial certification. At the time of analysis, 23 of 33 (66.6%) candidates were employed in full-time academic practice (1 DR candidate remained in a fellowship and was not evaluated regarding employment status). Fifteen of 20 (75%) RO candidates were in faculty positions compared with 7 of 13 (53.8%) DR trainees. Additional academic productivity metrics are reported. A high percentage of HRP trainees remained in academic practice and demonstrated significant academic productivity as measured by manuscript authorship and research support. Additional time and observation will be needed to determine whether these findings will be sustained by past, current, and future HRP trainees. Copyright © 2013 Elsevier Inc. All rights reserved.

JELLYFISH GALAXY CANDIDATES AT LOW REDSHIFT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poggianti, B. M.; Fasano, G.; Omizzolo, A.

Galaxies that are being stripped of their gas can sometimes be recognized from their optical appearance. Extreme examples of stripped galaxies are the so-called “jellyfish galaxies” that exhibit tentacles of debris material with a characteristic jellyfish morphology. We have conducted the first systematic search for galaxies that are being stripped of their gas at low-z (z = 0.04−0.07) in different environments, selecting galaxies with varying degrees of morphological evidence for stripping. We have visually inspected B- and V-band images and identified 344 candidates in 71 galaxy clusters of the OMEGAWINGS+WINGS sample and 75 candidates in groups and lower mass structuresmore » in the PM2GC sample. We present the atlas of stripping candidates and a first analysis of their environment and their basic properties, such as morphologies, star formation rates and galaxy stellar masses. Candidates are found in all clusters and at all clustercentric radii, and their number does not correlate with the cluster velocity dispersion σ or X-ray luminosity L{sub X}. Interestingly, convincing cases of candidates are also found in groups and lower mass halos (10{sup 11}−10{sup 14}M{sub ⊙}), although the physical mechanism at work needs to be securely identified. All the candidates are disky, have stellar masses ranging from log M/M{sub ⊙} < 9 to > 11.5 and the majority of them form stars at a rate that is on average a factor of 2 higher (2.5σ) compared to non-stripped galaxies of similar mass. The few post-starburst and passive candidates have weak stripping evidence. We conclude that disturbed morphologies suggestive of stripping phenomena are ubiquitous in clusters and could be present even in groups and low mass halos. Further studies will reveal the physics of the gas stripping and clarify the mechanisms at work.« less

The American Board of Radiology Holman Research Pathway: 10-Year Retrospective Review of the Program and Participant Performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wallner, Paul E., E-mail: pwallner@theabr.org; Ang, K. Kian; Zietman, Anthony L.

2013-01-01

Introduction: In 1999, the American Board of Radiology (ABR) implemented an innovative training program track in diagnostic radiology (DR) and radiation oncology (RO) designed to stimulate development of a cadre of future academic researchers and educators in the 2 disciplines. The program was designated the Holman Research Pathway (HRP). An in-depth retrospective review of initial certification examination performance, post-training career choices, and academic productivity has not been written. This report represents a 10-year retrospective review of post-training performance of a cohort of trainees who have had sufficient time to complete their training and initial certification process and to enter practice.more » Methods and Materials: All pertinent proceedings of the ABR and Accreditation Council for Graduate Medical Education (ACGME) Residency Review Committees for DR and RO between 1997 and May 2011 were reviewed. Thirty-four HRP candidates who fulfilled the established evaluation criteria were identified, and their ABR data files were analyzed regarding performance on the qualifying and certifying examinations. All candidates were contacted directly to obtain a current curriculum vitae. Results: Twenty candidates in RO and 14 candidates in DR were identifiable for review. All candidates attained initial certification. At the time of analysis, 23 of 33 (66.6%) candidates were employed in full-time academic practice (1 DR candidate remained in a fellowship and was not evaluated regarding employment status). Fifteen of 20 (75%) RO candidates were in faculty positions compared with 7 of 13 (53.8%) DR trainees. Additional academic productivity metrics are reported. Conclusions: A high percentage of HRP trainees remained in academic practice and demonstrated significant academic productivity as measured by manuscript authorship and research support. Additional time and observation will be needed to determine whether these findings will be sustained by past, current, and future HRP trainees.« less

Alzheimer's disease master regulators analysis: search for potential molecular targets and drug repositioning candidates.

PubMed

Vargas, D M; De Bastiani, M A; Zimmer, E R; Klamt, F

2018-06-23

Alzheimer's disease (AD) is a multifactorial and complex neuropathology that involves impairment of many intricate molecular mechanisms. Despite recent advances, AD pathophysiological characterization remains incomplete, which hampers the development of effective treatments. In fact, currently, there are no effective pharmacological treatments for AD. Integrative strategies such as transcription regulatory network and master regulator analyses exemplify promising new approaches to study complex diseases and may help in the identification of potential pharmacological targets. In this study, we used transcription regulatory network and master regulator analyses on transcriptomic data of human hippocampus to identify transcription factors (TFs) that can potentially act as master regulators in AD. All expression profiles were obtained from the Gene Expression Omnibus database using the GEOquery package. A normal hippocampus transcription factor-centered regulatory network was reconstructed using the ARACNe algorithm. Master regulator analysis and two-tail gene set enrichment analysis were employed to evaluate the inferred regulatory units in AD case-control studies. Finally, we used a connectivity map adaptation to prospect new potential therapeutic interventions by drug repurposing. We identified TFs with already reported involvement in AD, such as ATF2 and PARK2, as well as possible new targets for future investigations, such as CNOT7, CSRNP2, SLC30A9, and TSC22D1. Furthermore, Connectivity Map Analysis adaptation suggested the repositioning of six FDA-approved drugs that can potentially modulate master regulator candidate regulatory units (Cefuroxime, Cyproterone, Dydrogesterone, Metrizamide, Trimethadione, and Vorinostat). Using a transcription factor-centered regulatory network reconstruction we were able to identify several potential molecular targets and six drug candidates for repositioning in AD. Our study provides further support for the use of bioinformatics tools as exploratory strategies in neurodegenerative diseases research, and also provides new perspectives on molecular targets and drug therapies for future investigation and validation in AD.

THE CANDIDATE CLUSTER AND PROTOCLUSTER CATALOG (CCPC). II. SPECTROSCOPICALLY IDENTIFIED STRUCTURES SPANNING 2 <  z  < 6.6

DOE Office of Scientific and Technical Information (OSTI.GOV)

Franck, J. R.; McGaugh, S. S.

2016-12-10

The Candidate Cluster and Protocluster Catalog (CCPC) is a list of objects at redshifts z  > 2 composed of galaxies with spectroscopically confirmed redshifts that are coincident on the sky and in redshift. These protoclusters are identified by searching for groups in volumes corresponding to the expected size of the most massive protoclusters at these redshifts. In CCPC1 we identified 43 candidate protoclusters among 14,000 galaxies between 2.74 <  z  < 3.71. Here we expand our search to more than 40,000 galaxies with spectroscopic redshifts z  > 2.00, resulting in an additional 173 candidate structures. The most significant of these are 36 protoclusters withmore » overdensities δ {sub gal} > 7. We also identify three large proto-supercluster candidates containing multiple protoclusters at z  = 2.3, 3.5 and z  = 6.56. Eight candidates with N  ≥ 10 galaxies are found at redshifts z  > 4.0. The last system in the catalog is the most distant spectroscopic protocluster candidate known to date at z  = 6.56.« less

confFuse: High-Confidence Fusion Gene Detection across Tumor Entities.

PubMed

Huang, Zhiqin; Jones, David T W; Wu, Yonghe; Lichter, Peter; Zapatka, Marc

2017-01-01

Background: Fusion genes play an important role in the tumorigenesis of many cancers. Next-generation sequencing (NGS) technologies have been successfully applied in fusion gene detection for the last several years, and a number of NGS-based tools have been developed for identifying fusion genes during this period. Most fusion gene detection tools based on RNA-seq data report a large number of candidates (mostly false positives), making it hard to prioritize candidates for experimental validation and further analysis. Selection of reliable fusion genes for downstream analysis becomes very important in cancer research. We therefore developed confFuse, a scoring algorithm to reliably select high-confidence fusion genes which are likely to be biologically relevant. Results: confFuse takes multiple parameters into account in order to assign each fusion candidate a confidence score, of which score ≥8 indicates high-confidence fusion gene predictions. These parameters were manually curated based on our experience and on certain structural motifs of fusion genes. Compared with alternative tools, based on 96 published RNA-seq samples from different tumor entities, our method can significantly reduce the number of fusion candidates (301 high-confidence from 8,083 total predicted fusion genes) and keep high detection accuracy (recovery rate 85.7%). Validation of 18 novel, high-confidence fusions detected in three breast tumor samples resulted in a 100% validation rate. Conclusions: confFuse is a novel downstream filtering method that allows selection of highly reliable fusion gene candidates for further downstream analysis and experimental validations. confFuse is available at https://github.com/Zhiqin-HUANG/confFuse.

Stellar Stream Candidates in the Solar Neighborhood Found in the LAMOST DR3 and TGAS

NASA Astrophysics Data System (ADS)

Liang, X. L.; Zhao, J. K.; Oswalt, T. D.; Chen, Y. Q.; Zhang, L.; Zhao, G.

2017-08-01

We have cross-matched the LAMOST DR3 with the Gaia DR1 TGAS catalogs and obtained a sample of 166,827 stars with reliable kinematics. A technique based on the wavelet transform was applied to detect significant overdensities in velocity space among five subsamples divided by spatial position. In total, 16 significant overdensities of stars with very similar kinematics were identified. Among these, four are new stream candidates and the rest are previously known groups. Both the U-V velocity and metallicity distributions of the local sample show a clear gap between the Hercules structure and the Hyades-Pleiades structure. The U-V positions of these peaks shift with the spatial position. Following a description of our analysis, we speculate on possible origins of our stream candidates.

Establishment of a Comprehensive List of Candidate Antiaging Medicinal Herb Used in Korean Medicine by Text Mining of the Classical Korean Medical Literature, “Dongeuibogam,” and Preliminary Evaluation of the Antiaging Effects of These Herbs

PubMed Central

Choi, Moo Jin; Choi, Byung Tae; Shin, Hwa Kyoung; Shin, Byung Cheul; Han, Yoo Kyoung; Baek, Jin Ung

2015-01-01

The major objectives of this study were to provide a list of candidate antiaging medicinal herbs that have been widely utilized in Korean medicine and to organize preliminary data for the benefit of experimental and clinical researchers to develop new drug therapies by analyzing previous studies. “Dongeuibogam,” a representative source of the Korean medicine literature, was selected to investigate candidate antiaging medicinal herbs and to identify appropriate terms that describe the specific antiaging effects that these herbs are predicted to elicit. In addition, we aimed to review previous studies that referenced the selected candidate antiaging medicinal herbs. From our chosen source, “Dongeuibogam,” we were able to screen 102 terms describing antiaging effects, which were further classified into 11 subtypes. Ninety-seven candidate antiaging medicinal herbs were selected using the criterion that their antiaging effects were described using the same terms as those employed in “Dongeuibogam.” These candidates were classified into 11 subtypes. Of the 97 candidate antiaging medicinal herbs selected, 47 are widely used by Korean medical doctors in Korea and were selected for further analysis of their antiaging effects. Overall, we found an average of 7.7 previous studies per candidate herb that described their antiaging effects. PMID:25861371

Single nucleotide polymorphisms in bone turnover-related genes in Koreans: ethnic differences in linkage disequilibrium and haplotype

PubMed Central

Kim, Kyung-Seon; Kim, Ghi-Su; Hwang, Joo-Yeon; Lee, Hye-Ja; Park, Mi-Hyun; Kim, Kwang-joong; Jung, Jongsun; Cha, Hyo-Soung; Shin, Hyoung Doo; Kang, Jong-Ho; Park, Eui Kyun; Kim, Tae-Ho; Hong, Jung-Min; Koh, Jung-Min; Oh, Bermseok; Kimm, Kuchan; Kim, Shin-Yoon; Lee, Jong-Young

2007-01-01

Background Osteoporosis is defined as the loss of bone mineral density that leads to bone fragility with aging. Population-based case-control studies have identified polymorphisms in many candidate genes that have been associated with bone mass maintenance or osteoporotic fracture. To investigate single nucleotide polymorphisms (SNPs) that are associated with osteoporosis, we examined the genetic variation among Koreans by analyzing 81 genes according to their function in bone formation and resorption during bone remodeling. Methods We resequenced all the exons, splice junctions and promoter regions of candidate osteoporosis genes using 24 unrelated Korean individuals. Using the common SNPs from our study and the HapMap database, a statistical analysis of deviation in heterozygosity depicted. Results We identified 942 variants, including 888 SNPs, 43 insertion/deletion polymorphisms, and 11 microsatellite markers. Of the SNPs, 557 (63%) had been previously identified and 331 (37%) were newly discovered in the Korean population. When compared SNPs in the Korean population with those in HapMap database, 1% (or less) of SNPs in the Japanese and Chinese subpopulations and 20% of those in Caucasian and African subpopulations were significantly differentiated from the Hardy-Weinberg expectations. In addition, an analysis of the genetic diversity showed that there were no significant differences among Korean, Han Chinese and Japanese populations, but African and Caucasian populations were significantly differentiated in selected genes. Nevertheless, in the detailed analysis of genetic properties, the LD and Haplotype block patterns among the five sub-populations were substantially different from one another. Conclusion Through the resequencing of 81 osteoporosis candidate genes, 118 unknown SNPs with a minor allele frequency (MAF) > 0.05 were discovered in the Korean population. In addition, using the common SNPs between our study and HapMap, an analysis of genetic diversity and deviation in heterozygosity was performed and the polymorphisms of the above genes among the five populations were substantially differentiated from one another. Further studies of osteoporosis could utilize the polymorphisms identified in our data since they may have important implications for the selection of highly informative SNPs for future association studies. PMID:18036257

Academic performance of ethnic minority candidates and discrimination in the MRCGP examinations between 2010 and 2012: analysis of data

PubMed Central

Roberts, Chris

2013-01-01

Objective To determine the difference in failure rates in the postgraduate examination of the Royal College of General Practitioners (MRCGP) by ethnic or national background, and to identify factors associated with pass rates in the clinical skills assessment component of the examination. Design Analysis of data provided by the Royal College of General Practitioners and the General Medical Council. Participants Cohort of 5095 candidates sitting the applied knowledge test and clinical skills assessment components of the MRCGP examination between November 2010 and November 2012. A further analysis was carried out on 1175 candidates not trained in the United Kingdom, who sat an English language capability test (IELTS) and the Professional and Linguistic Assessment Board (PLAB) examination (as required for full medical registration), controlling for scores on these examinations and relating them to pass rates of the clinical skills assessment. Setting United Kingdom. Results After controlling for age, sex, and performance in the applied knowledge test, significant differences persisted between white UK graduates and other candidate groups. Black and minority ethnic graduates trained in the UK were more likely to fail the clinical skills assessment at their first attempt than their white UK colleagues (odds ratio 3.536 (95% confidence interval 2.701 to 4.629), P<0.001; failure rate 17% v 4.5%). Black and minority ethnic candidates who trained abroad were also more likely to fail the clinical skills assessment than white UK candidates (14.741 (11.397 to 19.065), P<0.001; 65% v 4.5%). For candidates not trained in the UK, black or minority ethnic candidates were more likely to fail than white candidates, but this difference was no longer significant after controlling for scores in the applied knowledge test, IELTS, and PLAB examinations (adjusted odds ratio 1.580 (95% confidence interval 0.878 to 2.845), P=0.127). Conclusions Subjective bias due to racial discrimination in the clinical skills assessment may be a cause of failure for UK trained candidates and international medical graduates. The difference between British black and minority ethnic candidates and British white candidates in the pass rates of the clinical skills assessment, despite controlling for prior attainment, suggests that subjective bias could also be a factor. Changes to the clinical skills assessment could improve the perception of the examination as being biased against black and minority ethnic candidates. The difference in training experience and other cultural factors between candidates trained in the UK and abroad could affect outcomes. Consideration should be given to strengthening postgraduate training for international medical graduates. PMID:24072882

Signatures of positive selection and local adaptation to urbanization in white-footed mice (Peromyscus leucopus).

PubMed

Harris, Stephen E; Munshi-South, Jason

2017-11-01

Urbanization significantly alters natural ecosystems and has accelerated globally. Urban wildlife populations are often highly fragmented by human infrastructure, and isolated populations may adapt in response to local urban pressures. However, relatively few studies have identified genomic signatures of adaptation in urban animals. We used a landscape genomic approach to examine signatures of selection in urban populations of white-footed mice (Peromyscus leucopus) in New York City. We analysed 154,770 SNPs identified from transcriptome data from 48 P. leucopus individuals from three urban and three rural populations and used outlier tests to identify evidence of urban adaptation. We accounted for demography by simulating a neutral SNP data set under an inferred demographic history as a null model for outlier analysis. We also tested whether candidate genes were associated with environmental variables related to urbanization. In total, we detected 381 outlier loci and after stringent filtering, identified and annotated 19 candidate loci. Many of the candidate genes were involved in metabolic processes and have well-established roles in metabolizing lipids and carbohydrates. Our results indicate that white-footed mice in New York City are adapting at the biomolecular level to local selective pressures in urban habitats. Annotation of outlier loci suggests selection is acting on metabolic pathways in urban populations, likely related to novel diets in cities that differ from diets in less disturbed areas. © 2017 John Wiley & Sons Ltd.

Kepler AutoRegressive Planet Search

NASA Astrophysics Data System (ADS)

Feigelson, Eric

NASA's Kepler mission is the source of more exoplanets than any other instrument, but the discovery depends on complex statistical analysis procedures embedded in the Kepler pipeline. A particular challenge is mitigating irregular stellar variability without loss of sensitivity to faint periodic planetary transits. This proposal presents a two-stage alternative analysis procedure. First, parametric autoregressive ARFIMA models, commonly used in econometrics, remove most of the stellar variations. Second, a novel matched filter is used to create a periodogram from which transit-like periodicities are identified. This analysis procedure, the Kepler AutoRegressive Planet Search (KARPS), is confirming most of the Kepler Objects of Interest and is expected to identify additional planetary candidates. The proposed research will complete application of the KARPS methodology to the prime Kepler mission light curves of 200,000: stars, and compare the results with Kepler Objects of Interest obtained with the Kepler pipeline. We will then conduct a variety of astronomical studies based on the KARPS results. Important subsamples will be extracted including Habitable Zone planets, hot super-Earths, grazing-transit hot Jupiters, and multi-planet systems. Groundbased spectroscopy of poorly studied candidates will be performed to better characterize the host stars. Studies of stellar variability will then be pursued based on KARPS analysis. The autocorrelation function and nonstationarity measures will be used to identify spotted stars at different stages of autoregressive modeling. Periodic variables with folded light curves inconsistent with planetary transits will be identified; they may be eclipsing or mutually-illuminating binary star systems. Classification of stellar variables with KARPS-derived statistical properties will be attempted. KARPS procedures will then be applied to archived K2 data to identify planetary transits and characterize stellar variability.

Fisher: a program for the detection of H/ACA snoRNAs using MFE secondary structure prediction and comparative genomics - assessment and update.

PubMed

Freyhult, Eva; Edvardsson, Sverker; Tamas, Ivica; Moulton, Vincent; Poole, Anthony M

2008-07-21

The H/ACA family of small nucleolar RNAs (snoRNAs) plays a central role in guiding the pseudouridylation of ribosomal RNA (rRNA). In an effort to systematically identify the complete set of rRNA-modifying H/ACA snoRNAs from the genome sequence of the budding yeast, Saccharomyces cerevisiae, we developed a program - Fisher - and previously presented several candidate snoRNAs based on our analysis 1. In this report, we provide a brief update of this work, which was aborted after the publication of experimentally-identified snoRNAs 2 identical to candidates we had identified bioinformatically using Fisher. Our motivation for revisiting this work is to report on the status of the candidate snoRNAs described in 1, and secondly, to report that a modified version of Fisher together with the available multiple yeast genome sequences was able to correctly identify several H/ACA snoRNAs for modification sites not identified by the snoGPS program 3. While we are no longer developing Fisher, we briefly consider the merits of the Fisher algorithm relative to snoGPS, which may be of use for workers considering pursuing a similar search strategy for the identification of small RNAs. The modified source code for Fisher is made available as supplementary material. Our results confirm the validity of using minimum free energy (MFE) secondary structure prediction to guide comparative genomic screening for RNA families with few sequence constraints.

Geostationary platform systems concepts definition study. Volume 2: Technical, book 1

NASA Technical Reports Server (NTRS)

1980-01-01

The initial selection and definition of operational geostationary platform concepts is discussed. Candidate geostationary platform missions and payloads were identified from COMSAT, Aerospace, and NASA studies. These missions and payloads were cataloged; classified with to communications, military, or scientific uses; screened for application and compatibility with geostationary platforms; and analyzed to identify platform requirements. Two platform locations were then selected (Western Hemisphere - 110 deg W, and Atlantic - 15 deg W), and payloads allocated based on nominal and high traffic models. Trade studies were performed leading to recommendation of selected concepts. Of 30 Orbit Transfer Vehicle (0TV) configuration and operating mode options identified, 18 viable candidates compatible with the operational geostationary platform missions were selected for analysis. Each was considered using four platform operational modes - 8 or 16 year life, and serviced or nonserviced, providing a total of 72 OTV/platform-mode options. For final trade study concept selection, a cost program was developed considering payload and platform costs and weight; transportation unit and total costs for the shuttle and OTV; and operational costs such as assembly or construction time, mating time, and loiter time. Servicing costs were added for final analysis and recommended selection.

Identification of candidate genes associated with porcine meat color traits by genome-wide transcriptome analysis.

PubMed

Li, Bojiang; Dong, Chao; Li, Pinghua; Ren, Zhuqing; Wang, Han; Yu, Fengxiang; Ning, Caibo; Liu, Kaiqing; Wei, Wei; Huang, Ruihua; Chen, Jie; Wu, Wangjun; Liu, Honglin

2016-10-17

Meat color is considered to be the most important indicator of meat quality, however, the molecular mechanisms underlying traits related to meat color remain mostly unknown. In this study, to elucidate the molecular basis of meat color, we constructed six cDNA libraries from biceps femoris (Bf) and soleus (Sol), which exhibit obvious differences in meat color, and analyzed the whole-transcriptome differences between Bf (white muscle) and Sol (red muscle) using high-throughput sequencing technology. Using DEseq2 method, we identified 138 differentially expressed genes (DEGs) between Bf and Sol. Using DEGseq method, we identified 770, 810, and 476 DEGs in comparisons between Bf and Sol in three separate animals. Of these DEGs, 52 were overlapping DEGs. Using these data, we determined the enriched GO terms, metabolic pathways and candidate genes associated with meat color traits. Additionally, we mapped 114 non-redundant DEGs to the meat color QTLs via a comparative analysis with the porcine quantitative trait loci (QTL) database. Overall, our data serve as a valuable resource for identifying genes whose functions are critical for meat color traits and can accelerate studies of the molecular mechanisms of meat color formation.

Identification of candidate genes associated with porcine meat color traits by genome-wide transcriptome analysis

PubMed Central

Li, Bojiang; Dong, Chao; Li, Pinghua; Ren, Zhuqing; Wang, Han; Yu, Fengxiang; Ning, Caibo; Liu, Kaiqing; Wei, Wei; Huang, Ruihua; Chen, Jie; Wu, Wangjun; Liu, Honglin

2016-01-01

Meat color is considered to be the most important indicator of meat quality, however, the molecular mechanisms underlying traits related to meat color remain mostly unknown. In this study, to elucidate the molecular basis of meat color, we constructed six cDNA libraries from biceps femoris (Bf) and soleus (Sol), which exhibit obvious differences in meat color, and analyzed the whole-transcriptome differences between Bf (white muscle) and Sol (red muscle) using high-throughput sequencing technology. Using DEseq2 method, we identified 138 differentially expressed genes (DEGs) between Bf and Sol. Using DEGseq method, we identified 770, 810, and 476 DEGs in comparisons between Bf and Sol in three separate animals. Of these DEGs, 52 were overlapping DEGs. Using these data, we determined the enriched GO terms, metabolic pathways and candidate genes associated with meat color traits. Additionally, we mapped 114 non-redundant DEGs to the meat color QTLs via a comparative analysis with the porcine quantitative trait loci (QTL) database. Overall, our data serve as a valuable resource for identifying genes whose functions are critical for meat color traits and can accelerate studies of the molecular mechanisms of meat color formation. PMID:27748458

Allosteric binding sites in Rab11 for potential drug candidates

PubMed Central

2018-01-01

Rab11 is an important protein subfamily in the RabGTPase family. These proteins physiologically function as key regulators of intracellular membrane trafficking processes. Pathologically, Rab11 proteins are implicated in many diseases including cancers, neurodegenerative diseases and type 2 diabetes. Although they are medically important, no previous study has found Rab11 allosteric binding sites where potential drug candidates can bind to. In this study, by employing multiple clustering approaches integrating principal component analysis, independent component analysis and locally linear embedding, we performed structural analyses of Rab11 and identified eight representative structures. Using these representatives to perform binding site mapping and virtual screening, we identified two novel binding sites in Rab11 and small molecules that can preferentially bind to different conformations of these sites with high affinities. After identifying the binding sites and the residue interaction networks in the representatives, we computationally showed that these binding sites may allosterically regulate Rab11, as these sites communicate with switch 2 region that binds to GTP/GDP. These two allosteric binding sites in Rab11 are also similar to two allosteric pockets in Ras that we discovered previously. PMID:29874286

Genes for seed longevity in barley identified by genomic analysis on Near Isogenic Lines.

PubMed

Wozny, Dorothee; Kramer, Katharina; Finkemeier, Iris; Acosta, Ivan F; Koornneef, Maarten

2018-05-09

Genes controlling differences in seed longevity between two barley (Hordeum vulgare) accessions were identified by combining quantitative genetics 'omics' technologies in Near Isogenic Lines (NILs). The NILs were derived from crosses between the spring barley landraces L94 from Ethiopia and Cebada Capa from Argentina. A combined transcriptome and proteome analysis on mature, non-aged seeds of the two parental lines and the L94 NILs by RNA-sequencing and total seed proteomic profiling identified the UDP-glycosyltransferase MLOC_11661.1 as candidate gene for the QTL on 2H, and the NADP-dependent malic enzyme (NADP-ME) MLOC_35785.1 as possible downstream target gene. To validate these candidates, they were expressed in Arabidopsis under the control of constitutive promoters to attempt complementing the T-DNA knock-out line nadp-me1. Both the NADP-ME MLOC_35785.1 and the UDP-glycosyltransferase MLOC_11661.1 were able to rescue the nadp-me1 seed longevity phenotype. In the case of the UDP-glycosyltransferase, with high accumulation in NILs, only the coding sequence of Cebada Capa had a rescue effect. This article is protected by copyright. All rights reserved.

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

PubMed Central

Li, Yun R; Li, Jin; Zhao, Sihai D; Bradfield, Jonathan P; Mentch, Frank D; Maggadottir, S Melkorka; Hou, Cuiping; Abrams, Debra J; Chang, Diana; Gao, Feng; Guo, Yiran; Wei, Zhi; Connolly, John J; Cardinale, Christopher J; Bakay, Marina; Glessner, Joseph T; Li, Dong; Kao, Charlly; Thomas, Kelly A; Qiu, Haijun; Chiavacci, Rosetta M; Kim, Cecilia E; Wang, Fengxiang; Snyder, James; Richie, Marylyn D; Flatø, Berit; Førre, Øystein; Denson, Lee A; Thompson, Susan D; Becker, Mara L; Guthery, Stephen L; Latiano, Anna; Perez, Elena; Resnick, Elena; Russell, Richard K; Wilson, David C; Silverberg, Mark S; Annese, Vito; Lie, Benedicte A; Punaro, Marilynn; Dubinsky, Marla C; Monos, Dimitri S; Strisciuglio, Caterina; Staiano, Annamaria; Miele, Erasmo; Kugathasan, Subra; Ellis, Justine A; Munro, Jane E; Sullivan, Kathleen E; Wise, Carol A; Chapel, Helen; Cunningham-Rundles, Charlotte; Grant, Struan F A; Orange, Jordan S; Sleiman, Patrick M A; Behrens, Edward M; Griffiths, Anne M; Satsangi, Jack; Finkel, Terri H; Keinan, Alon; Prak, Eline T Luning; Polychronakos, Constantin; Baldassano, Robert N; Li, Hongzhe; Keating, Brendan J; Hakonarson, Hakon

2016-01-01

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico–replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases. PMID:26301688

Genetic variants in two pathways influence serum urate levels and gout risk: a systematic pathway analysis.

PubMed

Dong, Zheng; Zhou, Jingru; Xu, Xia; Jiang, Shuai; Li, Yuan; Zhao, Dongbao; Yang, Chengde; Ma, Yanyun; Wang, Yi; He, Hongjun; Ji, Hengdong; Zhang, Juan; Yuan, Ziyu; Yang, Yajun; Wang, Xiaofeng; Pang, Yafei; Jin, Li; Zou, Hejian; Wang, Jiucun

2018-03-01

The aims of this study were to identify candidate pathways associated with serum urate and to explore the genetic effect of those pathways on the risk of gout. Pathway analysis of the loci identified in genome-wide association studies (GWASs) showed that the ion transmembrane transporter activity pathway (GO: 0015075) and the secondary active transmembrane transporter activity pathway (GO: 0015291) were both associated with serum urate concentrations, with P FDR values of 0.004 and 0.007, respectively. In a Chinese population of 4,332 individuals, the two pathways were also found to be associated with serum urate (P FDR  = 1.88E-05 and 3.44E-04, separately). In addition, these two pathways were further associated with the pathogenesis of gout (P FDR  = 1.08E-08 and 2.66E-03, respectively) in the Chinese population and a novel gout-associated gene, SLC17A2, was identified (OR = 0.83, P FDR  = 0.017). The mRNA expression of candidate genes also showed significant differences among different groups at pathway level. The present study identified two transmembrane transporter activity pathways (GO: 0015075 and GO: 0015291) were associations with serum urate concentrations and the risk of gout. SLC17A2 was identified as a novel gene that influenced the risk of gout.

Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.

PubMed

Dinckan, N; Du, R; Petty, L E; Coban-Akdemir, Z; Jhangiani, S N; Paine, I; Baugh, E H; Erdem, A P; Kayserili, H; Doddapaneni, H; Hu, J; Muzny, D M; Boerwinkle, E; Gibbs, R A; Lupski, J R; Uyguner, Z O; Below, J E; Letra, A

2018-01-01

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

Pooled Genome-Wide Analysis to Identify Novel Risk Loci for Pediatric Allergic Asthma

PubMed Central

Ricci, Giampaolo; Astolfi, Annalisa; Remondini, Daniel; Cipriani, Francesca; Formica, Serena; Dondi, Arianna; Pession, Andrea

2011-01-01

Background Genome-wide association studies of pooled DNA samples were shown to be a valuable tool to identify candidate SNPs associated to a phenotype. No such study was up to now applied to childhood allergic asthma, even if the very high complexity of asthma genetics is an appropriate field to explore the potential of pooled GWAS approach. Methodology/Principal Findings We performed a pooled GWAS and individual genotyping in 269 children with allergic respiratory diseases comparing allergic children with and without asthma. We used a modular approach to identify the most significant loci associated with asthma by combining silhouette statistics and physical distance method with cluster-adapted thresholding. We found 97% concordance between pooled GWAS and individual genotyping, with 36 out of 37 top-scoring SNPs significant at individual genotyping level. The most significant SNP is located inside the coding sequence of C5, an already identified asthma susceptibility gene, while the other loci regulate functions that are relevant to bronchial physiopathology, as immune- or inflammation-mediated mechanisms and airway smooth muscle contraction. Integration with gene expression data showed that almost half of the putative susceptibility genes are differentially expressed in experimental asthma mouse models. Conclusion/Significance Combined silhouette statistics and cluster-adapted physical distance threshold analysis of pooled GWAS data is an efficient method to identify candidate SNP associated to asthma development in an allergic pediatric population. PMID:21359210

Identifying candidate drivers of drug response in heterogeneous cancer by mining high throughput genomics data.

PubMed

Nabavi, Sheida

2016-08-15

With advances in technologies, huge amounts of multiple types of high-throughput genomics data are available. These data have tremendous potential to identify new and clinically valuable biomarkers to guide the diagnosis, assessment of prognosis, and treatment of complex diseases, such as cancer. Integrating, analyzing, and interpreting big and noisy genomics data to obtain biologically meaningful results, however, remains highly challenging. Mining genomics datasets by utilizing advanced computational methods can help to address these issues. To facilitate the identification of a short list of biologically meaningful genes as candidate drivers of anti-cancer drug resistance from an enormous amount of heterogeneous data, we employed statistical machine-learning techniques and integrated genomics datasets. We developed a computational method that integrates gene expression, somatic mutation, and copy number aberration data of sensitive and resistant tumors. In this method, an integrative method based on module network analysis is applied to identify potential driver genes. This is followed by cross-validation and a comparison of the results of sensitive and resistance groups to obtain the final list of candidate biomarkers. We applied this method to the ovarian cancer data from the cancer genome atlas. The final result contains biologically relevant genes, such as COL11A1, which has been reported as a cis-platinum resistant biomarker for epithelial ovarian carcinoma in several recent studies. The described method yields a short list of aberrant genes that also control the expression of their co-regulated genes. The results suggest that the unbiased data driven computational method can identify biologically relevant candidate biomarkers. It can be utilized in a wide range of applications that compare two conditions with highly heterogeneous datasets.

Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs

PubMed Central

Theunert, Christoph; Pugach, Irina; Li, Jing; Nandineni, Madhusudan R.; Gross, Arnd; Scholz, Markus; Stoneking, Mark

2009-01-01

Background Genome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world. Methodology We genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level. Conclusions Our analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature. PMID:19924308

A multiple-dimension liquid chromatography coupled with mass spectrometry data strategy for the rapid discovery and identification of unknown compounds from a Chinese herbal formula (Er-xian decoction).

PubMed

Wang, Caihong; Zhang, Jinlan; Wu, Caisheng; Wang, Zhe

2017-10-06

It is very important to rapidly discover and identify the multiple components of traditional Chinese medicine (TCM) formula. High performance liquid chromatography with high resolution tandem mass spectrometry (HPLC-HRMS/MS) has been widely used to analyze TCM formula and contains multiple-dimension data including retention time (RT), high resolution mass (HRMS), multiple-stage mass spectrometric (MS n ), and isotope intensity distribution (IID) data. So it is very necessary to exploit a useful strategy to utilize multiple-dimension data to rapidly probe structural information and identify chemical compounds. In this study, a new strategy to initiatively use the multiple-dimension LC-MS data has been developed to discover and identify unknown compounds of TCM in many styles. The strategy guarantees the fast discovery of candidate structural information and provides efficient structure clues for identification. The strategy contains four steps in sequence: (1) to discover potential compounds and obtain sub-structure information by the mass spectral tree similarity filter (MTSF) technique, based on HRMS and MS n data; (2) to classify potential compounds into known chemical classes by discriminant analysis (DA) on the basis of RT and HRMS data; (3) to hit the candidate structural information of compounds by intersection sub-structure between MTSF and DA (M,D-INSS); (4) to annotate and confirm candidate structures by IID data. This strategy allowed for the high exclusion efficiency (greater than 41%) of irrelevant ions in er-xian decoction (EXD) while providing accurate structural information of 553 potential compounds and identifying 66 candidates, therefore accelerating and simplifying the discovery and identification of unknown compounds in TCM formula. Copyright © 2017 Elsevier B.V. All rights reserved.

IFRD1 Is a Candidate Gene for SMNA on Chromosome 7q22-q23

PubMed Central

Brkanac, Zoran; Spencer, David; Shendure, Jay; Robertson, Peggy D.; Matsushita, Mark; Vu, Tiffany; Bird, Thomas D.; Olson, Maynard V.; Raskind, Wendy H.

2009-01-01

We have established strong linkage evidence that supports mapping autosomal-dominant sensory/motor neuropathy with ataxia (SMNA) to chromosome 7q22-q32. SMNA is a rare neurological disorder whose phenotype encompasses both the central and the peripheral nervous system. In order to identify a gene responsible for SMNA, we have undertaken a comprehensive genomic evaluation of the region of linkage, including evaluation for repeat expansion and small deletions or duplications, capillary sequencing of candidate genes, and massively parallel sequencing of all coding exons. We excluded repeat expansion and small deletions or duplications as causative, and through microarray-based hybrid capture and massively parallel short-read sequencing, we identified a nonsynonymous variant in the human interferon-related developmental regulator gene 1 (IFRD1) as a disease-causing candidate. Sequence conservation, animal models, and protein structure evaluation support the involvement of IFRD1 in SMNA. Mutation analysis of IFRD1 in additional patients with similar phenotypes is needed for demonstration of causality and further evaluation of its importance in neurological diseases. PMID:19409521

A novel nonsense mutation in CRYBB1 associated with autosomal dominant congenital cataract

PubMed Central

Yang, Juhua; Zhu, Yihua; Gu, Feng; He, Xiang; Cao, Zongfu; Li, Xuexi; Tong, Yi

2008-01-01

Purpose To identify the molecular defect underlying an autosomal dominant congenital nuclear cataract in a Chinese family. Methods Twenty-two members of a three-generation pedigree were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. All members were genotyped with polymorphic microsatellite markers adjacent to each of the known cataract-related genes. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing. Individuals were screened for presence of a mutation by restriction fragment length polymorphism (RFLP) analysis. Results Linkage analysis identified a maximum LOD score of 3.31 (recombination fraction [θ]=0.0) with marker D22S1167 on chromosome 22, which flanks the β-crystallin gene cluster (CRYBB3, CRYBB2, CRYBB1, and CRYBA4). Sequencing the coding regions and the flanking intronic sequences of these four candidate genes identified a novel, heterozygous C→T transition in exon 6 of CRYBB1 in the affected individuals of the family. This single nucleotide change introduced a novel BfaI site and was predicted to result in a nonsense mutation at codon 223 that changed a phylogenetically conserved amino acid to a stop codon (p.Q223X). RFLP analysis confirmed that this mutation co-segregated with the disease phenotype in all available family members and was not found in 100 normal unrelated individuals from the same ethnic background. Conclusions This study has identified a novel nonsense mutation in CRYBB1 (p.Q223X) associated with autosomal dominant congenital nuclear cataract. PMID:18432316

Performance studies of D-meson tagged jets in pp collisions at \\sqrt{s}=7\\,{TeV} with ALICE

NASA Astrophysics Data System (ADS)

Aiola, Salvatore; ALICE Collaboration

2017-04-01

We present the current status of the measurement of jets that contain a D meson (D-tagged jets) with the ALICE detector. D0-meson candidates, identified via their hadronic decay into a Kπ pair, were combined with the other charged tracks reconstructed with the central tracking system, using the anti-kT jet-finding algorithm. The yield of D-tagged jets was extracted through an invariant mass analysis of the D-meson candidates. A Monte Carlo simulation was used to determine the detector performance and validate the signal extraction techniques.

Identification and Analysis of Future Aeronautical Communications Candidates: A Study of Concepts and Technologies to Support the Aeronautical Communications Needs in the NextGen and Beyond National Airspace System

NASA Technical Reports Server (NTRS)

Wichgers, Joel M.; Mitchell, James P.

2015-01-01

This report describes the results of future aeronautical communications research conducted by Rockwell Collins employees under NRA contract to NASA. The overall goal of this research was to identify and begin to evaluate communication technology candidates expected to meet the long-term aircraft-to-aircraft and aircraft-to-ground data communications needs of Air Traffic Management in the NextGen and beyond National Airspace System (NAS), considering how the NAS and communications technologies will evolve during a 50-year modernization time horizon.

A genome-wide association study of corneal astigmatism: The CREAM Consortium

PubMed Central

Shah, Rupal L.; Li, Qing; Zhao, Wanting; Tedja, Milly S.; Tideman, J. Willem L.; Khawaja, Anthony P.; Fan, Qiao; Yazar, Seyhan; Williams, Katie M.; Verhoeven, Virginie J.M.; Xie, Jing; Wang, Ya Xing; Hess, Moritz; Nickels, Stefan; Lackner, Karl J.; Pärssinen, Olavi; Wedenoja, Juho; Biino, Ginevra; Concas, Maria Pina; Uitterlinden, André; Rivadeneira, Fernando; Jaddoe, Vincent W.V.; Hysi, Pirro G.; Sim, Xueling; Tan, Nicholas; Tham, Yih-Chung; Sensaki, Sonoko; Hofman, Albert; Vingerling, Johannes R.; Jonas, Jost B.; Mitchell, Paul; Hammond, Christopher J.; Höhn, René; Baird, Paul N.; Wong, Tien-Yin; Cheng, Chinfsg-Yu; Teo, Yik Ying; Mackey, David A.; Williams, Cathy; Saw, Seang-Mei; Klaver, Caroline C.W.; Bailey-Wilson, Joan E.

2018-01-01

Purpose To identify genes and genetic markers associated with corneal astigmatism. Methods A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08–1.16), p=5.55×10−9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans—claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism. PMID:29422769

Vitamin D receptor gene Alw I, Fok I, Apa I, and Taq I polymorphisms in patients with urinary stone.

PubMed

Seo, Ill Young; Kang, In-Hong; Chae, Soo-Cheon; Park, Seung Chol; Lee, Young-Jin; Yang, Yun Sik; Ryu, Soo Bang; Rim, Joung Sik

2010-04-01

To evaluate vitamin D receptor (VDR) gene polymorphisms in Korean patients so as to identify the candidate genes associated with urinary stones. Urinary stones are a multifactorial disease that includes various genetic factors. A normal control group of 535 healthy subjects and 278 patients with urinary stones was evaluated. Of 125 patients who presented stone samples, 102 had calcium stones on chemical analysis. The VDR gene Alw I, Fok I, Apa I, and Taq I polymorphisms were evaluated using the polymerase chain reaction-restriction fragment length polymorphism analysis. Allelic and genotypic frequencies were calculated to identify associations in both groups. The haplotype frequencies of the VDR gene polymorphisms for multiple loci were also determined. For the VDR gene Alw I, Fok I, Apa I, and Taq I polymorphisms, there was no statistically significant difference between the patients with urinary stones and the healthy controls. There was also no statistically significant difference between the patients with calcium stones and the healthy controls. A novel haplotype (Ht 4; CTTT) was identified in 13.5% of the patients with urinary stones and in 8.3% of the controls (P = .001). The haplotype frequencies were significantly different between the patients with calcium stones and the controls (P = .004). The VDR gene Alw I, Fok I, Apa I, and Taq I polymorphisms does not seem to be candidate genetic markers for urinary stones in Korean patients. However, 1 novel haplotype of the VDR gene polymorphisms for multiple loci might be a candidate genetic marker. Copyright 2010 Elsevier Inc. All rights reserved.

Analysis of X chromosome genomic DNA sequence copy number variation associated with premature ovarian failure (POF)

PubMed Central

Quilter, C.R.; Karcanias, A.C.; Bagga, M.R.; Duncan, S.; Murray, A.; Conway, G.S.; Sargent, C.A.; Affara, N.A.

2013-01-01

BACKGROUND Premature ovarian failure (POF) is a heterogeneous disease defined as amenorrhoea for >6 months before age 40, with an FSH serum level >40 mIU/ml (menopausal levels). While there is a strong genetic association with POF, familial studies have also indicated that idiopathic POF may also be genetically linked. Conventional cytogenetic analyses have identified regions of the X chromosome that are strongly associated with ovarian function, as well as several POF candidate genes. Cryptic chromosome abnormalities that have been missed might be detected by array comparative genomic hybridization. METHODS In this study, samples from 42 idiopathic POF patients were subjected to a complete end-to-end X/Y chromosome tiling path array to achieve a detailed copy number variation (CNV) analysis of X chromosome involvement in POF. The arrays also contained a 1 Mb autosomal tiling path as a reference control. Quantitative PCR for selected genes contained within the CNVs was used to confirm the majority of the changes detected. The expression pattern of some of these genes in human tissue RNA was examined by reverse transcription (RT)–PCR. RESULTS A number of CNVs were identified on both Xp and Xq, with several being shared among the POF cases. Some CNVs fall within known polymorphic CNV regions, and others span previously identified POF candidate regions and genes. CONCLUSIONS The new data reported in this study reveal further discrete X chromosome intervals not previously associated with the disease and therefore implicate new clusters of candidate genes. Further studies will be required to elucidate their involvement in POF. PMID:20570974

QTL analysis and candidate gene mapping for the polyphenol content in cider apple.

PubMed

Verdu, Cindy F; Guyot, Sylvain; Childebrand, Nicolas; Bahut, Muriel; Celton, Jean-Marc; Gaillard, Sylvain; Lasserre-Zuber, Pauline; Troggio, Michela; Guilet, David; Laurens, François

2014-01-01

Polyphenols have favorable antioxidant potential on human health suggesting that their high content is responsible for the beneficial effects of apple consumption. They control the quality of ciders as they predominantly account for astringency, bitterness, color and aroma. In this study, we identified QTLs controlling phenolic compound concentrations and the average polymerization degree of flavanols in a cider apple progeny. Thirty-two compounds belonging to five groups of phenolic compounds were identified and quantified by reversed phase liquid chromatography on both fruit extract and juice, over three years. The average polymerization degree of flavanols was estimated in fruit by phloroglucinolysis coupled to HPLC. Parental maps were built using SSR and SNP markers and used for the QTL analysis. Sixty-nine and 72 QTLs were detected on 14 and 11 linkage groups of the female and male maps, respectively. A majority of the QTLs identified in this study are specific to this population, while others are consistent with previous studies. This study presents for the first time in apple, QTLs for the mean polymerization degree of procyanidins, for which the mechanisms involved remains unknown to this day. Identification of candidate genes underlying major QTLs was then performed in silico and permitted the identification of 18 enzymes of the polyphenol pathway and six transcription factors involved in the apple anthocyanin regulation. New markers were designed from sequences of the most interesting candidate genes in order to confirm their co-localization with underlying QTLs by genetic mapping. Finally, the potential use of these QTLs in breeding programs is discussed.

Educational Progress: Cities Mobilize To Improve Their Schools.

ERIC Educational Resources Information Center

Hill, Paul T.; And Others

This report identifies the strategies that multiproblem urban school districts have used to make major improvements in recent years. A panel of experts familiar with urban school systems nominated over 30 candidate urban districts for study. The following districts were chosen for analysis: (1) Atlanta (Georgia); (2) Cincinnati (Ohio); (3) Memphis…

Combined Analysis of the Fruit Metabolome and Transcriptome Reveals Candidate Genes Involved in Flavonoid Biosynthesis in Actinidia arguta.

PubMed

Li, Yukuo; Fang, Jinbao; Qi, Xiujuan; Lin, Miaomiao; Zhong, Yunpeng; Sun, Leiming; Cui, Wen

2018-05-15

To assess the interrelation between the change of metabolites and the change of fruit color, we performed a combined metabolome and transcriptome analysis of the flesh in two different Actinidia arguta cultivars: "HB" ("Hongbaoshixing") and "YF" ("Yongfengyihao") at two different fruit developmental stages: 70d (days after full bloom) and 100d (days after full bloom). Metabolite and transcript profiling was obtained by ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometer and high-throughput RNA sequencing, respectively. The identification and quantification results of metabolites showed that a total of 28,837 metabolites had been obtained, of which 13,715 were annotated. In comparison of HB100 vs. HB70, 41 metabolites were identified as being flavonoids, 7 of which, with significant difference, were identified as bracteatin, luteolin, dihydromyricetin, cyanidin, pelargonidin, delphinidin and (-)-epigallocatechin. Association analysis between metabolome and transcriptome revealed that there were two metabolic pathways presenting significant differences during fruit development, one of which was flavonoid biosynthesis, in which 14 structural genes were selected to conduct expression analysis, as well as 5 transcription factor genes obtained by transcriptome analysis. RT-qPCR results and cluster analysis revealed that AaF3H , AaLDOX , AaUFGT , AaMYB , AabHLH , and AaHB2 showed the best possibility of being candidate genes. A regulatory network of flavonoid biosynthesis was established to illustrate differentially expressed candidate genes involved in accumulation of metabolites with significant differences, inducing red coloring during fruit development. Such a regulatory network linking genes and flavonoids revealed a system involved in the pigmentation of all-red-fleshed and all-green-fleshed A. arguta , suggesting this conjunct analysis approach is not only useful in understanding the relationship between genotype and phenotype, but is also a powerful tool for providing more valuable information for breeding.

Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases.

PubMed

Li, Matthew D; Burns, Terry C; Morgan, Alexander A; Khatri, Purvesh

2014-09-04

Neurodegenerative diseases share common pathologic features including neuroinflammation, mitochondrial dysfunction and protein aggregation, suggesting common underlying mechanisms of neurodegeneration. We undertook a meta-analysis of public gene expression data for neurodegenerative diseases to identify a common transcriptional signature of neurodegeneration. Using 1,270 post-mortem central nervous system tissue samples from 13 patient cohorts covering four neurodegenerative diseases, we identified 243 differentially expressed genes, which were similarly dysregulated in 15 additional patient cohorts of 205 samples including seven neurodegenerative diseases. This gene signature correlated with histologic disease severity. Metallothioneins featured prominently among differentially expressed genes, and functional pathway analysis identified specific convergent themes of dysregulation. MetaCore network analyses revealed various novel candidate hub genes (e.g. STAU2). Genes associated with M1-polarized macrophages and reactive astrocytes were strongly enriched in the meta-analysis data. Evaluation of genes enriched in neurons revealed 70 down-regulated genes, over half not previously associated with neurodegeneration. Comparison with aging brain data (3 patient cohorts, 221 samples) revealed 53 of these to be unique to neurodegenerative disease, many of which are strong candidates to be important in neuropathogenesis (e.g. NDN, NAP1L2). ENCODE ChIP-seq analysis predicted common upstream transcriptional regulators not associated with normal aging (REST, RBBP5, SIN3A, SP2, YY1, ZNF143, IKZF1). Finally, we removed genes common to neurodegeneration from disease-specific gene signatures, revealing uniquely robust immune response and JAK-STAT signaling in amyotrophic lateral sclerosis. Our results implicate pervasive bioenergetic deficits, M1-type microglial activation and gliosis as unifying themes of neurodegeneration, and identify numerous novel genes associated with neurodegenerative processes.

Detection of sub-kilometer craters in high resolution planetary images using shape and texture features

NASA Astrophysics Data System (ADS)

Bandeira, Lourenço; Ding, Wei; Stepinski, Tomasz F.

2012-01-01

Counting craters is a paramount tool of planetary analysis because it provides relative dating of planetary surfaces. Dating surfaces with high spatial resolution requires counting a very large number of small, sub-kilometer size craters. Exhaustive manual surveys of such craters over extensive regions are impractical, sparking interest in designing crater detection algorithms (CDAs). As a part of our effort to design a CDA, which is robust and practical for planetary research analysis, we propose a crater detection approach that utilizes both shape and texture features to identify efficiently sub-kilometer craters in high resolution panchromatic images. First, a mathematical morphology-based shape analysis is used to identify regions in an image that may contain craters; only those regions - crater candidates - are the subject of further processing. Second, image texture features in combination with the boosting ensemble supervised learning algorithm are used to accurately classify previously identified candidates into craters and non-craters. The design of the proposed CDA is described and its performance is evaluated using a high resolution image of Mars for which sub-kilometer craters have been manually identified. The overall detection rate of the proposed CDA is 81%, the branching factor is 0.14, and the overall quality factor is 72%. This performance is a significant improvement over the previous CDA based exclusively on the shape features. The combination of performance level and computational efficiency offered by this CDA makes it attractive for practical application.

Applying Qualitative Hazard Analysis to Support Quantitative Safety Analysis for Proposed Reduced Wake Separation Conops

NASA Technical Reports Server (NTRS)

Shortle, John F.; Allocco, Michael

2005-01-01

This paper describes a scenario-driven hazard analysis process to identify, eliminate, and control safety-related risks. Within this process, we develop selective criteria to determine the applicability of applying engineering modeling to hypothesized hazard scenarios. This provides a basis for evaluating and prioritizing the scenarios as candidates for further quantitative analysis. We have applied this methodology to proposed concepts of operations for reduced wake separation for closely spaced parallel runways. For arrivals, the process identified 43 core hazard scenarios. Of these, we classified 12 as appropriate for further quantitative modeling, 24 that should be mitigated through controls, recommendations, and / or procedures (that is, scenarios not appropriate for quantitative modeling), and 7 that have the lowest priority for further analysis.

Dynamic changes in transcriptome and cell wall composition underlying brassinosteroid-mediated lignification of switchgrass suspension cells.

PubMed

Rao, Xiaolan; Shen, Hui; Pattathil, Sivakumar; Hahn, Michael G; Gelineo-Albersheim, Ivana; Mohnen, Debra; Pu, Yunqiao; Ragauskas, Arthur J; Chen, Xin; Chen, Fang; Dixon, Richard A

2017-01-01

Plant cell walls contribute the majority of plant biomass that can be used to produce transportation fuels. However, the complexity and variability in composition and structure of cell walls, particularly the presence of lignin, negatively impacts their deconstruction for bioenergy. Metabolic and genetic changes associated with secondary wall development in the biofuel crop switchgrass ( Panicum virgatum ) have yet to be reported. Our previous studies have established a cell suspension system for switchgrass, in which cell wall lignification can be induced by application of brassinolide (BL). We have now collected cell wall composition and microarray-based transcriptome profiles for BL-induced and non-induced suspension cultures to provide an overview of the dynamic changes in transcriptional reprogramming during BL-induced cell wall modification. From this analysis, we have identified changes in candidate genes involved in cell wall precursor synthesis, cellulose, hemicellulose, and pectin formation and ester-linkage generation. We have also identified a large number of transcription factors with expression correlated with lignin biosynthesis genes, among which are candidates for control of syringyl (S) lignin accumulation. Together, this work provides an overview of the dynamic compositional changes during brassinosteroid-induced cell wall remodeling, and identifies candidate genes for future plant genetic engineering to overcome cell wall recalcitrance.

Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate.

PubMed

Mackiewicz, M; Paigen, B; Naidoo, N; Pack, A I

2008-03-14

Electroencephalographic oscillations in the frequency range of 0.5-4 Hz, characteristic of slow-wave sleep (SWS), are often referred to as the delta oscillation or delta power. Delta power reflects sleep intensity and correlates with the homeostatic response to sleep loss. A published survey of inbred strains of mice demonstrated that the time course of accumulation of delta power varied among inbred strains, and the segregation of the rebound of delta power in BxD recombinant inbred strains identified a genomic region on chromosome 13 referred to as the delta power in SWS (or Dps1). The quantitative trait locus (QTL) contains genes that modify the accumulation of delta power after sleep deprivation. Here, we narrow the QTL using interval-specific haplotype analysis and present a comprehensive annotation of the remaining genes in the Dps1 region with sequence comparisons to identify polymorphisms within the coding and regulatory regions. We established the expression pattern of selected genes located in the Dps1 interval in sleep and wakefulness in B6 and D2 parental strains. Taken together, these steps reduced the number of potential candidate genes that may underlie the accumulation of delta power after sleep deprivation and explain the Dps1 QTL. The strongest candidate gene is Homer1a, which is supported by expression differences between sleep and wakefulness and the SNP polymorphism in the upstream regulatory regions.

Thermomechanics of candidate coatings for advanced gas reactor fuels

NASA Astrophysics Data System (ADS)

Nosek, A.; Conzen, J.; Doescher, H.; Martin, C.; Blanchard, J.

2007-09-01

Candidate fuel/coating combinations for an advanced, coated-fuel particle for a gas-cooled fast reactor (GFR) have been evaluated. These all-ceramic fuel forms consist of a fuel kernel made of UC or UN, surrounded with two shells (a buffer and a coating) made of TiC, SiC, ZrC, TiN, or ZrN. These carbides and nitrides are analyzed with finite element models to determine the stresses produced in the micro fuel particles from differential thermal expansion, fission gas release, swelling, and creep during particle fabrication and reactor operation. This study will help determine the feasibility of different fuel and coating combinations and identify the critical loads. The analysis shows that differential thermal expansion of the fuel and coating dictate the amount of stress for changing temperatures (such as during fabrication), and that the coating creep is able to mitigate an otherwise overwhelming amount of stress from fuel swelling. Because fracture is a likely mode of failure, a fracture mechanics study is also included to identify the relative likelihood of catastrophic fracture of the coating and resulting gas release. Overall, the analysis predicts that UN/ZrC is the best thermomechanical fuel/coating combination for mitigating the stress within the new fuel particle, but UN/TiN and UN/ZrN could also be strong candidates if their unknown creep rates are sufficiently large.

Epigenetic discrimination of identical twins from blood under the forensic scenario.

PubMed

Vidaki, Athina; Díez López, Celia; Carnero-Montoro, Elena; Ralf, Arwin; Ward, Kirsten; Spector, Timothy; Bell, Jordana T; Kayser, Manfred

2017-11-01

Monozygotic (MZ) twins share the same STR profile, demonstrating a practical problem in forensic casework. DNA methylation has provided a suitable resource for MZ twin differentiation; however, studies addressing the forensic feasibility are lacking. Here, we investigated epigenetic MZ twin differentiation from blood under the forensic scenario comprising i) the discovery of candidate markers in reference-type blood DNA via genome-wide analysis, ii) the technical validation of candidate markers in reference-type blood DNA using a suitable targeted method, and iii) the analysis of the validated markers in trace-type DNA. Genome-wide methylation analysis in blood DNA from 10 MZ twin pairs resulted in 19-111 twin-differentially methylated sites (tDMSs) per pair with >0.3 twin-to-twin differences. Considering all top three candidate tDMSs across all pairs in the technical validation based on methylation-specific qPCR, 67.85% generated >0.1 twin-to-twin differences. Of the validated tDMSs, 68.4% showed >0.1 twin-to-twin differences with qPCR in trace-type DNA across 8 pairs. Using an updated marker selection strategy, 8 additional candidate tDMSs were obtained for an example MZ pair, of which 7 showed >0.1 twin-to-twin differences in both reference- and trace-type DNA. Lastly, we introduce a high-resolution melting curve analysis of the entire fragment that can complement the proposed approach. Overall, our study demonstrates the general feasibility of epigenetic twin differentiation in the forensic context and highlights that the number of informative tDMSs in the final trace DNA analysis is crucial, as some candidate markers identified in reference DNA were shown not informative in the trace DNA due to various, including technical, reasons. Future studies will need to address the optimal number of epigenetic markers required for reliable identification of MZ twin individuals including statistical considerations. Copyright © 2017 Elsevier B.V. All rights reserved.

Selection of reference genes for expression analysis in the entomophthoralean fungus Pandora neoaphidis.

PubMed

Chen, Chun; Xie, Tingna; Ye, Sudan; Jensen, Annette Bruun; Eilenberg, Jørgen

2016-01-01

The selection of suitable reference genes is crucial for accurate quantification of gene expression and can add to our understanding of host-pathogen interactions. To identify suitable reference genes in Pandora neoaphidis, an obligate aphid pathogenic fungus, the expression of three traditional candidate genes including 18S rRNA(18S), 28S rRNA(28S) and elongation factor 1 alpha-like protein (EF1), were measured by quantitative polymerase chain reaction at different developmental stages (conidia, conidia with germ tubes, short hyphae and elongated hyphae), and under different nutritional conditions. We calculated the expression stability of candidate reference genes using four algorithms including geNorm, NormFinder, BestKeeper and Delta Ct. The analysis results revealed that the comprehensive ranking of candidate reference genes from the most stable to the least stable was 18S (1.189), 28S (1.414) and EF1 (3). The 18S was, therefore, the most suitable reference gene for real-time RT-PCR analysis of gene expression under all conditions. These results will support further studies on gene expression in P. neoaphidis. Copyright © 2015 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. All rights reserved.

Genome-Wide Identification of Different Dormant Medicago sativa L. MicroRNAs in Response to Fall Dormancy

PubMed Central

Du, Hongqi; Sun, Xiaoge; Shi, Yinghua; Wang, Chengzhang

2014-01-01

Background MicroRNAs (miRNAs) are a class of regulatory small RNAs (sRNAs) that regulate gene post-transcriptional expression in plants and animals. High-throughput sequencing technology is capable of identifying small RNAs in plant species. Alfalfa (Medicago sativa L.) is one of the most widely cultivated perennial forage legumes worldwide, and fall dormancy is an adaptive characteristic related to the biomass production and winter survival in alfalfa. Here, we applied high-throughput sRNA sequencing to identify some miRNAs that were responsive to fall dormancy in standard variety (Maverick and CUF101) of alfalfa. Results Four sRNA libraries were generated and sequenced from alfalfa leaves in two typical varieties at distinct seasons. Through integrative analysis, we identified 51 novel miRNA candidates of 206 families. Additionally, we identified 28 miRNAs associated with fall dormancy in standard variety (Maverick and CUF101), including 20 known miRNAs and eight novel miRNAs. Both high-throughput sequencing and RT-qPCR confirmed that eight known miRNA members were up-regulated and six known miRNA members were down-regulated in response to fall dormancy in standard variety (Maverick and CUF101). Among the 51 novel miRNA candidates, five miRNAs were up-regulated and three miRNAs were down-regulated in response to fall dormancy in standard variety (Maverick and CUF101), and five of them were confirmed by Northern blot analysis. Conclusion We identified 20 known miRNAs and eight new miRNA candidates that were responsive to fall dormancy in standard variety (Maverick and CUF101) by high-throughput sequencing of small RNAs from Medicago sativa. Our data provide a useful resource for investigating miRNA-mediated regulatory mechanisms of fall dormancy in alfalfa, and these findings are important for our understanding of the roles played by miRNAs in the response of plants to abiotic stress in general and fall dormancy in alfalfa. PMID:25473944

Genome-wide identification of different dormant Medicago sativa L. MicroRNAs in response to fall dormancy.

PubMed

Fan, Wenna; Zhang, Senhao; Du, Hongqi; Sun, Xiaoge; Shi, Yinghua; Wang, Chengzhang

2014-01-01

MicroRNAs (miRNAs) are a class of regulatory small RNAs (sRNAs) that regulate gene post-transcriptional expression in plants and animals. High-throughput sequencing technology is capable of identifying small RNAs in plant species. Alfalfa (Medicago sativa L.) is one of the most widely cultivated perennial forage legumes worldwide, and fall dormancy is an adaptive characteristic related to the biomass production and winter survival in alfalfa. Here, we applied high-throughput sRNA sequencing to identify some miRNAs that were responsive to fall dormancy in standard variety (Maverick and CUF101) of alfalfa. Four sRNA libraries were generated and sequenced from alfalfa leaves in two typical varieties at distinct seasons. Through integrative analysis, we identified 51 novel miRNA candidates of 206 families. Additionally, we identified 28 miRNAs associated with fall dormancy in standard variety (Maverick and CUF101), including 20 known miRNAs and eight novel miRNAs. Both high-throughput sequencing and RT-qPCR confirmed that eight known miRNA members were up-regulated and six known miRNA members were down-regulated in response to fall dormancy in standard variety (Maverick and CUF101). Among the 51 novel miRNA candidates, five miRNAs were up-regulated and three miRNAs were down-regulated in response to fall dormancy in standard variety (Maverick and CUF101), and five of them were confirmed by Northern blot analysis. We identified 20 known miRNAs and eight new miRNA candidates that were responsive to fall dormancy in standard variety (Maverick and CUF101) by high-throughput sequencing of small RNAs from Medicago sativa. Our data provide a useful resource for investigating miRNA-mediated regulatory mechanisms of fall dormancy in alfalfa, and these findings are important for our understanding of the roles played by miRNAs in the response of plants to abiotic stress in general and fall dormancy in alfalfa.

Searching for new white dwarf pulsators for TESS observations at Konkoly Observatory

NASA Astrophysics Data System (ADS)

Bognár, Zs; Kalup, Cs; Sódor, Á.; Charpinet, S.; Hermes, J. J.

2018-07-01

We present the results of our survey searching for new white dwarf pulsators for observations by the TESS space telescope. We collected photometric time-series data on 14 white dwarf variable candidates at Konkoly Observatory, and found two new bright ZZ Ceti stars, namely EGGR 120 and WD 1310+583. We performed a Fourier analysis of the datasets. In the case of EGGR 120, which was observed on one night only, we found one significant frequency at 1332μHz with 2.3 mmag amplitude. We successfully observed WD 1310+583 on eight nights, and determined 17 significant frequencies in the whole dataset. Seven of them seem to be independent pulsation modes between 634 and 2740μHz, and we performed preliminary asteroseismic investigations of the star utilizing six of these periods. We also identified three new light variables on the fields of white dwarf candidates: an eclipsing binary, a candidate delta Scuti/beta Cephei and a candidate W UMa-type star.

Spiritual and ceremonial plants in North America: an assessment of Moerman's ethnobotanical database comparing Residual, Binomial, Bayesian and Imprecise Dirichlet Model (IDM) analysis.

PubMed

Turi, Christina E; Murch, Susan J

2013-07-09

Ethnobotanical research and the study of plants used for rituals, ceremonies and to connect with the spirit world have led to the discovery of many novel psychoactive compounds such as nicotine, caffeine, and cocaine. In North America, spiritual and ceremonial uses of plants are well documented and can be accessed online via the University of Michigan's Native American Ethnobotany Database. The objective of the study was to compare Residual, Bayesian, Binomial and Imprecise Dirichlet Model (IDM) analyses of ritual, ceremonial and spiritual plants in Moerman's ethnobotanical database and to identify genera that may be good candidates for the discovery of novel psychoactive compounds. The database was queried with the following format "Family Name AND Ceremonial OR Spiritual" for 263 North American botanical families. Spiritual and ceremonial flora consisted of 86 families with 517 species belonging to 292 genera. Spiritual taxa were then grouped further into ceremonial medicines and items categories. Residual, Bayesian, Binomial and IDM analysis were performed to identify over and under-utilized families. The 4 statistical approaches were in good agreement when identifying under-utilized families but large families (>393 species) were underemphasized by Binomial, Bayesian and IDM approaches for over-utilization. Residual, Binomial, and IDM analysis identified similar families as over-utilized in the medium (92-392 species) and small (<92 species) classes. The families Apiaceae, Asteraceae, Ericacea, Pinaceae and Salicaceae were identified as significantly over-utilized as ceremonial medicines in medium and large sized families. Analysis of genera within the Apiaceae and Asteraceae suggest that the genus Ligusticum and Artemisia are good candidates for facilitating the discovery of novel psychoactive compounds. The 4 statistical approaches were not consistent in the selection of over-utilization of flora. Residual analysis revealed overall trends that were supported by Binomial analysis when separated into small, medium and large families. The Bayesian, Binomial and IDM approaches identified different genera as potentially important. Species belonging to the genus Artemisia and Ligusticum were most consistently identified and may be valuable in future studies of the ethnopharmacology. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Next-generation sequencing to identify candidate genes and develop diagnostic markers for a novel Phytophthora resistance gene, RpsHC18, in soybean.

PubMed

Zhong, Chao; Sun, Suli; Li, Yinping; Duan, Canxing; Zhu, Zhendong

2018-03-01

A novel Phytophthora sojae resistance gene RpsHC18 was identified and finely mapped on soybean chromosome 3. Two NBS-LRR candidate genes were identified and two diagnostic markers of RpsHC18 were developed. Phytophthora root rot caused by Phytophthora sojae is a destructive disease of soybean. The most effective disease-control strategy is to deploy resistant cultivars carrying Phytophthora-resistant Rps genes. The soybean cultivar Huachun 18 has a broad and distinct resistance spectrum to 12 P. sojae isolates. Quantitative trait loci sequencing (QTL-seq), based on the whole-genome resequencing (WGRS) of two extreme resistant and susceptible phenotype bulks from an F 2:3 population, was performed, and one 767-kb genomic region with ΔSNP-index ≥ 0.9 on chromosome 3 was identified as the RpsHC18 candidate region in Huachun 18. The candidate region was reduced to a 146-kb region by fine mapping. Nonsynonymous SNP and haplotype analyses were carried out in the 146-kb region among ten soybean genotypes using WGRS. Four specific nonsynonymous SNPs were identified in two nucleotide-binding sites-leucine-rich repeat (NBS-LRR) genes, RpsHC18-NBL1 and RpsHC18-NBL2, which were considered to be the candidate genes. Finally, one specific SNP marker in each candidate gene was successfully developed using a tetra-primer ARMS-PCR assay, and the two markers were verified to be specific for RpsHC18 and to effectively distinguish other known Rps genes. In this study, we applied an integrated genomic-based strategy combining WGRS with traditional genetic mapping to identify RpsHC18 candidate genes and develop diagnostic markers. These results suggest that next-generation sequencing is a precise, rapid and cost-effective way to identify candidate genes and develop diagnostic markers, and it can accelerate Rps gene cloning and marker-assisted selection for breeding of P. sojae-resistant soybean cultivars.

Genome-Wide Association Study Identifying Candidate Genes Influencing Important Agronomic Traits of Flax (Linum usitatissimum L.) Using SLAF-seq

PubMed Central

Xie, Dongwei; Dai, Zhigang; Yang, Zemao; Sun, Jian; Zhao, Debao; Yang, Xue; Zhang, Liguo; Tang, Qing; Su, Jianguang

2018-01-01

Flax (Linum usitatissimum L.) is an important cash crop, and its agronomic traits directly affect yield and quality. Molecular studies on flax remain inadequate because relatively few flax genes have been associated with agronomic traits or have been identified as having potential applications. To identify markers and candidate genes that can potentially be used for genetic improvement of crucial agronomic traits, we examined 224 specimens of core flax germplasm; specifically, phenotypic data for key traits, including plant height, technical length, number of branches, number of fruits, and 1000-grain weight were investigated under three environmental conditions before specific-locus amplified fragment sequencing (SLAF-seq) was employed to perform a genome-wide association study (GWAS) for these five agronomic traits. Subsequently, the results were used to screen single nucleotide polymorphism (SNP) loci and candidate genes that exhibited a significant correlation with the important agronomic traits. Our analyses identified a total of 42 SNP loci that showed significant correlations with the five important agronomic flax traits. Next, candidate genes were screened in the 10 kb zone of each of the 42 SNP loci. These SNP loci were then analyzed by a more stringent screening via co-identification using both a general linear model (GLM) and a mixed linear model (MLM) as well as co-occurrences in at least two of the three environments, whereby 15 final candidate genes were obtained. Based on these results, we determined that UGT and PL are candidate genes for plant height, GRAS and XTH are candidate genes for the number of branches, Contig1437 and LU0019C12 are candidate genes for the number of fruits, and PHO1 is a candidate gene for the 1000-seed weight. We propose that the identified SNP loci and corresponding candidate genes might serve as a biological basis for improving crucial agronomic flax traits. PMID:29375606

Genome-Wide Association Study Identifying Candidate Genes Influencing Important Agronomic Traits of Flax (Linum usitatissimum L.) Using SLAF-seq.

PubMed

Xie, Dongwei; Dai, Zhigang; Yang, Zemao; Sun, Jian; Zhao, Debao; Yang, Xue; Zhang, Liguo; Tang, Qing; Su, Jianguang

2017-01-01

Flax ( Linum usitatissimum L.) is an important cash crop, and its agronomic traits directly affect yield and quality. Molecular studies on flax remain inadequate because relatively few flax genes have been associated with agronomic traits or have been identified as having potential applications. To identify markers and candidate genes that can potentially be used for genetic improvement of crucial agronomic traits, we examined 224 specimens of core flax germplasm; specifically, phenotypic data for key traits, including plant height, technical length, number of branches, number of fruits, and 1000-grain weight were investigated under three environmental conditions before specific-locus amplified fragment sequencing (SLAF-seq) was employed to perform a genome-wide association study (GWAS) for these five agronomic traits. Subsequently, the results were used to screen single nucleotide polymorphism (SNP) loci and candidate genes that exhibited a significant correlation with the important agronomic traits. Our analyses identified a total of 42 SNP loci that showed significant correlations with the five important agronomic flax traits. Next, candidate genes were screened in the 10 kb zone of each of the 42 SNP loci. These SNP loci were then analyzed by a more stringent screening via co-identification using both a general linear model (GLM) and a mixed linear model (MLM) as well as co-occurrences in at least two of the three environments, whereby 15 final candidate genes were obtained. Based on these results, we determined that UGT and PL are candidate genes for plant height, GRAS and XTH are candidate genes for the number of branches, Contig1437 and LU0019C12 are candidate genes for the number of fruits, and PHO1 is a candidate gene for the 1000-seed weight. We propose that the identified SNP loci and corresponding candidate genes might serve as a biological basis for improving crucial agronomic flax traits.

Identification of the chemical components of Saussurea involucrata by high-resolution mass spectrometry and the mass spectral trees similarity filter technique.

PubMed

Jia, Zhixin; Wu, Caisheng; Jin, Hongtao; Zhang, Jinlan

2014-11-15

Saussurea involucrata is a rare traditional Chinese medicine (TCM) that displays anti-fatigue, anti-inflammatory and anti-tumor effects. In this paper, the different chemical components of Saussurea involucrata were characterized and identified over a wide dynamic range by high-performance liquid chromatography coupled with high-resolution hybrid mass spectrometry (HPLC/HRMS/MS(n)) and the mass spectral trees similarity filter (MTSF) technique. The aerial parts of Saussurea involucrata were extracted with 75% ethanol. The partial extract was separated on a chromatography column to concentrate the low-concentration compounds. Mass data were acquired using full-scan mass analysis (resolving power 50,000) with data-dependent incorporation of dynamic exclusion analysis. The identified compounds were used as templates to construct a database of mass spectral trees. Data for the unknown compounds were matched with those templates and matching candidate structures were obtained. The detected compounds were characterized based on matching to candidate structures by the MTSF technique and were further identified by their accurate mass weight, multiple-stage analysis and fragmentation patterns and through comparison with literature data. A total of 38 compounds were identified including 19 flavones, 11 phenylpropanoids and 8 sphingolipids. Among them, 7 flavonoids, 8 phenylpropanoids and 8 sphingolipids were identified for the first time in Saussurea involucrata. HPLC/HRMS/MS(n) combined with MTSF was successfully used to discover and identify the chemical compounds in Saussurea involucrata. The results indicated that this combined technique was extremely useful for the rapid detection and identification of the chemical components in TCMs. Copyright © 2014 John Wiley & Sons, Ltd.

Identification of microRNAs differentially expressed involved in male flower development.

PubMed

Wang, Zhengjia; Huang, Jianqin; Sun, Zhichao; Zheng, Bingsong

2015-03-01

Hickory (Carya cathayensis Sarg.) is one of the most economically important woody trees in eastern China, but its long flowering phase delays yield. Our understanding of the regulatory roles of microRNAs (miRNAs) in male flower development in hickory remains poor. Using high-throughput sequencing technology, we have pyrosequenced two small RNA libraries from two male flower differentiation stages in hickory. Analysis of the sequencing data identified 114 conserved miRNAs that belonged to 23 miRNA families, five novel miRNAs including their corresponding miRNA*s, and 22 plausible miRNA candidates. Differential expression analysis revealed 12 miRNA sequences that were upregulated in the later (reproductive) stage of male flower development. Quantitative real-time PCR showed similar expression trends as that of the deep sequencing. Novel miRNAs and plausible miRNA candidates were predicted using bioinformatic analysis methods. The miRNAs newly identified in this study have increased the number of known miRNAs in hickory, and the identification of differentially expressed miRNAs will provide new avenues for studies into miRNAs involved in the process of male flower development in hickory and other related trees.

A proteomic analysis identifies candidate early biomarkers to predict ovarian hyperstimulation syndrome in polycystic ovarian syndrome patients.

PubMed

Wu, Lan; Sun, Yazhou; Wan, Jun; Luan, Ting; Cheng, Qing; Tan, Yong

2017-07-01

Ovarian hyperstimulation syndrome (OHSS) is a potentially life‑threatening, iatrogenic complication that occurs during assisted reproduction. Polycystic ovarian syndrome (PCOS) significantly increases the risk of OHSS during controlled ovarian stimulation. Therefore, a more effective early prediction technique is required in PCOS patients. Quantitative proteomic analysis of serum proteins indicates the potential diagnostic value for disease. In the present study, the authors revealed the differentially expressed proteins in OHSS patients with PCOS as new diagnostic biomarkers. The promising proteins obtained from liquid chromatography‑mass spectrometry were subjected to ELISA and western blotting assay for further confirmation. A total of 57 proteins were identified with significant difference, of which 29 proteins were upregulated and 28 proteins were downregulated in OHSS patients. Haptoglobin, fibrinogen and lipoprotein lipase were selected as candidate biomarkers. Receiver operating characteristic curve analysis demonstrated all three proteins may have potential as biomarkers to discriminate OHSS in PCOS patients. Haptoglobin, fibrinogen and lipoprotein lipase have never been reported as a predictive marker of OHSS in PCOS patients, and their potential roles in OHSS occurrence deserve further studies. The proteomic results reported in the present study may gain deeper insights into the pathophysiology of OHSS.

System diagnostics using qualitative analysis and component functional classification

DOEpatents

Reifman, J.; Wei, T.Y.C.

1993-11-23

A method for detecting and identifying faulty component candidates during off-normal operations of nuclear power plants involves the qualitative analysis of macroscopic imbalances in the conservation equations of mass, energy and momentum in thermal-hydraulic control volumes associated with one or more plant components and the functional classification of components. The qualitative analysis of mass and energy is performed through the associated equations of state, while imbalances in momentum are obtained by tracking mass flow rates which are incorporated into a first knowledge base. The plant components are functionally classified, according to their type, as sources or sinks of mass, energy and momentum, depending upon which of the three balance equations is most strongly affected by a faulty component which is incorporated into a second knowledge base. Information describing the connections among the components of the system forms a third knowledge base. The method is particularly adapted for use in a diagnostic expert system to detect and identify faulty component candidates in the presence of component failures and is not limited to use in a nuclear power plant, but may be used with virtually any type of thermal-hydraulic operating system. 5 figures.

System diagnostics using qualitative analysis and component functional classification

DOEpatents

Reifman, Jaques; Wei, Thomas Y. C.

1993-01-01

A method for detecting and identifying faulty component candidates during off-normal operations of nuclear power plants involves the qualitative analysis of macroscopic imbalances in the conservation equations of mass, energy and momentum in thermal-hydraulic control volumes associated with one or more plant components and the functional classification of components. The qualitative analysis of mass and energy is performed through the associated equations of state, while imbalances in momentum are obtained by tracking mass flow rates which are incorporated into a first knowledge base. The plant components are functionally classified, according to their type, as sources or sinks of mass, energy and momentum, depending upon which of the three balance equations is most strongly affected by a faulty component which is incorporated into a second knowledge base. Information describing the connections among the components of the system forms a third knowledge base. The method is particularly adapted for use in a diagnostic expert system to detect and identify faulty component candidates in the presence of component failures and is not limited to use in a nuclear power plant, but may be used with virtually any type of thermal-hydraulic operating system.

Readability and Content of Patient Education Material Related to Implantable Cardioverter Defibrillators

PubMed Central

Strachan, Patricia H.; de Laat, Sonya; Carroll, Sandra L.; Schwartz, Lisa; Vaandering, Katie; Toor, Gurjit K.; Arthur, Heather M.

2012-01-01

Background Implantable cardioverter defibrillators (ICDs) are increasingly offered to patients for primary prevention of sudden cardiac death. Candidates for ICD receive ICD-related patient education material when they make decisions to consent or decline a primary prevention ICD. Printed patient education material directed at ICD candidates has not been the focus of direct appraisal. Objective We evaluated the readability and content of ICD-related print education materials made available to patients who were enrolled in a study involving patient decision making for ICD from 3 ICD sites in southern Ontario, Canada. Methods All ICD print materials referred to during interviews and/or that were available in ICD site waiting rooms were collected for analysis. Readability testing was conducted using the SMOG (“simple measurement of gobbledygook”) and Fry methods. The material was evaluated according to selected plain-language criteria, thematic content analysis, and rhetoric analysis. Results Twenty-one print materials were identified and analyzed. Documents were authored by device manufacturers, tertiary care hospitals, and cardiac support organizations. Although many documents adhered to plain-language recommendations, text-reading levels were higher than recommended. Twelve major content themes were identified. Content focused heavily on the positive aspects of living with the device to the exclusion of other possible information that could be relevant to the decisions that patients made. Conclusions Print-based patient education materials for ICD candidates are geared to a highly literate population. The focus on positive information to the exclusion of potentially negative aspects of the ICD, or alternatives to accepting 1, could influence and/or confuse patients about the purpose and implications of this medical device. Development of print materials is indicated that includes information about possible problems and that would be relevant for the multicultural and debilitated population who may require ICDs. The findings are highly relevant for nurses who care for primary prevention ICD candidates. PMID:21926915

Identifying candidate driver genes by integrative ovarian cancer genomics data

NASA Astrophysics Data System (ADS)

Lu, Xinguo; Lu, Jibo

2017-08-01

Integrative analysis of molecular mechanics underlying cancer can distinguish interactions that cannot be revealed based on one kind of data for the appropriate diagnosis and treatment of cancer patients. Tumor samples exhibit heterogeneity in omics data, such as somatic mutations, Copy Number Variations CNVs), gene expression profiles and so on. In this paper we combined gene co-expression modules and mutation modulators separately in tumor patients to obtain the candidate driver genes for resistant and sensitive tumor from the heterogeneous data. The final list of modulators identified are well known in biological processes associated with ovarian cancer, such as CCL17, CACTIN, CCL16, CCL22, APOB, KDF1, CCL11, HNF1B, LRG1, MED1 and so on, which can help to facilitate the discovery of biomarkers, molecular diagnostics, and drug discovery.

Co-expression analysis identifies CRC and AP1 the regulator of Arabidopsis fatty acid biosynthesis.

PubMed

Han, Xinxin; Yin, Linlin; Xue, Hongwei

2012-07-01

Fatty acids (FAs) play crucial rules in signal transduction and plant development, however, the regulation of FA metabolism is still poorly understood. To study the relevant regulatory network, fifty-eight FA biosynthesis genes including de novo synthases, desaturases and elongases were selected as "guide genes" to construct the co-expression network. Calculation of the correlation between all Arabidopsis thaliana (L.) genes with each guide gene by Arabidopsis co-expression dating mining tools (ACT) identifies 797 candidate FA-correlated genes. Gene ontology (GO) analysis of these co-expressed genes showed they are tightly correlated to photosynthesis and carbohydrate metabolism, and function in many processes. Interestingly, 63 transcription factors (TFs) were identified as candidate FA biosynthesis regulators and 8 TF families are enriched. Two TF genes, CRC and AP1, both correlating with 8 FA guide genes, were further characterized. Analyses of the ap1 and crc mutant showed the altered total FA composition of mature seeds. The contents of palmitoleic acid, stearic acid, arachidic acid and eicosadienoic acid are decreased, whereas that of oleic acid is increased in ap1 and crc seeds, which is consistent with the qRT-PCR analysis revealing the suppressed expression of the corresponding guide genes. In addition, yeast one-hybrid analysis and electrophoretic mobility shift assay (EMSA) revealed that CRC can bind to the promoter regions of KCS7 and KCS15, indicating that CRC may directly regulate FA biosynthesis. © 2012 Institute of Botany, Chinese Academy of Sciences.

De Novo Sequencing and Analysis of Lemongrass Transcriptome Provide First Insights into the Essential Oil Biosynthesis of Aromatic Grasses.

PubMed

Meena, Seema; Kumar, Sarma R; Venkata Rao, D K; Dwivedi, Varun; Shilpashree, H B; Rastogi, Shubhra; Shasany, Ajit K; Nagegowda, Dinesh A

2016-01-01

Aromatic grasses of the genus Cymbopogon (Poaceae family) represent unique group of plants that produce diverse composition of monoterpene rich essential oils, which have great value in flavor, fragrance, cosmetic, and aromatherapy industries. Despite the commercial importance of these natural aromatic oils, their biosynthesis at the molecular level remains unexplored. As the first step toward understanding the essential oil biosynthesis, we performed de novo transcriptome assembly and analysis of C. flexuosus (lemongrass) by employing Illumina sequencing. Mining of transcriptome data and subsequent phylogenetic analysis led to identification of terpene synthases, pyrophosphatases, alcohol dehydrogenases, aldo-keto reductases, carotenoid cleavage dioxygenases, alcohol acetyltransferases, and aldehyde dehydrogenases, which are potentially involved in essential oil biosynthesis. Comparative essential oil profiling and mRNA expression analysis in three Cymbopogon species (C. flexuosus, aldehyde type; C. martinii, alcohol type; and C. winterianus, intermediate type) with varying essential oil composition indicated the involvement of identified candidate genes in the formation of alcohols, aldehydes, and acetates. Molecular modeling and docking further supported the role of identified protein sequences in aroma formation in Cymbopogon. Also, simple sequence repeats were found in the transcriptome with many linked to terpene pathway genes including the genes potentially involved in aroma biosynthesis. This work provides the first insights into the essential oil biosynthesis of aromatic grasses, and the identified candidate genes and markers can be a great resource for biotechnological and molecular breeding approaches to modulate the essential oil composition.

Transcriptomic analysis of Prunus domestica undergoing hypersensitive response to plum pox virus infection.

PubMed

Rodamilans, Bernardo; San León, David; Mühlberger, Louisa; Candresse, Thierry; Neumüller, Michael; Oliveros, Juan Carlos; García, Juan Antonio

2014-01-01

Plum pox virus (PPV) infects Prunus trees around the globe, posing serious fruit production problems and causing severe economic losses. One variety of Prunus domestica, named 'Jojo', develops a hypersensitive response to viral infection. Here we compared infected and non-infected samples using next-generation RNA sequencing to characterize the genetic complexity of the viral population in infected samples and to identify genes involved in development of the resistance response. Analysis of viral reads from the infected samples allowed reconstruction of a PPV-D consensus sequence. De novo reconstruction showed a second viral isolate of the PPV-Rec strain. RNA-seq analysis of PPV-infected 'Jojo' trees identified 2,234 and 786 unigenes that were significantly up- or downregulated, respectively (false discovery rate; FDR≤0.01). Expression of genes associated with defense was generally enhanced, while expression of those related to photosynthesis was repressed. Of the total of 3,020 differentially expressed unigenes, 154 were characterized as potential resistance genes, 10 of which were included in the NBS-LRR type. Given their possible role in plant defense, we selected 75 additional unigenes as candidates for further study. The combination of next-generation sequencing and a Prunus variety that develops a hypersensitive response to PPV infection provided an opportunity to study the factors involved in this plant defense mechanism. Transcriptomic analysis presented an overview of the changes that occur during PPV infection as a whole, and identified candidates suitable for further functional characterization.

De Novo Sequencing and Analysis of Lemongrass Transcriptome Provide First Insights into the Essential Oil Biosynthesis of Aromatic Grasses

PubMed Central

Meena, Seema; Kumar, Sarma R.; Venkata Rao, D. K.; Dwivedi, Varun; Shilpashree, H. B.; Rastogi, Shubhra; Shasany, Ajit K.; Nagegowda, Dinesh A.

2016-01-01

Aromatic grasses of the genus Cymbopogon (Poaceae family) represent unique group of plants that produce diverse composition of monoterpene rich essential oils, which have great value in flavor, fragrance, cosmetic, and aromatherapy industries. Despite the commercial importance of these natural aromatic oils, their biosynthesis at the molecular level remains unexplored. As the first step toward understanding the essential oil biosynthesis, we performed de novo transcriptome assembly and analysis of C. flexuosus (lemongrass) by employing Illumina sequencing. Mining of transcriptome data and subsequent phylogenetic analysis led to identification of terpene synthases, pyrophosphatases, alcohol dehydrogenases, aldo-keto reductases, carotenoid cleavage dioxygenases, alcohol acetyltransferases, and aldehyde dehydrogenases, which are potentially involved in essential oil biosynthesis. Comparative essential oil profiling and mRNA expression analysis in three Cymbopogon species (C. flexuosus, aldehyde type; C. martinii, alcohol type; and C. winterianus, intermediate type) with varying essential oil composition indicated the involvement of identified candidate genes in the formation of alcohols, aldehydes, and acetates. Molecular modeling and docking further supported the role of identified protein sequences in aroma formation in Cymbopogon. Also, simple sequence repeats were found in the transcriptome with many linked to terpene pathway genes including the genes potentially involved in aroma biosynthesis. This work provides the first insights into the essential oil biosynthesis of aromatic grasses, and the identified candidate genes and markers can be a great resource for biotechnological and molecular breeding approaches to modulate the essential oil composition. PMID:27516768

Anxiety after completion of treatment for early-stage breast cancer: a systematic review to identify candidate predictors and evaluate multivariable model development.

PubMed

Harris, Jenny; Cornelius, Victoria; Ream, Emma; Cheevers, Katy; Armes, Jo

2017-07-01

The purpose of this review was to identify potential candidate predictors of anxiety in women with early-stage breast cancer (BC) after adjuvant treatments and evaluate methodological development of existing multivariable models to inform the future development of a predictive risk stratification model (PRSM). Databases (MEDLINE, Web of Science, CINAHL, CENTRAL and PsycINFO) were searched from inception to November 2015. Eligible studies were prospective, recruited women with stage 0-3 BC, used a validated anxiety outcome ≥3 months post-treatment completion and used multivariable prediction models. Internationally accepted quality standards were used to assess predictive risk of bias and strength of evidence. Seven studies were identified: five were observational cohorts and two secondary analyses of RCTs. Variability of measurement and selective reporting precluded meta-analysis. Twenty-one candidate predictors were identified in total. Younger age and previous mental health problems were identified as risk factors in ≥3 studies. Clinical variables (e.g. treatment, tumour grade) were not identified as predictors in any studies. No studies adhered to all quality standards. Pre-existing vulnerability to mental health problems and younger age increased the risk of anxiety after completion of treatment for BC survivors, but there was no evidence that chemotherapy was a predictor. Multiple predictors were identified but many lacked reproducibility or were not measured across studies, and inadequate reporting did not allow full evaluation of the multivariable models. The use of quality standards in the development of PRSM within supportive cancer care would improve model quality and performance, thereby allowing professionals to better target support for patients.

Genome-Wide Identification and Expression Analyses of Aquaporin Gene Family during Development and Abiotic Stress in Banana

PubMed Central

Hu, Wei; Hou, Xiaowan; Huang, Chao; Yan, Yan; Tie, Weiwei; Ding, Zehong; Wei, Yunxie; Liu, Juhua; Miao, Hongxia; Lu, Zhiwei; Li, Meiying; Xu, Biyu; Jin, Zhiqiang

2015-01-01

Aquaporins (AQPs) function to selectively control the flow of water and other small molecules through biological membranes, playing crucial roles in various biological processes. However, little information is available on the AQP gene family in bananas. In this study, we identified 47 banana AQP genes based on the banana genome sequence. Evolutionary analysis of AQPs from banana, Arabidopsis, poplar, and rice indicated that banana AQPs (MaAQPs) were clustered into four subfamilies. Conserved motif analysis showed that all banana AQPs contained the typical AQP-like or major intrinsic protein (MIP) domain. Gene structure analysis suggested the majority of MaAQPs had two to four introns with a highly specific number and length for each subfamily. Expression analysis of MaAQP genes during fruit development and postharvest ripening showed that some MaAQP genes exhibited high expression levels during these stages, indicating the involvement of MaAQP genes in banana fruit development and ripening. Additionally, some MaAQP genes showed strong induction after stress treatment and therefore, may represent potential candidates for improving banana resistance to abiotic stress. Taken together, this study identified some excellent tissue-specific, fruit development- and ripening-dependent, and abiotic stress-responsive candidate MaAQP genes, which could lay a solid foundation for genetic improvement of banana cultivars. PMID:26307965

Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis.

PubMed

Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

2016-07-14

Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis.

Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis

PubMed Central

Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

2016-01-01

Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis. PMID:27411928

Identification of Linkages between EDCs in Personal Care Products and Breast Cancer through Data Integration Combined with Gene Network Analysis.

PubMed

Jeong, Hyeri; Kim, Jongwoon; Kim, Youngjun

2017-09-30

Approximately 1000 chemicals have been reported to possibly have endocrine disrupting effects, some of which are used in consumer products, such as personal care products (PCPs) and cosmetics. We conducted data integration combined with gene network analysis to: (i) identify causal molecular mechanisms between endocrine disrupting chemicals (EDCs) used in PCPs and breast cancer; and (ii) screen candidate EDCs associated with breast cancer. Among EDCs used in PCPs, four EDCs having correlation with breast cancer were selected, and we curated 27 common interacting genes between those EDCs and breast cancer to perform the gene network analysis. Based on the gene network analysis, ESR1, TP53, NCOA1, AKT1, and BCL6 were found to be key genes to demonstrate the molecular mechanisms of EDCs in the development of breast cancer. Using GeneMANIA, we additionally predicted 20 genes which could interact with the 27 common genes. In total, 47 genes combining the common and predicted genes were functionally grouped with the gene ontology and KEGG pathway terms. With those genes, we finally screened candidate EDCs for their potential to increase breast cancer risk. This study highlights that our approach can provide insights to understand mechanisms of breast cancer and identify potential EDCs which are in association with breast cancer.

[BIOINFORMATIC SEARCH AND PHYLOGENETIC ANALYSIS OF THE CELLULOSE SYNTHASE GENES OF FLAX (LINUM USITATISSIMUM)].

PubMed

Pydiura, N A; Bayer, G Ya; Galinousky, D V; Yemets, A I; Pirko, Ya V; Podvitski, T A; Anisimova, N V; Khotyleva, L V; Kilchevsky, A V; Blume, Ya B

2015-01-01

A bioinformatic search of sequences encoding cellulose synthase genes in the flax genome, and their comparison to dicots orthologs was carried out. The analysis revealed 32 cellulose synthase gene candidates, 16 of which are highly likely to encode cellulose synthases, and the remaining 16--cellulose synthase-like proteins (Csl). Phylogenetic analysis of gene products of cellulose synthase genes allowed distinguishing 6 groups of cellulose synthase genes of different classes: CesA1/10, CesA3, CesA4, CesA5/6/2/9, CesA7 and CesA8. Paralogous sequences within classes CesA1/10 and CesA5/6/2/9 which are associated with the primary cell wall formation are characterized by a greater similarity within these classes than orthologous sequences. Whereas the genes controlling the biosynthesis of secondary cell wall cellulose form distinct clades: CesA4, CesA7, and CesA8. The analysis of 16 identified flax cellulose synthase gene candidates shows the presence of at least 12 different cellulose synthase gene variants in flax genome which are represented in all six clades of cellulose synthase genes. Thus, at this point genes of all ten known cellulose synthase classes are identify in flax genome, but their correct classification requires additional research.

Comparative Studies of the Proteome, Glycoproteome, and N-Glycome of Clear Cell Renal Cell Carcinoma Plasma before and after Curative Nephrectomy

PubMed Central

2015-01-01

Clear cell renal cell carcinoma is the most prevalent of all reported kidney cancer cases, and currently there are no markers for early diagnosis. This has stimulated great research interest recently because early detection of the disease can significantly improve the low survival rate. Combining the proteome, glycoproteome, and N-glycome data from clear cell renal cell carcinoma plasma has the potential of identifying candidate markers for early diagnosis and prognosis and/or to monitor disease recurrence. Here, we report on the utilization of a multi-dimensional fractionation approach (12P-M-LAC) and LC–MS/MS to comprehensively investigate clear cell renal cell carcinoma plasma collected before (disease) and after (non-disease) curative nephrectomy (n = 40). Proteins detected in the subproteomes were investigated via label-free quantification. Protein abundance analysis revealed a number of low-level proteins with significant differential expression levels in disease samples, including HSPG2, CD146, ECM1, SELL, SYNE1, and VCAM1. Importantly, we observed a strong correlation between differentially expressed proteins and clinical status of the patient. Investigation of the glycoproteome returned 13 candidate glycoproteins with significant differential M-LAC column binding. Qualitative analysis indicated that 62% of selected candidate glycoproteins showed higher levels (upregulation) in M-LAC bound fraction of disease samples. This observation was further confirmed by released N-glycans data in which 53% of identified N-glycans were present at different levels in plasma in the disease vs non-disease samples. This striking result demonstrates the potential for significant protein glycosylation alterations in clear cell renal cell carcinoma cancer plasma. With future validation in a larger cohort, information derived from this study may lead to the development of clear cell renal cell carcinoma candidate biomarkers. PMID:25184692

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

PubMed Central

Bagheri, Hani; Badduke, Chansonette; Qiao, Ying; Colnaghi, Rita; Abramowicz, Iga; Alcantara, Diana; Dunham, Christopher; Wen, Jiadi; Wildin, Robert S.; Nowaczyk, Malgorzata J.M.; Eichmeyer, Jennifer; Lehman, Anna; Maranda, Bruno; Martell, Sally; Shan, Xianghong; Lewis, Suzanne M.E.; O’Driscoll, Mark; Gregory-Evans, Cheryl Y.

2016-01-01

The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome. Here, we describe 8 new patients with the 2p15p16.1 deletion and review all published cases to date. We demonstrate functional deficits for the above 4 candidate genes using patients’ lymphoblast cell lines (LCLs) and knockdown of their orthologs in zebrafish. All genes were dosage sensitive on the basis of reduced protein expression in LCLs. In addition, deletion of XPO1, a nuclear exporter, cosegregated with nuclear accumulation of one of its cargo molecules (rpS5) in patients’ LCLs. Other pathways associated with these genes (e.g., NF-κB and Wnt signaling as well as the DNA damage response) were not impaired in patients’ LCLs. Knockdown of xpo1a, rel, bcl11aa, and bcl11ab resulted in abnormal zebrafish embryonic development including microcephaly, dysmorphic body, hindered growth, and small fins as well as structural brain abnormalities. Our multifaceted analysis strongly implicates XPO1, REL, and BCL11A as candidate genes for 2p15p16.1 microdeletion syndrome. PMID:27699255

A Genomic Resource for the Development, Improvement, and Exploitation of Sorghum for Bioenergy.

PubMed

Brenton, Zachary W; Cooper, Elizabeth A; Myers, Mathew T; Boyles, Richard E; Shakoor, Nadia; Zielinski, Kelsey J; Rauh, Bradley L; Bridges, William C; Morris, Geoffrey P; Kresovich, Stephen

2016-09-01

With high productivity and stress tolerance, numerous grass genera of the Andropogoneae have emerged as candidates for bioenergy production. To optimize these candidates, research examining the genetic architecture of yield, carbon partitioning, and composition is required to advance breeding objectives. Significant progress has been made developing genetic and genomic resources for Andropogoneae, and advances in comparative and computational genomics have enabled research examining the genetic basis of photosynthesis, carbon partitioning, composition, and sink strength. To provide a pivotal resource aimed at developing a comparative understanding of key bioenergy traits in the Andropogoneae, we have established and characterized an association panel of 390 racially, geographically, and phenotypically diverse Sorghum bicolor accessions with 232,303 genetic markers. Sorghum bicolor was selected because of its genomic simplicity, phenotypic diversity, significant genomic tools, and its agricultural productivity and resilience. We have demonstrated the value of sorghum as a functional model for candidate gene discovery for bioenergy Andropogoneae by performing genome-wide association analysis for two contrasting phenotypes representing key components of structural and non-structural carbohydrates. We identified potential genes, including a cellulase enzyme and a vacuolar transporter, associated with increased non-structural carbohydrates that could lead to bioenergy sorghum improvement. Although our analysis identified genes with potentially clear functions, other candidates did not have assigned functions, suggesting novel molecular mechanisms for carbon partitioning traits. These results, combined with our characterization of phenotypic and genetic diversity and the public accessibility of each accession and genomic data, demonstrate the value of this resource and provide a foundation for future improvement of sorghum and related grasses for bioenergy production. Copyright © 2016 by the Genetics Society of America.

Proteomic analysis of isolated chlamydomonas centrioles reveals orthologs of ciliary-disease genes.

PubMed

Keller, Lani C; Romijn, Edwin P; Zamora, Ivan; Yates, John R; Marshall, Wallace F

2005-06-21

The centriole is one of the most enigmatic organelles in the cell. Centrioles are cylindrical, microtubule-based barrels found in the core of the centrosome. Centrioles also act as basal bodies during interphase to nucleate the assembly of cilia and flagella. There are currently only a handful of known centriole proteins. We used mass-spectrometry-based MudPIT (multidimensional protein identification technology) to identify the protein composition of basal bodies (centrioles) isolated from the green alga Chlamydomonas reinhardtii. This analysis detected the majority of known centriole proteins, including centrin, epsilon tubulin, and the cartwheel protein BLD10p. By combining proteomic data with information about gene expression and comparative genomics, we identified 45 cross-validated centriole candidate proteins in two classes. Members of the first class of proteins (BUG1-BUG27) are encoded by genes whose expression correlates with flagellar assembly and which therefore may play a role in ciliogenesis-related functions of basal bodies. Members of the second class (POC1-POC18) are implicated by comparative-genomics and -proteomics studies to be conserved components of the centriole. We confirmed centriolar localization for the human homologs of four candidate proteins. Three of the cross-validated centriole candidate proteins are encoded by orthologs of genes (OFD1, NPHP-4, and PACRG) implicated in mammalian ciliary function and disease, suggesting that oral-facial-digital syndrome and nephronophthisis may involve a dysfunction of centrioles and/or basal bodies. By analyzing isolated Chlamydomonas basal bodies, we have been able to obtain the first reported proteomic analysis of the centriole.

Power-Production Diagnostic Tools for Low-Density Wind Farms with Applications to Wake Steering

NASA Astrophysics Data System (ADS)

Takle, E. S.; Herzmann, D.; Rajewski, D. A.; Lundquist, J. K.; Rhodes, M. E.

2016-12-01

Hansen (2011) provided guidelines for wind farm wake analysis with applications to "high density" wind farms (where average distance between turbines is less than ten times rotor diameter). For "low-density" (average distance greater than fifteen times rotor diameter) wind farms, or sections of wind farms we demonstrate simpler sorting and visualization tools that reveal wake interactions and opportunities for wind farm power prediction and wake steering. SCADA data from a segment of a large mid-continent wind farm, together with surface flux measurements and lidar data are subjected to analysis and visualization of wake interactions. A time-history animated visualization of a plan view of power level of individual turbines provides a quick analysis of wake interaction dynamics. Yaw-based sectoral histograms of enhancement/decline of wind speed and power from wind farm reference levels reveals angular width of wake interactions and identifies the turbine(s) responsible for the power reduction. Concurrent surface flux measurements within the wind farm allowed us to evaluate stability influence on wake loss. A one-season climatology is used to identify high-priority candidates for wake steering based on estimated power recovery. Typical clearing prices on the day-ahead market are used to estimate the added value of wake steering. Current research is exploring options for identifying candidate locations for wind farm "build-in" in existing low-density wind farms.

Bovine Polledness – An Autosomal Dominant Trait with Allelic Heterogeneity

PubMed Central

Medugorac, Ivica; Seichter, Doris; Graf, Alexander; Russ, Ingolf; Blum, Helmut; Göpel, Karl Heinrich; Rothammer, Sophie; Förster, Martin; Krebs, Stefan

2012-01-01

The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than 70 years ago, and the causative mutation was mapped almost 20 years ago, its molecular nature remained unknown. Here, we report allelic heterogeneity of the POLLED locus. First, we mapped the POLLED locus to a ∼381-kb interval in a multi-breed case-control design. Targeted re-sequencing of an enlarged candidate interval (547 kb) in 16 sires with known POLLED genotype did not detect a common allele associated with polled status. In eight sires of Alpine and Scottish origin (four polled versus four horned), we identified a single candidate mutation, a complex 202 bp insertion-deletion event that showed perfect association to the polled phenotype in various European cattle breeds, except Holstein-Friesian. The analysis of the same candidate interval in eight Holsteins identified five candidate variants which segregate as a 260 kb haplotype also perfectly associated with the POLLED gene without recombination or interference with the 202 bp insertion-deletion. We further identified bulls which are progeny tested as homozygous polled but bearing both, 202 bp insertion-deletion and Friesian haplotype. The distribution of genotypes of the two putative POLLED alleles in large semi-random sample (1,261 animals) supports the hypothesis of two independent mutations. PMID:22737241

Signatures of positive selection in East African Shorthorn Zebu: A genome-wide single nucleotide polymorphism analysis

PubMed Central

Bahbahani, Hussain; Clifford, Harry; Wragg, David; Mbole-Kariuki, Mary N; Van Tassell, Curtis; Sonstegard, Tad; Woolhouse, Mark; Hanotte, Olivier

2015-01-01

The small East African Shorthorn Zebu (EASZ) is the main indigenous cattle across East Africa. A recent genome wide SNP analysis revealed an ancient stable African taurine x Asian zebu admixture. Here, we assess the presence of candidate signatures of positive selection in their genome, with the aim to provide qualitative insights about the corresponding selective pressures. Four hundred and twenty-five EASZ and four reference populations (Holstein-Friesian, Jersey, N’Dama and Nellore) were analysed using 46,171 SNPs covering all autosomes and the X chromosome. Following FST and two extended haplotype homozygosity-based (iHS and Rsb) analyses 24 candidate genome regions within 14 autosomes and the X chromosome were revealed, in which 18 and 4 were previously identified in tropical-adapted and commercial breeds, respectively. These regions overlap with 340 bovine QTL. They include 409 annotated genes, in which 37 were considered as candidates. These genes are involved in various biological pathways (e.g. immunity, reproduction, development and heat tolerance). Our results support that different selection pressures (e.g. environmental constraints, human selection, genome admixture constrains) have shaped the genome of EASZ. We argue that these candidate regions represent genome landmarks to be maintained in breeding programs aiming to improve sustainable livestock productivity in the tropics. PMID:26130263

The ALMA Spectroscopic Survey in the Hubble Ultra Deep Field: Search for [CII] Line and Dust Emission in 6

NASA Astrophysics Data System (ADS)

Aravena, M.; Decarli, R.; Walter, F.; Bouwens, R.; Oesch, P. A.; Carilli, C. L.; Bauer, F. E.; Da Cunha, E.; Daddi, E.; Gónzalez-López, J.; Ivison, R. J.; Riechers, D. A.; Smail, I.; Swinbank, A. M.; Weiss, A.; Anguita, T.; Bacon, R.; Bell, E.; Bertoldi, F.; Cortes, P.; Cox, P.; Hodge, J.; Ibar, E.; Inami, H.; Infante, L.; Karim, A.; Magnelli, B.; Ota, K.; Popping, G.; van der Werf, P.; Wagg, J.; Fudamoto, Y.

2016-12-01

We present a search for [C II] line and dust continuum emission from optical dropout galaxies at z > 6 using ASPECS, our Atacama Large Millimeter submillimeter Array Spectroscopic Survey in the Hubble Ultra-deep Field (UDF). Our observations, which cover the frequency range of 212-272 GHz, encompass approximately the range of 6 < z < 8 for [C II] line emission and reach a limiting luminosity of L [C II] ˜ (1.6-2.5) × 108 L ⊙. We identify 14 [C II] line emitting candidates in this redshift range with significances >4.5σ, two of which correspond to blind detections with no optical counterparts. At this significance level, our statistical analysis shows that about 60% of our candidates are expected to be spurious. For one of our blindly selected [C II] line candidates, we tentatively detect the CO(6-5) line in our parallel 3 mm line scan. None of the line candidates are individually detected in the 1.2 mm continuum. A stack of all [C II] candidates results in a tentative detection with S 1.2 mm = 14 ± 5 μJy. This implies a dust-obscured star-formation rate (SFR) of (3 ± 1) M ⊙ yr-1. We find that the two highest-SFR objects have candidate [C II] lines with luminosities that are consistent with the low-redshift L [C II] versus SFR relation. The other candidates have significantly higher [C II] luminosities than expected from their UV-based SFR. At the current sensitivity, it is unclear whether the majority of these sources are intrinsically bright [C II] emitters, or spurious sources. If only one of our line candidates was real (a scenario greatly favored by our statistical analysis), we find a source density for [C II] emitters at 6 < z < 8 that is significantly higher than predicted by current models and some extrapolations from galaxies in the local universe.

Axon Regeneration Genes Identified by RNAi Screening in C. elegans

PubMed Central

Nix, Paola; Hammarlund, Marc; Hauth, Linda; Lachnit, Martina; Jorgensen, Erik M.

2014-01-01

Axons of the mammalian CNS lose the ability to regenerate soon after development due to both an inhibitory CNS environment and the loss of cell-intrinsic factors necessary for regeneration. The complex molecular events required for robust regeneration of mature neurons are not fully understood, particularly in vivo. To identify genes affecting axon regeneration in Caenorhabditis elegans, we performed both an RNAi-based screen for defective motor axon regeneration in unc-70/β-spectrin mutants and a candidate gene screen. From these screens, we identified at least 50 conserved genes with growth-promoting or growth-inhibiting functions. Through our analysis of mutants, we shed new light on certain aspects of regeneration, including the role of β-spectrin and membrane dynamics, the antagonistic activity of MAP kinase signaling pathways, and the role of stress in promoting axon regeneration. Many gene candidates had not previously been associated with axon regeneration and implicate new pathways of interest for therapeutic intervention. PMID:24403161

Candidate predators for biological control of the poultry red mite Dermanyssus gallinae.

PubMed

Lesna, Izabela; Wolfs, Peter; Faraji, Farid; Roy, Lise; Komdeur, Jan; Sabelis, Maurice W

2009-06-01

The poultry red mite, Dermanyssus gallinae, is currently a significant pest in the poultry industry in Europe. Biological control by the introduction of predatory mites is one of the various options for controlling poultry red mites. Here, we present the first results of an attempt to identify potential predators by surveying the mite fauna of European starling (Sturnus vulgaris) nests, by assessing their ability to feed on poultry red mites and by testing for their inability to extract blood from bird hosts, i.e., newly hatched, young starlings and chickens. Two genuine predators of poultry red mites are identified: Hypoaspis aculeifer and Androlaelaps casalis. A review of the literature shows that some authors suspected the latter species to parasitize on the blood of birds and mammals, but they did not provide experimental evidence for these feeding habits and/or overlooked published evidence showing the reverse. We advocate careful analysis of the trophic structure of arthropods inhabiting bird nests as a basis for identifying candidate predators for control of poultry red mites.

The Calcitonin Receptor Gene Is a Candidate for Regulation of Susceptibility to Herpes simplex Type 1 Neuronal Infection Leading to Encephalitis in Rat

PubMed Central

Abdelmagid, Nada; Bereczky-Veress, Biborka; Guerreiro-Cacais, André Ortlieb; Bergman, Petra; Luhr, Katarina M.; Bergström, Tomas; Sköldenberg, Birgit; Piehl, Fredrik

2012-01-01

Herpes simplex encephalitis (HSE) is a fatal infection of the central nervous system (CNS) predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s) regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL), Hse1, on rat chromosome 4 (confidence interval 24.3–31 Mb; LOD score 29.5) governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr) as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development. PMID:22761571

Text mining-based in silico drug discovery in oral mucositis caused by high-dose cancer therapy.

PubMed

Kirk, Jon; Shah, Nirav; Noll, Braxton; Stevens, Craig B; Lawler, Marshall; Mougeot, Farah B; Mougeot, Jean-Luc C

2018-08-01

Oral mucositis (OM) is a major dose-limiting side effect of chemotherapy and radiation used in cancer treatment. Due to the complex nature of OM, currently available drug-based treatments are of limited efficacy. Our objectives were (i) to determine genes and molecular pathways associated with OM and wound healing using computational tools and publicly available data and (ii) to identify drugs formulated for topical use targeting the relevant OM molecular pathways. OM and wound healing-associated genes were determined by text mining, and the intersection of the two gene sets was selected for gene ontology analysis using the GeneCodis program. Protein interaction network analysis was performed using STRING-db. Enriched gene sets belonging to the identified pathways were queried against the Drug-Gene Interaction database to find drug candidates for topical use in OM. Our analysis identified 447 genes common to both the "OM" and "wound healing" text mining concepts. Gene enrichment analysis yielded 20 genes representing six pathways and targetable by a total of 32 drugs which could possibly be formulated for topical application. A manual search on ClinicalTrials.gov confirmed no relevant pathway/drug candidate had been overlooked. Twenty-five of the 32 drugs can directly affect the PTGS2 (COX-2) pathway, the pathway that has been targeted in previous clinical trials with limited success. Drug discovery using in silico text mining and pathway analysis tools can facilitate the identification of existing drugs that have the potential of topical administration to improve OM treatment.

Genome-wide significant localization for working and spatial memory: Identifying genes for psychosis using models of cognition.

PubMed

Knowles, Emma E M; Carless, Melanie A; de Almeida, Marcio A A; Curran, Joanne E; McKay, D Reese; Sprooten, Emma; Dyer, Thomas D; Göring, Harald H; Olvera, Rene; Fox, Peter; Almasy, Laura; Duggirala, Ravi; Kent, Jack W; Blangero, John; Glahn, David C

2014-01-01

It is well established that risk for developing psychosis is largely mediated by the influence of genes, but identifying precisely which genes underlie that risk has been problematic. Focusing on endophenotypes, rather than illness risk, is one solution to this problem. Impaired cognition is a well-established endophenotype of psychosis. Here we aimed to characterize the genetic architecture of cognition using phenotypically detailed models as opposed to relying on general IQ or individual neuropsychological measures. In so doing we hoped to identify genes that mediate cognitive ability, which might also contribute to psychosis risk. Hierarchical factor models of genetically clustered cognitive traits were subjected to linkage analysis followed by QTL region-specific association analyses in a sample of 1,269 Mexican American individuals from extended pedigrees. We identified four genome wide significant QTLs, two for working and two for spatial memory, and a number of plausible and interesting candidate genes. The creation of detailed models of cognition seemingly enhanced the power to detect genetic effects on cognition and provided a number of possible candidate genes for psychosis. © 2013 Wiley Periodicals, Inc.

Genetic Mapping of Fixed Phenotypes: Disease Frequency as a Breed Characteristic

PubMed Central

Jones, Paul; Martin, Alan; Ostrander, Elaine A.; Lark, Karl G.

2009-01-01

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis. PMID:19321632

A novel quantification-driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer's disease.

PubMed

Skillbäck, Tobias; Mattsson, Niklas; Hansson, Karl; Mirgorodskaya, Ekaterina; Dahlén, Rahil; van der Flier, Wiesje; Scheltens, Philip; Duits, Floor; Hansson, Oskar; Teunissen, Charlotte; Blennow, Kaj; Zetterberg, Henrik; Gobom, Johan

2017-10-17

We present a new, quantification-driven proteomic approach to identifying biomarkers. In contrast to the identification-driven approach, limited in scope to peptides that are identified by database searching in the first step, all MS data are considered to select biomarker candidates. The endopeptidome of cerebrospinal fluid from 40 Alzheimer's disease (AD) patients, 40 subjects with mild cognitive impairment, and 40 controls with subjective cognitive decline was analyzed using multiplex isobaric labeling. Spectral clustering was used to match MS/MS spectra. The top biomarker candidate cluster (215% higher in AD compared to controls, area under ROC curve = 0.96) was identified as a fragment of pleiotrophin located near the protein's C-terminus. Analysis of another cohort (n = 60 over four clinical groups) verified that the biomarker was increased in AD patients while no change in controls, Parkinson's disease or progressive supranuclear palsy was observed. The identification of the novel biomarker pleiotrophin 151-166 demonstrates that our quantification-driven proteomic approach is a promising method for biomarker discovery, which may be universally applicable in clinical proteomics.

Genetic mapping of fixed phenotypes: disease frequency as a breed characteristic.

PubMed

Chase, Kevin; Jones, Paul; Martin, Alan; Ostrander, Elaine A; Lark, Karl G

2009-01-01

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pancreatitis.

Surviving the cold: molecular analyses of insect cryoprotective dehydration in the Arctic springtail Megaphorura arctica (Tullberg)

PubMed Central

Clark, Melody S; Thorne, Michael AS; Purać, Jelena; Burns, Gavin; Hillyard, Guy; Popović, Željko D; Grubor-Lajšić, Gordana; Worland, M Roger

2009-01-01

Background Insects provide tractable models for enhancing our understanding of the physiological and cellular processes that enable survival at extreme low temperatures. They possess three main strategies to survive the cold: freeze tolerance, freeze avoidance or cryoprotective dehydration, of which the latter method is exploited by our model species, the Arctic springtail Megaphorura arctica, formerly Onychiurus arcticus (Tullberg 1876). The physiological mechanisms underlying cryoprotective dehydration have been well characterised in M. arctica and to date this process has been described in only a few other species: the Antarctic nematode Panagrolaimus davidi, an enchytraied worm, the larvae of the Antarctic midge Belgica antarctica and the cocoons of the earthworm Dendrobaena octaedra. There are no in-depth molecular studies on the underlying cold survival mechanisms in any species. Results A cDNA microarray was generated using 6,912 M. arctica clones printed in duplicate. Analysis of clones up-regulated during dehydration procedures (using both cold- and salt-induced dehydration) has identified a number of significant cellular processes, namely the production and mobilisation of trehalose, protection of cellular systems via small heat shock proteins and tissue/cellular remodelling during the dehydration process. Energy production, initiation of protein translation and cell division, plus potential tissue repair processes dominate genes identified during recovery. Heat map analysis identified a duplication of the trehalose-6-phosphate synthase (TPS) gene in M. arctica and also 53 clones co-regulated with TPS, including a number of membrane associated and cell signalling proteins. Q-PCR on selected candidate genes has also contributed to our understanding with glutathione-S-transferase identified as the major antioxdidant enzyme protecting the cells during these stressful procedures, and a number of protein kinase signalling molecules involved in recovery. Conclusion Microarray analysis has proved to be a powerful technique for understanding the processes and genes involved in cryoprotective dehydration, beyond the few candidate genes identified in the current literature. Dehydration is associated with the mobilisation of trehalose, cell protection and tissue remodelling. Energy production, leading to protein production, and cell division characterise the recovery process. Novel membrane proteins, along with aquaporins and desaturases, have been identified as promising candidates for future functional analyses to better understand membrane remodelling during cellular dehydration. PMID:19622137

Differential proteome analysis of serum proteins associated with the development of type 2 diabetes mellitus in the KK-A(y) mouse model using the iTRAQ technique.

PubMed

Takahashi, Eri; Okumura, Akinori; Unoki-Kubota, Hiroyuki; Hirano, Hisashi; Kasuga, Masato; Kaburagi, Yasushi

2013-06-12

To identify candidate serum molecules associated with the progression of type 2 diabetes mellitus (T2DM), we carried out differential proteomic analysis using the KK-A(y) mouse, an animal model of T2DM with obesity. We employed an iTRAQ-based quantitative proteomic approach to analyze the proteomic changes in the sera collected from a pair of 4-week-old KK-A(y) versus C57BL/6 mice. Among the 227 proteins identified, a total of 45 proteins were differentially expressed in KK-A(y) versus C57BL/6 mice. We comparatively analyzed a series of the sera collected at 4 and 12weeks of age from KK-A(y) and C57BL/6 mice for the target protein using multiple reaction monitoring analysis, and identified 8 differentially expressed proteins between the sera of these mice at both time points. Among them, serine (or cysteine) peptidase inhibitor, clade A, member 3K (SERPINA3K) levels were elevated significantly in the sera of KK-A(y) mice compared to C57BL/6 mice. An in vitro assay revealed that the human homologue SERPINA3 increased the transendothelial permeability of retinal microvascular endothelial cells, which may be involved in the pathogenesis of diabetes and/or diabetic retinopathy. With the identified proteins, our proteomics study could provide valuable clues for a better understanding of the underlying mechanisms associated with T2DM. In this paper, we investigated the serum proteome of KK-A(y) mice in a pre-diabetic state compared to that of wild type controls in an attempt to uncover early diagnostic markers of diabetes that are maintained through a diabetic phenotype. We used iTRAQ-based two-dimensional LC-MS/MS serum profiling, and identified several differentially expressed proteins at the pre-diabetic stage. The differential expression was confirmed by multiple reaction monitoring assay, which is fast gaining ground as a sensitive, specific, and cost-effective methodology for relative quantification of the candidate proteins. Using these techniques, we have identified eight candidate proteins of interest including SERPINA3K, which may be important in the pathology of T2DM and/or diabetic retinopathy. Copyright © 2013 Elsevier B.V. All rights reserved.

Linkage study of nonsyndromic cleft lip with or without cleft palate using candidate genes and mapped polymorphic markers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stein, J.D.; Nelson, L.D.; Conner, B.J.

1994-09-01

Nonsyndromic cleft lip with or without cleft palate (CL(P)) involves fusion or growth failure of facial primordia during development. Complex segregation analysis of clefting populations suggest that an autosomal dominant gene may play a role in this common craniofacial disorder. We have ascertained 16 multigenerational families with CL(P) and tested linkage to 29 candidate genes and 139 mapped short tandem repeat markers. The candidate genes were selected based on their expression in craniofacial development or were identified through murine models. These include: TGF{alpha}, TGF{beta}1, TGF{beta}2, TGF{beta}3, EGF, EGFR, GRAS, cMyc, FGFR, Jun, JunB, PDFG{alpha}, PDGF{beta}, IGF2R, GCR Hox7, Hox8, Hox2B,more » twirler, 5 collagen and 3 extracellular matrix genes. Linkage was tested assuming an autosomal dominant model with sex-specific decreased penetrance. Linkage to all of the candidate loci was excluded in 11 families. RARA was tested and was not informative. However, haplotype analysis of markers flanking RARA on 17q allowed exclusion of this candidate locus. We have previously excluded linkage to 61 STR markers in 11 families. Seventy-eight mapped short tandem repeat markers have recently been tested in 16 families and 30 have been excluded. The remaining are being analyzed and an exclusion map is being developed based on the entire study results.« less

A comprehensive meta-analysis of plant morphology, yield, stay-green, and virus disease resistance QTL in maize (Zea mays L.).

PubMed

Wang, Yijun; Xu, Jing; Deng, Dexiang; Ding, Haidong; Bian, Yunlong; Yin, Zhitong; Wu, Yarong; Zhou, Bo; Zhao, Ye

2016-02-01

The meta-QTL and candidate genes will facilitate the elucidation of molecular bases underlying agriculturally important traits and open new avenues for functional markers development and elite alleles introgression in maize breeding program. A large number of QTLs attributed to grain productivity and other agriculturally important traits have been identified and deposited in public repositories. The integration of fruitful QTL becomes a major issue in current plant genomics. To this end, we first collected QTL for six agriculturally important traits in maize, including yield, plant height, ear height, leaf angle, stay-green, and maize rough dwarf disease resistance. The meta-analysis method was then employed to retrieve 113 meta-QTL. Additionally, we also isolated candidate genes for target traits by the bioinformatic technique. Several candidates, including some well-characterized genes, GA3ox2 for plant height, lg1 and lg4 for leaf angle, zfl1 and zfl2 for flowering time, were co-localized with established meta-QTL intervals. Intriguingly, in a relatively narrow meta-QTL region, the maize ortholog of rice yield-related gene GW8/OsSPL16 was believed to be a candidate for yield. Leveraging results presented in this study will provide further insights into the genetic architecture of maize agronomic traits. Moreover, the meta-QTL and candidate genes reported here could be harnessed for the enhancement of stress tolerance and yield performance in maize and translation to other crops.

An inventory of continental U.S. terrestrial candidate ecological restoration areas based on landscape context

Treesearch

James Wickham; Kurt Riitters; Peter Vogt; Jennifer Costanza; Anne Neale

2017-01-01

Landscape context is an important factor in restoration ecology, but the use of landscape context for site prioritization has not been as fully developed.We used morphological image processing to identify candidate ecological restoration areas based on their proximity to existing natural vegetation. We identified 1,102,720 candidate ecological restoration areas across...

Candidate causative mutation on BTA18 associated with calving and conformation traits in Holstein bulls

USDA-ARS?s Scientific Manuscript database

Complementing quantitative methods with sequence data analysis is a major goal of the post-genome era of biology. In this study, we analyzed Illumina HiSeq sequence data derived from 11 US Holstein bulls in order to identify putative causal mutations associated with calving and conformation traits. ...

Toward The Identification Of Candidate Genes Involved In Black Pod Disease Resistance In Theobroma cacao L.

USDA-ARS?s Scientific Manuscript database

Black Pod (Phytophthora sp.) has a devastating effect on the worldwide cacao (Theobroma cacao) yield and incorporating resistance into production fields has been an ongoing effort of breeding programs. Previous meta-QTL analysis of genetic maps created with a variety of molecular markers identified...

Toward the identification of candidate genes involved In black pod disease resistance in Theobroma cacao L.

USDA-ARS?s Scientific Manuscript database

Black Pod (Phytophthora sp.) has a devastating effect on the worldwide cacao (Theobroma cacao) yield and incorporating resistance into production fields has been an ongoing effort of breeding programs. Previous meta-QTL analysis of genetic maps created with a variety of molecular markers identified...

DEVELOPING A NATIONALLY CONSISTENT APPROACH FOR ASSESSING REGIONAL ASSOCIATIONS BETWEEN NUTRIENTS AND BENTHIC BIOLOGICAL CONDITION IN ESTUARINE WATERS. AN ANALYSIS USING NATIONAL COASTAL ASSESSMENT DATA

EPA Science Inventory

Identifying candidate water quality criteria in estuarine waters is confounded by differences among estuaries and biogeographic regions. Dealing with these differences is paramount to successfully addressing estuarine water quality impairment. As such, we outline an approach to...

Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations

USDA-ARS?s Scientific Manuscript database

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of circa 2,000 candidate genes in 7,657 African Americans, 1,315 Hi...

Genome-wide association analysis identifies candidate genes associated with iron deficiency chlorosis in soybean

USDA-ARS?s Scientific Manuscript database

Iron deficiency chlorosis (IDC) is a significant yield-limiting problem in some of the major soybean production regions in the United States. Soybean plants display a variety of symptoms, ranging from slight yellowing of the leaves to interveinal chlorosis and sometimes it is followed by stunted gr...

Saturation analysis of ChIP-seq data for reproducible identification of binding peaks

PubMed Central

Hansen, Peter; Hecht, Jochen; Ibrahim, Daniel M.; Krannich, Alexander; Truss, Matthias; Robinson, Peter N.

2015-01-01

Chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) is a powerful technology to identify the genome-wide locations of transcription factors and other DNA binding proteins. Computational ChIP-seq peak calling infers the location of protein–DNA interactions based on various measures of enrichment of sequence reads. In this work, we introduce an algorithm, Q, that uses an assessment of the quadratic enrichment of reads to center candidate peaks followed by statistical analysis of saturation of candidate peaks by 5′ ends of reads. We show that our method not only is substantially faster than several competing methods but also demonstrates statistically significant advantages with respect to reproducibility of results and in its ability to identify peaks with reproducible binding site motifs. We show that Q has superior performance in the delineation of double RNAPII and H3K4me3 peaks surrounding transcription start sites related to a better ability to resolve individual peaks. The method is implemented in C+l+ and is freely available under an open source license. PMID:26163319

Molecular cloning and characterization of a cytochrome P450 taxoid 9á-hydroxylase in Ginkgo biloba cells.

PubMed

Zhang, Nan; Han, Zhentai; Sun, Guiling; Hoffman, Angela; Wilson, Iain W; Yang, Yanfang; Gao, Qian; Wu, Jianqiang; Xie, Dan; Dai, Jungui; Qiu, Deyou

2014-01-17

Taxol is a well-known effective anticancer compound. Due to the inability to synthesize sufficient quantities of taxol to satisfy commercial demand, a biotechnological approach for a large-scale cell or cell-free system for its production is highly desirable. Several important genes in taxol biosynthesis are currently still unknown and have been shown to be difficult to isolate directly from Taxus, including the gene encoding taxoid 9α-hydroxylase. Ginkgo biloba suspension cells exhibit taxoid hydroxylation activity and provides an alternate means of identifying genes encoding enzymes with taxoid 9α-hydroxylation activity. Through analysis of high throughput RNA sequencing data from G. biloba, we identified two candidate genes with high similarity to Taxus CYP450s. Using in vitro cell-free protein synthesis assays and LC-MS analysis, we show that one candidate that belongs to the CYP716B, a subfamily whose biochemical functions have not been previously studied, possessed 9α-hydroxylation activity. This work will aid future identification of the taxoid 9α-hydroxylase gene from Taxus sp. Copyright © 2013 Elsevier Inc. All rights reserved.

Characterization of Novel Genes Within 8P11-12 Amplicon in Breast Cancer

DTIC Science & Technology

2007-06-01

C-myc amplification in breast cancer: a meta - analysis of its occurrence and prognostic relevance. Br J Cancer, 83: 1688-1695, 2000. 2. Hui, R...Nass SJ, Dickson RB, Trock BJ. C-myc amplification in breast cancer: a meta - analysis of its occurrence and prognostic relevance. Br J Cancer 2000;83...a detailed genomic and expression analysis of the 8p11-p12 amplicon in breast cancer cell lines and identified several novel candidate genes

A computational approach to candidate gene prioritization for X-linked mental retardation using annotation-based binary filtering and motif-based linear discriminatory analysis

PubMed Central

2011-01-01

Background Several computational candidate gene selection and prioritization methods have recently been developed. These in silico selection and prioritization techniques are usually based on two central approaches - the examination of similarities to known disease genes and/or the evaluation of functional annotation of genes. Each of these approaches has its own caveats. Here we employ a previously described method of candidate gene prioritization based mainly on gene annotation, in accompaniment with a technique based on the evaluation of pertinent sequence motifs or signatures, in an attempt to refine the gene prioritization approach. We apply this approach to X-linked mental retardation (XLMR), a group of heterogeneous disorders for which some of the underlying genetics is known. Results The gene annotation-based binary filtering method yielded a ranked list of putative XLMR candidate genes with good plausibility of being associated with the development of mental retardation. In parallel, a motif finding approach based on linear discriminatory analysis (LDA) was employed to identify short sequence patterns that may discriminate XLMR from non-XLMR genes. High rates (>80%) of correct classification was achieved, suggesting that the identification of these motifs effectively captures genomic signals associated with XLMR vs. non-XLMR genes. The computational tools developed for the motif-based LDA is integrated into the freely available genomic analysis portal Galaxy (http://main.g2.bx.psu.edu/). Nine genes (APLN, ZC4H2, MAGED4, MAGED4B, RAP2C, FAM156A, FAM156B, TBL1X, and UXT) were highlighted as highly-ranked XLMR methods. Conclusions The combination of gene annotation information and sequence motif-orientated computational candidate gene prediction methods highlight an added benefit in generating a list of plausible candidate genes, as has been demonstrated for XLMR. Reviewers: This article was reviewed by Dr Barbara Bardoni (nominated by Prof Juergen Brosius); Prof Neil Smalheiser and Dr Dustin Holloway (nominated by Prof Charles DeLisi). PMID:21668950

An integrated approach of comparative genomics and heritability analysis of pig and human on obesity trait: evidence for candidate genes on human chromosome 2.

PubMed

Kim, Jaemin; Lee, Taeheon; Kim, Tae-Hun; Lee, Kyung-Tai; Kim, Heebal

2012-12-19

Traditional candidate gene approach has been widely used for the study of complex diseases including obesity. However, this approach is largely limited by its dependence on existing knowledge of presumed biology of the phenotype under investigation. Our combined strategy of comparative genomics and chromosomal heritability estimate analysis of obesity traits, subscapular skinfold thickness and back-fat thickness in Korean cohorts and pig (Sus scrofa), may overcome the limitations of candidate gene analysis and allow us to better understand genetic predisposition to human obesity. We found common genes including FTO, the fat mass and obesity associated gene, identified from significant SNPs by association studies of each trait. These common genes were related to blood pressure and arterial stiffness (P = 1.65E-05) and type 2 diabetes (P = 0.00578). Through the estimation of variance of genetic component (heritability) for each chromosome by SNPs, we observed a significant positive correlation (r = 0.479) between genetic contributions of human and pig to obesity traits. Furthermore, we noted that human chromosome 2 (syntenic to pig chromosomes 3 and 15) was most important in explaining the phenotypic variance for obesity. Obesity genetics still awaits further discovery. Navigating syntenic regions suggests obesity candidate genes on chromosome 2 that are previously known to be associated with obesity-related diseases: MRPL33, PARD3B, ERBB4, STK39, and ZNF385B.

Biomarker candidates for the detection of an infectious etiology of febrile neutropenia.

PubMed

Richter, Martin E; Neugebauer, Sophie; Engelmann, Falco; Hagel, Stefan; Ludewig, Katrin; La Rosée, Paul; Sayer, Herbert G; Hochhaus, Andreas; von Lilienfeld-Toal, Marie; Bretschneider, Tom; Pausch, Christine; Engel, Christoph; Brunkhorst, Frank M; Kiehntopf, Michael

2016-04-01

Infections and subsequent septicemia are major complications in neutropenic patients with hematological malignancies. Here, we identify biomarker candidates for the early detection of an infectious origin, and monitoring of febrile neutropenia (FN). Proteome, metabolome, and conventional biomarkers from 20 patients with febrile neutropenia without proven infection (FNPI) were compared to 28 patients with proven infection, including 17 patients with bacteremia. Three peptides (mass to charge ratio 1017.4-1057.3; p-values 0.011-0.024), six proteins (mass to charge ratio 6881-17,215; p-values 0.002-0.004), and six phosphatidylcholines (p-values 0.007-0.037) were identified that differed in FNPI patients compared to patients with infection or bacteremia. Seven of these marker candidates discriminated FNPI from infection at fever onset with higher sensitivity and specificity (ROC-AUC 0.688-0.824) than conventional biomarkers i.e., procalcitonin, C-reactive protein, or interleukin-6 (ROC-AUC 0.535-0.672). In a post hoc analysis, monitoring the time course of four lysophosphatidylcholines, threonine, and tryptophan allowed for discrimination of patients with or without resolution of FN (ROC-AUC 0.648-0.919) with higher accuracy compared to conventional markers (ROC-AUC 0.514-0.871). Twenty-one promising biomarker candidates for the early detection of an infectious origin or for monitoring the course of FN were found which might overcome known shortcomings of conventional markers.

Application of metabonomics in a compound ranking study in early drug development revealing drug-induced excretion of choline into urine.

PubMed

Dieterle, Frank; Schlotterbeck, Götz; Ross, Alfred; Niederhauser, Urs; Senn, Hans

2006-09-01

Selecting drug candidates based on toxicity is an important step in early drug development. In this case study, it is shown how metabonomics is applied to a ranking study, in which drug candidates with equal pharmacological activities are selected based on least toxic side effects. The metabonomic analyses were carried out on an animal study that followed an established protocol for pilot toxicology/ranking studies in rats, however, not specifically modified for a metabonomic assessment. It is shown how conditions not specificially adopted for metabonomics investigations can significantly influence the metabolic profiles recorded by NMR. Furthermore, it is shown how the multivariate analysis of the NMR spectra identified an extreme excretion of an endogenous metabolite into urine induced by two out of the five drug candidates. The subsequent structure elucidation by two-dimensional NMR experiments and a subsequent validation by spiking experiments identified the metabolite as choline. The discussion of the mechanistic background for the excretion of choline, which is usually well-conserved in the body, results in two hypotheses of either a massive degradation of cell membranes or an inhibition of the choline oxidation. Although the validation of these hypotheses needs a follow-up study, the finding of a increased excretion of the important metabolite choline warrants exclusion of these two compounds as viable drug candidates from a metabonomics point of view.

Identification and phylogenetic analysis of a sheep pox virus isolated from the Ningxia Hui Autonomous Region of China.

PubMed

Zhu, X L; Yang, F; Li, H X; Dou, Y X; Meng, X L; Li, H; Luo, X N; Cai, X P

2013-05-14

An outbreak of sheep pox was investigated in the Ningxia Hui Autonomous Region in China. Through immunofluorescence testing, isolated viruses, polymerase chain reaction identification, and electron microscopic examination, the isolated strain was identified as a sheep pox virus. The virus was identified through sequence and phylogenetic analysis of the P32 gene, open reading frame (ORF) 095, and ORF 103 genes. This study is the first to use the ORF 095 and ORF 103 genes as candidate genes for the analysis of sheep pox. The results showed that the ORF 095 and ORF 103 genes could be used for the genotyping of the sheep pox virus.

Construction of a high-density genetic map by specific locus amplified fragment sequencing (SLAF-seq) and its application to Quantitative Trait Loci (QTL) analysis for boll weight in upland cotton (Gossypium hirsutum.).

PubMed

Zhang, Zhen; Shang, Haihong; Shi, Yuzhen; Huang, Long; Li, Junwen; Ge, Qun; Gong, Juwu; Liu, Aiying; Chen, Tingting; Wang, Dan; Wang, Yanling; Palanga, Koffi Kibalou; Muhammad, Jamshed; Li, Weijie; Lu, Quanwei; Deng, Xiaoying; Tan, Yunna; Song, Weiwu; Cai, Juan; Li, Pengtao; Rashid, Harun or; Gong, Wankui; Yuan, Youlu

2016-04-11

Upland Cotton (Gossypium hirsutum) is one of the most important worldwide crops it provides natural high-quality fiber for the industrial production and everyday use. Next-generation sequencing is a powerful method to identify single nucleotide polymorphism markers on a large scale for the construction of a high-density genetic map for quantitative trait loci mapping. In this research, a recombinant inbred lines population developed from two upland cotton cultivars 0-153 and sGK9708 was used to construct a high-density genetic map through the specific locus amplified fragment sequencing method. The high-density genetic map harbored 5521 single nucleotide polymorphism markers which covered a total distance of 3259.37 cM with an average marker interval of 0.78 cM without gaps larger than 10 cM. In total 18 quantitative trait loci of boll weight were identified as stable quantitative trait loci and were detected in at least three out of 11 environments and explained 4.15-16.70 % of the observed phenotypic variation. In total, 344 candidate genes were identified within the confidence intervals of these stable quantitative trait loci based on the cotton genome sequence. These genes were categorized based on their function through gene ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis and eukaryotic orthologous groups analysis. This research reported the first high-density genetic map for Upland Cotton (Gossypium hirsutum) with a recombinant inbred line population using single nucleotide polymorphism markers developed by specific locus amplified fragment sequencing. We also identified quantitative trait loci of boll weight across 11 environments and identified candidate genes within the quantitative trait loci confidence intervals. The results of this research would provide useful information for the next-step work including fine mapping, gene functional analysis, pyramiding breeding of functional genes as well as marker-assisted selection.

BallotMaps: detecting name bias in alphabetically ordered ballot papers.

PubMed

Wood, Jo; Badawood, Donia; Dykes, Jason; Slingsby, Aidan

2011-12-01

The relationship between candidates' position on a ballot paper and vote rank is explored in the case of 5000 candidates for the UK 2010 local government elections in the Greater London area. This design study uses hierarchical spatially arranged graphics to represent two locations that affect candidates at very different scales: the geographical areas for which they seek election and the spatial location of their names on the ballot paper. This approach allows the effect of position bias to be assessed; that is, the degree to which the position of a candidate's name on the ballot paper influences the number of votes received by the candidate, and whether this varies geographically. Results show that position bias was significant enough to influence rank order of candidates, and in the case of many marginal electoral wards, to influence who was elected to government. Position bias was observed most strongly for Liberal Democrat candidates but present for all major political parties. Visual analysis of classification of candidate names by ethnicity suggests that this too had an effect on votes received by candidates, in some cases overcoming alphabetic name bias. The results found contradict some earlier research suggesting that alphabetic name bias was not sufficiently significant to affect electoral outcome and add new evidence for the geographic and ethnicity influences on voting behaviour. The visual approach proposed here can be applied to a wider range of electoral data and the patterns identified and hypotheses derived from them could have significant implications for the design of ballot papers and the conduct of fair elections. © 2010 IEEE

In Silico Gene Prioritization by Integrating Multiple Data Sources

PubMed Central

Zhou, Yingyao; Shields, Robert; Chanda, Sumit K.; Elston, Robert C.; Li, Jing

2011-01-01

Identifying disease genes is crucial to the understanding of disease pathogenesis, and to the improvement of disease diagnosis and treatment. In recent years, many researchers have proposed approaches to prioritize candidate genes by considering the relationship of candidate genes and existing known disease genes, reflected in other data sources. In this paper, we propose an expandable framework for gene prioritization that can integrate multiple heterogeneous data sources by taking advantage of a unified graphic representation. Gene-gene relationships and gene-disease relationships are then defined based on the overall topology of each network using a diffusion kernel measure. These relationship measures are in turn normalized to derive an overall measure across all networks, which is utilized to rank all candidate genes. Based on the informativeness of available data sources with respect to each specific disease, we also propose an adaptive threshold score to select a small subset of candidate genes for further validation studies. We performed large scale cross-validation analysis on 110 disease families using three data sources. Results have shown that our approach consistently outperforms other two state of the art programs. A case study using Parkinson disease (PD) has identified four candidate genes (UBB, SEPT5, GPR37 and TH) that ranked higher than our adaptive threshold, all of which are involved in the PD pathway. In particular, a very recent study has observed a deletion of TH in a patient with PD, which supports the importance of the TH gene in PD pathogenesis. A web tool has been implemented to assist scientists in their genetic studies. PMID:21731658

Technology Candidates for Air-to-Air and Air-to-Ground Data Exchange

NASA Technical Reports Server (NTRS)

Haynes, Brian D.

2015-01-01

Technology Candidates for Air-to-Air and Air-to-Ground Data Exchange is a two-year research effort to visualize the U. S. aviation industry at a point 50 years in the future, and to define potential communication solutions to meet those future data exchange needs. The research team, led by XCELAR, was tasked with identifying future National Airspace System (NAS) scenarios, determining requirements and functions (including gaps), investigating technical and business issues for air, ground, & air-to-ground interactions, and reporting on the results. The project was conducted under technical direction from NASA and in collaboration with XCELAR's partner, National Institute of Aerospace, and NASA technical representatives. Parallel efforts were initiated to define the information exchange functional needs of the future NAS, and specific communication link technologies to potentially serve those needs. Those efforts converged with the mapping of each identified future NAS function to potential enabling communication solutions; those solutions were then compared with, and ranked relative to, each other on a technical basis in a structured analysis process. The technical solutions emerging from that process were then assessed from a business case perspective to determine their viability from a real-world adoption and deployment standpoint. The results of that analysis produced a proposed set of future solutions and most promising candidate technologies. Gap analyses were conducted at two points in the process, the first examining technical factors, and the second as part of the business case analysis. In each case, no gaps or unmet needs were identified in applying the solutions evaluated to the requirements identified. The future communication solutions identified in the research comprise both specific link technologies and two enabling technologies that apply to most or all specific links. As a result, the research resulted in a new analysis approach, viewing the underlying architecture of ground-air and air-air communications as a whole, rather than as simple "link to function" paired solutions. For the business case analysis, a number of "reference architectures" were developed for both the future technologies and the current systems, based on three typical configurations of current aircraft. Current and future costs were assigned, and various comparisons made between the current and future architectures. In general, it was assumed that if a future architecture offers lower cost than the current typical architecture, while delivering equivalent or better performance, it is likely that the future solution will gain industry acceptance. Conversely, future architectures presenting higher costs than their current counterparts must present a compelling benefit case in other areas or risk a lack of industry acceptance. The business case analysis consistently indicated lower costs for the proposed future architectures, and in most cases, significantly so. The proposed future solutions were found to offer significantly greater functionality, flexibility, and growth potential over time, at lower cost, than current systems. This was true for overall, fleet-wide equipage for domestic and oceanic air carriers, as well as for single, General Aviation (GA) aircraft. The overall research results indicate that all identified requirements can be met by the proposed solutions with significant capacity for future growth. Results also illustrate that the majority of the future communication needs can be met using currently allocated aviation RF spectrum, if used in more effective ways than it is today. A combination of such optimized aviation-specific links and commercial communication systems meets all identified needs for the 50-year future and beyond, with the caveat that a new, overall function will be needed to manage all information exchange, individual links, security, cost, and other factors. This function was labeled "Delivery Manager" (DM) within this research. DM employs a distributed client/server architecture, for both airborne and ground communications architectures. Final research results included identifying the most promising candidate technologies for the future system, conclusions and recommendations, and identifying areas where further research should be considered.

Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread.

PubMed

Spreafico, Filippo; Bongarzone, Italia; Pizzamiglio, Sara; Magni, Ruben; Taverna, Elena; De Bortoli, Maida; Ciniselli, Chiara M; Barzanò, Elena; Biassoni, Veronica; Luchini, Alessandra; Liotta, Lance A; Zhou, Weidong; Signore, Michele; Verderio, Paolo; Massimino, Maura

2017-07-11

Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status.

Coronin-1C is a novel biomarker for hepatocellular carcinoma invasive progression identified by proteomics analysis and clinical validation.

PubMed

Wu, Long; Peng, Chun-Wei; Hou, Jin-Xuan; Zhang, Yan-Hua; Chen, Chuang; Chen, Liang-Dong; Li, Yan

2010-02-24

To better search for potential markers for hepatocellular carcinoma (HCC) invasion and metastasis, proteomic approach was applied to identify potential metastasis biomarkers associated with HCC. Membrane proteins were extracted from MHCC97L and HCCLM9 cells, with a similar genetic background and remarkably different metastasis potential, and compared by SDS-PAGE and identified by ESI-MS/MS. The results were further validated by western blot analysis, immunohistochemistry (IHC) of tumor tissues from HCCLM9- and MHCC97L-nude mice, and clinical specimens. Membrane proteins were extracted from MHCC97L and HCCLM9 cell and compared by SDS-PAGE analyses. A total of 14 differentially expressed proteins were identified by ESI-MS/MS. Coronin-1C, a promising candidate, was found to be overexpressed in HCCLM9 cells as compared with MHCC97L cells, and validated by western blot and IHC from both nude mice tumor tissues and clinical specimens. Coronin-1C level showed an abrupt upsurge when pulmonary metastasis occurred. Increasing coronin-1C expression was found in liver cancer tissues of HCCLM9-nude mice with spontaneous pulmonary metastasis. IHC study on human HCC specimens revealed that more patients in the higher coronin-1C group had overt larger tumor and more advanced stage. Coronin-1C could be a candidate biomarker to predict HCC invasive behavior.

Discovering genetic variants in Crohn's disease by exploring genomic regions enriched of weak association signals.

PubMed

D'Addabbo, Annarita; Palmieri, Orazio; Maglietta, Rosalia; Latiano, Anna; Mukherjee, Sayan; Annese, Vito; Ancona, Nicola

2011-08-01

A meta-analysis has re-analysed previous genome-wide association scanning definitively confirming eleven genes and further identifying 21 new loci. However, the identified genes/loci still explain only the minority of genetic predisposition of Crohn's disease. To identify genes weakly involved in disease predisposition by analysing chromosomal regions enriched of single nucleotide polymorphisms with modest statistical association. We utilized the WTCCC data set evaluating 1748 CD and 2938 controls. The identification of candidate genes/loci was performed by a two-step procedure: first of all chromosomal regions enriched of weak association signals were localized; subsequently, weak signals clustered in gene regions were identified. The statistical significance was assessed by non parametric permutation tests. The cytoband enrichment analysis highlighted 44 regions (P≤0.05) enriched with single nucleotide polymorphisms significantly associated with the trait including 23 out of 31 previously confirmed and replicated genes. Importantly, we highlight further 20 novel chromosomal regions carrying approximately one hundred genes/loci with modest association. Amongst these we find compelling functional candidate genes such as MAPT, GRB2 and CREM, LCT, and IL12RB2. Our study suggests a different statistical perspective to discover genes weakly associated with a given trait, although further confirmatory functional studies are needed. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. All rights reserved.

Quantitative Trait Loci for Light Sensitivity, Body Weight, Body Size, and Morphological Eye Parameters in the Bumblebee, Bombus terrestris.

PubMed

Maebe, Kevin; Meeus, Ivan; De Riek, Jan; Smagghe, Guy

2015-01-01

Bumblebees such as Bombus terrestris are essential pollinators in natural and managed ecosystems. In addition, this species is intensively used in agriculture for its pollination services, for instance in tomato and pepper greenhouses. Here we performed a quantitative trait loci (QTL) analysis on B. terrestris using 136 microsatellite DNA markers to identify genes linked with 20 traits including light sensitivity, body size and mass, and eye and hind leg measures. By composite interval mapping (IM), we found 83 and 34 suggestive QTLs for 19 of the 20 traits at the linkage group wide significance levels of p = 0.05 and 0.01, respectively. Furthermore, we also found five significant QTLs at the genome wide significant level of p = 0.05. Individual QTLs accounted for 7.5-53.3% of the phenotypic variation. For 15 traits, at least one QTL was confirmed with multiple QTL model mapping. Multivariate principal components analysis confirmed 11 univariate suggestive QTLs but revealed three suggestive QTLs not identified by the individual traits. We also identified several candidate genes linked with light sensitivity, in particular the Phosrestin-1-like gene is a primary candidate for its phototransduction function. In conclusion, we believe that the suggestive and significant QTLs, and markers identified here, can be of use in marker-assisted breeding to improve selection towards light sensitive bumblebees, and thus also the pollination service of bumblebees.

POLR2C Mutations Are Associated With Primary Ovarian Insufficiency in Women.

PubMed

Moriwaki, Mika; Moore, Barry; Mosbruger, Timothy; Neklason, Deborah W; Yandell, Mark; Jorde, Lynn B; Welt, Corrine K

2017-03-01

Primary ovarian insufficiency (POI) results from a premature loss of oocytes, causing infertility and early menopause. The etiology of POI remains unknown in a majority of cases. To identify candidate genes in families affected by POI. This was a family-based genetic study. The study was performed at two academic institutions. A family with four generations of women affected by POI (n = 5). Four of these women, three with an associated autoimmune diagnosis, were studied. The controls (n = 387) were recruited for health in old age. Whole-genome sequencing was performed. Candidate genes were identified by comparing gene mutations in three family members and 387 control subjects analyzed simultaneously using the pedigree Variant Annotation, Analysis and Search Tool. Data were also compared with that in publicly available databases. We identified a heterozygous nonsense mutation in a subunit of RNA polymerase II ( POLR2C ) that synthesizes messenger RNA. A rare sequence variant in POLR2C was also identified in one of 96 women with sporadic POI. POLR2C expression was decreased in the proband compared with women with POI from another cause. Knockdown in an embryonic carcinoma cell line resulted in decreased protein production and impaired cell proliferation. These data support a role for RNA polymerase II mutations as candidates in the etiology of POI. The current data also support results from genome-wide association studies that hypothesize a role for RNA polymerase II subunits in age at menopause in the population.

A Planet Hunters Search of the Kepler TCE Inventory

NASA Astrophysics Data System (ADS)

Schwamb, Meg; Lintott, Chris; Fischer, Debra; Smith, Arfon; Boyajian, Tabetha; Brewer, John; Giguere, Matt; Lynn, Stuart; Schawinski, Kevin; Simpson, Rob; Wang, Ji

2013-07-01

NASA's Kepler spacecraft has spent the past 4 years monitoring ~160,000 stars for the signatures of transiting exoplanets. Planet Hunters (http://www.planethunters.org), part of the Zooniverse (http://www.zooniverse.org) collection of citizen science projects, uses the power of human pattern recognition via the World Wide Web to identify transits in the Kepler public data. We have demonstrated the success of a citizen science approach with the project's discoveries including PH1 b, a transiting circumbinary planet in a four star system., and over 20 previously unknown planet candidates. The Kepler team has released the list of 18,406 potential transit signals or threshold-crossing events (TCEs) identified in Quarters 1-12 (~1000 days) by their automated Transit Planet Search (TPS) algorithm. The majority of these detections found by TPS are triggered by transient events and are not valid planet candidates. To identify planetary candidates from the detected TCEs, a human review of the validation reports, generated by the Kepler pipeline for each TCE, is performed by several Kepler team members. We have undertaken an independent crowd-sourced effort to perform a systematic search of the Kepler Q1-12 TCE list. With the Internet we can obtain multiple assessments of each TCE's data validation report. Planet Hunters volunteers evaluate whether a transit is visible in the Kepler light curve folded on the expected period identified by TPS. We present the first results of this analysis.

VizieR Online Data Catalog: 231 AGN candidates from the 2FGL catalog (Doert+, 2014)

NASA Astrophysics Data System (ADS)

Doert, M.; Errando, M.

2016-01-01

The second Fermi-LAT source catalog (2FGL; Nolan et al. 2012, cat. J/ApJS/199/31) is the deepest all-sky survey available in the gamma-ray band. It contains 1873 sources, of which 576 remain unassociated. The Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope started operations in 2008. In this work, machine-learning algorithms are used to identify unassociated sources in the 2FGL catalog with properties similar to gamma-ray-emitting Active Galactic Nuclei (AGN). This analysis finds 231 high-confidence AGN candidates (see Table3). (1 data file).

A New M Dwarf Debris Disk Candidate in a Young Moving Group Discovered with Disk Detective

NASA Technical Reports Server (NTRS)

Silverberg, Steven M.; Kuchner, Marc J.; Wisniewski, John P.; Gagne, Jonathan; Bans, Alissa S.; Bhattacharjee, Shambo; Currie, Thayne R.; Debes, John R.; Biggs, Joseph R; Bosch, Milton

2016-01-01

We used the Disk Detective citizen science project and the BANYAN II Bayesian analysis tool to identify a new candidate member of a nearby young association with infrared excess. WISE J080822.18-644357.3, an M5.5-type debris disk system with significant excess at both 12 and 22 microns, is a likely member (approx.90% BANYAN II probability) of the approx.45 Myr old Carina association. Since this would be the oldest M dwarf debris disk detected in a moving group, this discovery could be an important constraint on our understanding of M dwarf debris disk evolution.

An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits

PubMed Central

Demissie, Serkalem; Soranzo, Nicole; Bianchi, Estelle N.; Grundberg, Elin; Liang, Liming; Richards, J. Brent; Estrada, Karol; Zhou, Yanhua; van Nas, Atila; Moffatt, Miriam F.; Zhai, Guangju; Hofman, Albert; van Meurs, Joyce B.; Pols, Huibert A. P.; Price, Roger I.; Nilsson, Olle; Pastinen, Tomi; Cupples, L. Adrienne; Lusis, Aldons J.; Schadt, Eric E.; Ferrari, Serge; Uitterlinden, André G.

2010-01-01

Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6×10−8), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6×10−13; SOX6, p = 6.4×10−10) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation. PMID:20548944

Comparative transcriptome analysis and identification of candidate effectors in two related rust species (Gymnosporangium yamadae and Gymnosporangium asiaticum).

PubMed

Tao, Si-Qi; Cao, Bin; Tian, Cheng-Ming; Liang, Ying-Mei

2017-08-23

Rust fungi constitute the largest group of plant fungal pathogens. However, a paucity of data, including genomic sequences, transcriptome sequences, and associated molecular markers, hinders the development of inhibitory compounds and prevents their analysis from an evolutionary perspective. Gymnosporangium yamadae and G. asiaticum are two closely related rust fungal species, which are ecologically and economically important pathogens that cause apple rust and pear rust, respectively, proved to be devastating to orchards. In this study, we investigated the transcriptomes of these two Gymnosporangium species during the telial stage of their lifecycles. The aim of this study was to understand the evolutionary patterns of these two related fungi and to identify genes that developed by selection. The transcriptomes of G. yamadae and G. asiaticum were generated from a mixture of RNA from three biological replicates of each species. We obtained 49,318 and 54,742 transcripts, with N50 values of 1957 and 1664, for G. yamadae and G. asiaticum, respectively. We also identified a repertoire of candidate effectors and other gene families associated with pathogenicity. A total of 4947 pairs of putative orthologues between the two species were identified. Estimation of the non-synonymous/synonymous substitution rate ratios for these orthologues identified 116 pairs with Ka/Ks values greater than1 that are under positive selection and 170 pairs with Ka/Ks values of 1 that are under neutral selection, whereas the remaining 4661 genes are subjected to purifying selection. We estimate that the divergence time between the two species is approximately 5.2 Mya. This study constitutes a de novo assembly and comparative analysis between the transcriptomes of the two rust species G. yamadae and G. asiaticum. The results identified several orthologous genes, and many expressed genes were identified by annotation. Our analysis of Ka/Ks ratios identified orthologous genes subjected to positive or purifying selection. An evolutionary analysis of these two species provided a relatively precise divergence time. Overall, the information obtained in this study increases the genetic resources available for research on the genetic diversity of the Gymnosporangium genus.

Identification of peptidase substrates in human plasma by FTMS based differential mass spectrometry

NASA Astrophysics Data System (ADS)

Yates, Nathan A.; Deyanova, Ekaterina G.; Geissler, Wayne; Wiener, Matthew C.; Sachs, Jeffrey R.; Wong, Kenny K.; Thornberry, Nancy A.; Sinha Roy, Ranabir; Settlage, Robert E.; Hendrickson, Ronald C.

2007-01-01

Approximately 2% of the human genome encodes for proteases. Unfortunately, however, the biological roles of most of these enzymes remain poorly defined, since the physiological substrates are typically unknown and are difficult to identify using traditional methods. We have developed a proteomics experiment based on FTMS profiling and differential mass spectrometry (dMS) to identify candidate endogenous substrates of proteases using fractionated human plasma as the candidate substrate pool. Here we report proof-of-concept experiments for identifying in vitro substrates of aminopeptidase P2, (APP2) and dipeptidyl peptidase 4 (DPP-4), a peptidase of therapeutic interest for the treatment of type 2 diabetes. For both proteases, previously validated peptide substrates spiked into the human plasma pool were identified. Of note, the differential mass spectrometry experiments also identified novel substrates for each peptidase in the subfraction of human plasma. Targeted MS/MS analysis of these peptides in the complex human plasma pool and manual confirmation of the amino acid sequences led to the identification of these substrates. The novel DPP-4 substrate EPLGRQLTSGP was chemically synthesized and cleavage kinetics were determined in an in vitro DPP-4 enzyme assay. The apparent second order rate constant (kcat/KM) for DPP-4-mediated cleavage was determined to be 2.3 x 105 M-1 s-1 confirming that this peptide is efficiently processed by the peptidase in vitro. Collectively, these results demonstrate that differential mass spectrometry has the potential to identify candidate endogenous substrates of target proteases from a human plasma pool. Importantly, knowledge of the endogenous substrates can provide useful insight into the biology of these enzymes and provides useful biomarkers for monitoring their activity in vivo.

Network-based analysis of differentially expressed genes in cerebrospinal fluid (CSF) and blood reveals new candidate genes for multiple sclerosis

PubMed Central

Safari-Alighiarloo, Nahid; Taghizadeh, Mohammad; Tabatabaei, Seyyed Mohammad; Namaki, Saeed

2016-01-01

Background The involvement of multiple genes and missing heritability, which are dominant in complex diseases such as multiple sclerosis (MS), entail using network biology to better elucidate their molecular basis and genetic factors. We therefore aimed to integrate interactome (protein–protein interaction (PPI)) and transcriptomes data to construct and analyze PPI networks for MS disease. Methods Gene expression profiles in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) samples from MS patients, sampled in relapse or remission and controls, were analyzed. Differentially expressed genes which determined only in CSF (MS vs. control) and PBMCs (relapse vs. remission) separately integrated with PPI data to construct the Query-Query PPI (QQPPI) networks. The networks were further analyzed to investigate more central genes, functional modules and complexes involved in MS progression. Results The networks were analyzed and high centrality genes were identified. Exploration of functional modules and complexes showed that the majority of high centrality genes incorporated in biological pathways driving MS pathogenesis. Proteasome and spliceosome were also noticeable in enriched pathways in PBMCs (relapse vs. remission) which were identified by both modularity and clique analyses. Finally, STK4, RB1, CDKN1A, CDK1, RAC1, EZH2, SDCBP genes in CSF (MS vs. control) and CDC37, MAP3K3, MYC genes in PBMCs (relapse vs. remission) were identified as potential candidate genes for MS, which were the more central genes involved in biological pathways. Discussion This study showed that network-based analysis could explicate the complex interplay between biological processes underlying MS. Furthermore, an experimental validation of candidate genes can lead to identification of potential therapeutic targets. PMID:28028462

The Acid Phosphatase-Encoding Gene GmACP1 Contributes to Soybean Tolerance to Low-Phosphorus Stress

PubMed Central

Hao, Derong; Wang, Hui; Kan, Guizhen; Jin, Hangxia; Yu, Deyue

2014-01-01

Phosphorus (P) is essential for all living cells and organisms, and low-P stress is a major factor constraining plant growth and yield worldwide. In plants, P efficiency is a complex quantitative trait involving multiple genes, and the mechanisms underlying P efficiency are largely unknown. Combining linkage analysis, genome-wide and candidate-gene association analyses, and plant transformation, we identified a soybean gene related to P efficiency, determined its favorable haplotypes and developed valuable functional markers. First, six major genomic regions associated with P efficiency were detected by performing genome-wide associations (GWAs) in various environments. A highly significant region located on chromosome 8, qPE8, was identified by both GWAs and linkage mapping and explained 41% of the phenotypic variation. Then, a regional mapping study was performed with 40 surrounding markers in 192 diverse soybean accessions. A strongly associated haplotype (P = 10−7) consisting of the markers Sat_233 and BARC-039899-07603 was identified, and qPE8 was located in a region of approximately 250 kb, which contained a candidate gene GmACP1 that encoded an acid phosphatase. GmACP1 overexpression in soybean hairy roots increased P efficiency by 11–20% relative to the control. A candidate-gene association analysis indicated that six natural GmACP1 polymorphisms explained 33% of the phenotypic variation. The favorable alleles and haplotypes of GmACP1 associated with increased transcript expression correlated with higher enzyme activity. The discovery of the optimal haplotype of GmACP1 will now enable the accurate selection of soybeans with higher P efficiencies and improve our understanding of the molecular mechanisms underlying P efficiency in plants. PMID:24391523

In Silico Identification of Epitopes in Mycobacterium avium subsp. paratuberculosis Proteins That Were Upregulated under Stress Conditions

PubMed Central

Gurung, Ratna B.; Purdie, Auriol C.; Begg, Douglas J.

2012-01-01

Johne's disease in ruminants is caused by Mycobacterium avium subsp. paratuberculosis. Diagnosis of M. avium subsp. paratuberculosis infection is difficult, especially in the early stages. To date, ideal antigen candidates are not available for efficient immunization or immunodiagnosis. This study reports the in silico selection and subsequent analysis of epitopes of M. avium subsp. paratuberculosis proteins that were found to be upregulated under stress conditions as a means to identify immunogenic candidate proteins. Previous studies have reported differential regulation of proteins when M. avium subsp. paratuberculosis is exposed to stressors which induce a response similar to dormancy. Dormancy may be involved in evading host defense mechanisms, and the host may also mount an immune response against these proteins. Twenty-five M. avium subsp. paratuberculosis proteins that were previously identified as being upregulated under in vitro stress conditions were analyzed for B and T cell epitopes by use of the prediction tools at the Immune Epitope Database and Analysis Resource. Major histocompatibility complex class I T cell epitopes were predicted using an artificial neural network method, and class II T cell epitopes were predicted using the consensus method. Conformational B cell epitopes were predicted from the relevant three-dimensional structure template for each protein. Based on the greatest number of predicted epitopes, eight proteins (MAP2698c [encoded by desA2], MAP2312c [encoded by fadE19], MAP3651c [encoded by fadE3_2], MAP2872c [encoded by fabG5_2], MAP3523c [encoded by oxcA], MAP0187c [encoded by sodA], and the hypothetical proteins MAP3567 and MAP1168c) were identified as potential candidates for study of antibody- and cell-mediated immune responses within infected hosts. PMID:22496492

Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat.

PubMed

Morrissey, Catherine; Grieve, Ian C; Heinig, Matthias; Atanur, Santosh; Petretto, Enrico; Pravenec, Michal; Hubner, Norbert; Aitman, Timothy J

2011-11-07

The spontaneously hypertensive rat (SHR) is a widely used rodent model of hypertension and metabolic syndrome. Previously we identified thousands of cis-regulated expression quantitative trait loci (eQTLs) across multiple tissues using a panel of rat recombinant inbred (RI) strains derived from Brown Norway and SHR progenitors. These cis-eQTLs represent potential susceptibility loci underlying physiological and pathophysiological traits manifested in SHR. We have prioritized 60 cis-eQTLs and confirmed differential expression between the parental strains by quantitative PCR in 43 (72%) of the eQTL transcripts. Quantitative trait transcript (QTT) analysis in the RI strains showed highly significant correlation between cis-eQTL transcript abundance and clinically relevant traits such as systolic blood pressure and blood glucose, with the physical location of a subset of the cis-eQTLs colocalizing with "physiological" QTLs (pQTLs) for these same traits. These colocalizing correlated cis-eQTLs (c3-eQTLs) are highly attractive as primary susceptibility loci for the colocalizing pQTLs. Furthermore, sequence analysis of the c3-eQTL genes identified single nucleotide polymorphisms (SNPs) that are predicted to affect transcription factor binding affinity, splicing and protein function. These SNPs, which potentially alter transcript abundance and stability, represent strong candidate factors underlying not just eQTL expression phenotypes, but also the correlated metabolic and physiological traits. In conclusion, by integration of genomic sequence, eQTL and QTT datasets we have identified several genes that are strong positional candidates for pathophysiological traits observed in the SHR strain. These findings provide a basis for the functional testing and ultimate elucidation of the molecular basis of these metabolic and cardiovascular phenotypes.

Pivotal role of the muscle-contraction pathway in cryptorchidism and evidence for genomic connections with cardiomyopathy pathways in RASopathies.

PubMed

Cannistraci, Carlo V; Ogorevc, Jernej; Zorc, Minja; Ravasi, Timothy; Dovc, Peter; Kunej, Tanja

2013-02-14

Cryptorchidism is the most frequent congenital disorder in male children; however the genetic causes of cryptorchidism remain poorly investigated. Comparative integratomics combined with systems biology approach was employed to elucidate genetic factors and molecular pathways underlying testis descent. Literature mining was performed to collect genomic loci associated with cryptorchidism in seven mammalian species. Information regarding the collected candidate genes was stored in MySQL relational database. Genomic view of the loci was presented using Flash GViewer web tool (http://gmod.org/wiki/Flashgviewer/). DAVID Bioinformatics Resources 6.7 was used for pathway enrichment analysis. Cytoscape plug-in PiNGO 1.11 was employed for protein-network-based prediction of novel candidate genes. Relevant protein-protein interactions were confirmed and visualized using the STRING database (version 9.0). The developed cryptorchidism gene atlas includes 217 candidate loci (genes, regions involved in chromosomal mutations, and copy number variations) identified at the genomic, transcriptomic, and proteomic level. Human orthologs of the collected candidate loci were presented using a genomic map viewer. The cryptorchidism gene atlas is freely available online: http://www.integratomics-time.com/cryptorchidism/. Pathway analysis suggested the presence of twelve enriched pathways associated with the list of 179 literature-derived candidate genes. Additionally, a list of 43 network-predicted novel candidate genes was significantly associated with four enriched pathways. Joint pathway analysis of the collected and predicted candidate genes revealed the pivotal importance of the muscle-contraction pathway in cryptorchidism and evidence for genomic associations with cardiomyopathy pathways in RASopathies. The developed gene atlas represents an important resource for the scientific community researching genetics of cryptorchidism. The collected data will further facilitate development of novel genetic markers and could be of interest for functional studies in animals and human. The proposed network-based systems biology approach elucidates molecular mechanisms underlying co-presence of cryptorchidism and cardiomyopathy in RASopathies. Such approach could also aid in molecular explanation of co-presence of diverse and apparently unrelated clinical manifestations in other syndromes.

Keeping Minorities Happy: Hierarchy Maintenance and Whites' Decreased Support for Highly Identified White Politicians.

PubMed

Jun, Sora; Lowery, Brian S; Guillory, Lucia

2017-12-01

We test the hypothesis that, to avoid provoking minorities, Whites will withhold their support for White political candidates who are highly identified with their race. In Study 1, we found that White Republicans were less supportive of White candidates the higher the perceived White identity of the candidate due to beliefs that such candidates would provoke racial minorities. In Study 2, we replicated this effect with a manipulation of candidates' White identity. Study 3 found that Whites reported less support for high-identity candidates when they were led to believe that the hierarchy was unstable rather than stable. Consistent with our hypothesis that those who have the most to lose are most likely to avoid provoking minorities, in Study 4, we found that Whites with high subjective socioeconomic status (SES) varied their support for provocative White candidates as a function of hierarchy stability, whereas those with low subjective SES did not.

Comparative molecular analyses of select pH- and osmoregulatory genes in three freshwater crayfish Cherax quadricarinatus, C. destructor and C. cainii

PubMed Central

Pavasovic, Ana; Dammannagoda, Lalith K.; Mather, Peter B.; Prentis, Peter J.

2017-01-01

Systemic acid-base balance and osmotic/ionic regulation in decapod crustaceans are in part maintained by a set of transport-related enzymes such as carbonic anhydrase (CA), Na+/K+-ATPase (NKA), H+-ATPase (HAT), Na+/K+/2Cl− cotransporter (NKCC), Na+/Cl−/HCO\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${}_{3}^{-}$\\end{document}3− cotransporter (NBC), Na+/H+ exchanger (NHE), Arginine kinase (AK), Sarcoplasmic Ca+2-ATPase (SERCA) and Calreticulin (CRT). We carried out a comparative molecular analysis of these genes in three commercially important yet eco-physiologically distinct freshwater crayfish, Cherax quadricarinatus, C. destructor and C. cainii, with the aim to identify mutations in these genes and determine if observed patterns of mutations were consistent with the action of natural selection. We also conducted a tissue-specific expression analysis of these genes across seven different organs, including gills, hepatopancreas, heart, kidney, liver, nerve and testes using NGS transcriptome data. The molecular analysis of the candidate genes revealed a high level of sequence conservation across the three Cherax sp. Hyphy analysis revealed that all candidate genes showed patterns of molecular variation consistent with neutral evolution. The tissue-specific expression analysis showed that 46% of candidate genes were expressed in all tissue types examined, while approximately 10% of candidate genes were only expressed in a single tissue type. The largest number of genes was observed in nerve (84%) and gills (78%) and the lowest in testes (66%). The tissue-specific expression analysis also revealed that most of the master genes regulating pH and osmoregulation (CA, NKA, HAT, NKCC, NBC, NHE) were expressed in all tissue types indicating an important physiological role for these genes outside of osmoregulation in other tissue types. The high level of sequence conservation observed in the candidate genes may be explained by the important role of these genes as well as potentially having a number of other basic physiological functions in different tissue types. PMID:28852583

Finding gene regulatory network candidates using the gene expression knowledge base.

PubMed

Venkatesan, Aravind; Tripathi, Sushil; Sanz de Galdeano, Alejandro; Blondé, Ward; Lægreid, Astrid; Mironov, Vladimir; Kuiper, Martin

2014-12-10

Network-based approaches for the analysis of large-scale genomics data have become well established. Biological networks provide a knowledge scaffold against which the patterns and dynamics of 'omics' data can be interpreted. The background information required for the construction of such networks is often dispersed across a multitude of knowledge bases in a variety of formats. The seamless integration of this information is one of the main challenges in bioinformatics. The Semantic Web offers powerful technologies for the assembly of integrated knowledge bases that are computationally comprehensible, thereby providing a potentially powerful resource for constructing biological networks and network-based analysis. We have developed the Gene eXpression Knowledge Base (GeXKB), a semantic web technology based resource that contains integrated knowledge about gene expression regulation. To affirm the utility of GeXKB we demonstrate how this resource can be exploited for the identification of candidate regulatory network proteins. We present four use cases that were designed from a biological perspective in order to find candidate members relevant for the gastrin hormone signaling network model. We show how a combination of specific query definitions and additional selection criteria derived from gene expression data and prior knowledge concerning candidate proteins can be used to retrieve a set of proteins that constitute valid candidates for regulatory network extensions. Semantic web technologies provide the means for processing and integrating various heterogeneous information sources. The GeXKB offers biologists such an integrated knowledge resource, allowing them to address complex biological questions pertaining to gene expression. This work illustrates how GeXKB can be used in combination with gene expression results and literature information to identify new potential candidates that may be considered for extending a gene regulatory network.

NAC transcription factor genes: genome-wide identification, phylogenetic, motif and cis-regulatory element analysis in pigeonpea (Cajanus cajan (L.) Millsp.).

PubMed

Satheesh, Viswanathan; Jagannadham, P Tej Kumar; Chidambaranathan, Parameswaran; Jain, P K; Srinivasan, R

2014-12-01

The NAC (NAM, ATAF and CUC) proteins are plant-specific transcription factors implicated in development and stress responses. In the present study 88 pigeonpea NAC genes were identified from the recently published draft genome of pigeonpea by using homology based and de novo prediction programmes. These sequences were further subjected to phylogenetic, motif and promoter analyses. In motif analysis, highly conserved motifs were identified in the NAC domain and also in the C-terminal region of the NAC proteins. A phylogenetic reconstruction using pigeonpea, Arabidopsis and soybean NAC genes revealed 33 putative stress-responsive pigeonpea NAC genes. Several stress-responsive cis-elements were identified through in silico analysis of the promoters of these putative stress-responsive genes. This analysis is the first report of NAC gene family in pigeonpea and will be useful for the identification and selection of candidate genes associated with stress tolerance.

Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma.

PubMed

Mendrzyk, Frank; Radlwimmer, Bernhard; Joos, Stefan; Kokocinski, Felix; Benner, Axel; Stange, Daniel E; Neben, Kai; Fiegler, Heike; Carter, Nigel P; Reifenberger, Guido; Korshunov, Andrey; Lichter, Peter

2005-12-01

Medulloblastoma is the most common malignant brain tumor in children. Despite multimodal aggressive treatment, nearly half of the patients die as a result of this tumor. Identification of molecular markers for prognosis and development of novel pathogenesis-based therapies depends crucially on a better understanding of medulloblastoma pathomechanisms. We performed genome-wide analysis of DNA copy number imbalances in 47 medulloblastomas using comparative genomic hybridization to large insert DNA microarrays (matrix-CGH). The expression of selected candidate genes identified by matrix-CGH was analyzed immunohistochemically on tissue microarrays representing medulloblastomas from 189 clinically well-documented patients. To identify novel prognostic markers, genomic findings and protein expression data were correlated to patient survival. Matrix-CGH analysis revealed frequent DNA copy number alterations of several novel candidate regions. Among these, gains at 17q23.2-qter (P < .01) and losses at 17p13.1 to 17p13.3 (P = .04) were significantly correlated to poor prognosis. Within 17q23.2-qter and 7q21.2, two of the most frequently gained chromosomal regions, confined amplicons were identified that contained the PPM1D and CDK6 genes, respectively. Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas. Overexpression of CDK6 correlated significantly with poor prognosis (P < .01) and represented an independent prognostic marker of overall survival on multivariate analysis (P = .02). We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.

Molecular Gas toward the Gemini OB1 Molecular Cloud Complex. II. CO Outflow Candidates with Possible WISE Associations

NASA Astrophysics Data System (ADS)

Li, Yingjie; Li, Fa-Cheng; Xu, Ye; Wang, Chen; Du, Xin-Yu; Yang, Wenjin; Yang, Ji

2018-03-01

We present a large-scale survey of CO outflows in the Gem OB1 molecular cloud complex and its surroundings, using the Purple Mountain Observatory Delingha 13.7 m telescope. A total of 198 outflow candidates were identified over a large area (∼58.5 square degrees), of which 193 are newly detected. Approximately 68% (134/198) are associated with the Gem OB1 molecular cloud complex, including clouds GGMC 1, GGMC 2, BFS 52, GGMC 3, and GGMC 4. Other regions studied are: the Local arm (Local Lynds, West Front), Swallow, Horn, and Remote cloud. Outflow candidates in GGMC 1, BFS 52, and Swallow are mainly located at ring-like or filamentary structures. To avoid excessive uncertainty in distant regions (≳3.8 kpc), we only estimated the physical parameters for clouds in the Gem OB1 molecular cloud complex and in the Local arm. In those clouds, the total kinetic energy and the energy injection rate of the identified outflow candidates are ≲1% and ≲3% of the turbulent energy and the turbulent dissipation rate of each cloud, indicating that the identified outflow candidates cannot provide enough energy to balance turbulence of their host cloud at the scale of the entire cloud (several to dozens of parsecs). The gravitational binding energy of each cloud is ≳135 times the total kinetic energy of the identified outflow candidates within the corresponding cloud, indicating that the identified outflow candidates cannot cause major disruptions to the integrity of their host cloud at the scale of the entire cloud.

Genome-wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma.

PubMed

Charlet, Jessica; Tomari, Ayumi; Dallosso, Anthony R; Szemes, Marianna; Kaselova, Martina; Curry, Thomas J; Almutairi, Bader; Etchevers, Heather C; McConville, Carmel; Malik, Karim T A; Brown, Keith W

2017-04-01

Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome-wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome-wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down-regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest-expressing tumors had reduced relapse-free survival. Our functional studies showed that knock-down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

Genome‐wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma

PubMed Central

Charlet, Jessica; Tomari, Ayumi; Dallosso, Anthony R.; Szemes, Marianna; Kaselova, Martina; Curry, Thomas J.; Almutairi, Bader; Etchevers, Heather C.; McConville, Carmel; Malik, Karim T. A.

2016-01-01

Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome‐wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome‐wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down‐regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest‐expressing tumors had reduced relapse‐free survival. Our functional studies showed that knock‐down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. PMID:27862318

Selection of reference genes for expression studies with fish myogenic cell cultures.

PubMed

Bower, Neil I; Johnston, Ian A

2009-08-10

Relatively few studies have used cell culture systems to investigate gene expression and the regulation of myogenesis in fish. To produce robust data from quantitative real-time PCR mRNA levels need to be normalised using internal reference genes which have stable expression across all experimental samples. We have investigated the expression of eight candidate genes to identify suitable reference genes for use in primary myogenic cell cultures from Atlantic salmon (Salmo salar L.). The software analysis packages geNorm, Normfinder and Best keeper were used to rank genes according to their stability across 42 samples during the course of myogenic differentiation. Initial results showed several of the candidate genes exhibited stable expression throughout myogenic culture while Sdha was identified as the least stable gene. Further analysis with geNorm, Normfinder and Bestkeeper identified Ef1alpha, Hprt1, Ppia and RNApolII as stably expressed. Comparison of data normalised with the geometric average obtained from combinations of any three of these genes showed no significant differences, indicating that any combination of these genes is valid. The geometric average of any three of Hprt1, Ef1alpha, Ppia and RNApolII is suitable for normalisation of gene expression data in primary myogenic cultures from Atlantic salmon.

Identification of suitable reference genes for hepatic microRNA quantitation.

PubMed

Lamba, Vishal; Ghodke-Puranik, Yogita; Guan, Weihua; Lamba, Jatinder K

2014-03-07

MicroRNAs (miRNAs) are short (~22 nt) endogenous RNAs that play important roles in regulating expression of a wide variety of genes involved in different cellular processes. Alterations in microRNA expression patterns have been associated with a number of human diseases. Accurate quantitation of microRNA levels is important for their use as biomarkers and in determining their functions. Real time PCR is the gold standard and the most frequently used technique for miRNA quantitation. Real time PCR data analysis includes normalizing the amplification data to suitable endogenous control/s to ensure that microRNA quantitation is not affected by the variability that is potentially introduced at different experimental steps. U6 (RNU6A) and RNU6B are two commonly used endogenous controls in microRNA quantitation. The present study was designed to investigate inter-individual variability and gender differences in hepatic microRNA expression as well as to identify the best endogenous control/s that could be used for normalization of real-time expression data in liver samples. We used Taqman based real time PCR to quantitate hepatic expression levels of 22 microRNAs along with U6 and RNU6B in 50 human livers samples (25 M, 25 F). To identify the best endogenous controls for use in data analysis, we evaluated the amplified candidates for their stability (least variability) in expression using two commonly used software programs: Normfinder and GeNormplus, Both Normfinder and GeNormplus identified U6 to be among the least stable of all the candidates analyzed, and RNU6B was also not among the top genes in stability. mir-152 and mir-23b were identified to be the two most stable candidates by both Normfinder and GeNormplus in our analysis, and were used as endogenous controls for normalization of hepatic miRNA levels. Measurements of microRNA stability indicate that U6 and RNU6B are not suitable for use as endogenous controls for normalizing microRNA relative quantitation data in hepatic tissue, and their use can led to possibly erroneous conclusions.

Structural and Functional Analysis of the GRAS Gene Family in Grapevine Indicates a Role of GRAS Proteins in the Control of Development and Stress Responses

PubMed Central

Grimplet, Jérôme; Agudelo-Romero, Patricia; Teixeira, Rita T.; Martinez-Zapater, Jose M.; Fortes, Ana M.

2016-01-01

GRAS transcription factors are involved in many processes of plant growth and development (e.g., axillary shoot meristem formation, root radial patterning, nodule morphogenesis, arbuscular development) as well as in plant disease resistance and abiotic stress responses. However, little information is available concerning this gene family in grapevine (Vitis vinifera L.), an economically important woody crop. We performed a model curation of GRAS genes identified in the latest genome annotation leading to the identification of 52 genes. Gene models were improved and three new genes were identified that could be grapevine- or woody-plant specific. Phylogenetic analysis showed that GRAS genes could be classified into 13 groups that mapped on the 19 V. vinifera chromosomes. Five new subfamilies, previously not characterized in other species, were identified. Multiple sequence alignment showed typical GRAS domain in the proteins and new motifs were also described. As observed in other species, both segmental and tandem duplications contributed significantly to the expansion and evolution of the GRAS gene family in grapevine. Expression patterns across a variety of tissues and upon abiotic and biotic conditions revealed possible divergent functions of GRAS genes in grapevine development and stress responses. By comparing the information available for tomato and grapevine GRAS genes, we identified candidate genes that might constitute conserved transcriptional regulators of both climacteric and non-climacteric fruit ripening. Altogether this study provides valuable information and robust candidate genes for future functional analysis aiming at improving the quality of fleshy fruits. PMID:27065316

Whole-genome resequencing of 292 pigeonpea accessions identifies genomic regions associated with domestication and agronomic traits.

PubMed

Varshney, Rajeev K; Saxena, Rachit K; Upadhyaya, Hari D; Khan, Aamir W; Yu, Yue; Kim, Changhoon; Rathore, Abhishek; Kim, Dongseon; Kim, Jihun; An, Shaun; Kumar, Vinay; Anuradha, Ghanta; Yamini, Kalinati Narasimhan; Zhang, Wei; Muniswamy, Sonnappa; Kim, Jong-So; Penmetsa, R Varma; von Wettberg, Eric; Datta, Swapan K

2017-07-01

Pigeonpea (Cajanus cajan), a tropical grain legume with low input requirements, is expected to continue to have an important role in supplying food and nutritional security in developing countries in Asia, Africa and the tropical Americas. From whole-genome resequencing of 292 Cajanus accessions encompassing breeding lines, landraces and wild species, we characterize genome-wide variation. On the basis of a scan for selective sweeps, we find several genomic regions that were likely targets of domestication and breeding. Using genome-wide association analysis, we identify associations between several candidate genes and agronomically important traits. Candidate genes for these traits in pigeonpea have sequence similarity to genes functionally characterized in other plants for flowering time control, seed development and pod dehiscence. Our findings will allow acceleration of genetic gains for key traits to improve yield and sustainability in pigeonpea.

Proteogenomic characterization of human colon and rectal cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Bing; Wang, Jing; Wang, Xiaojing

2014-09-18

We analyzed proteomes of colon and rectal tumors previously characterized by the Cancer Genome Atlas (TCGA) and performed integrated proteogenomic analyses. Protein sequence variants encoded by somatic genomic variations displayed reduced expression compared to protein variants encoded by germline variations. mRNA transcript abundance did not reliably predict protein expression differences between tumors. Proteomics identified five protein expression subtypes, two of which were associated with the TCGA "MSI/CIMP" transcriptional subtype, but had distinct mutation and methylation patterns and associated with different clinical outcomes. Although CNAs showed strong cis- and trans-effects on mRNA expression, relatively few of these extend to the proteinmore » level. Thus, proteomics data enabled prioritization of candidate driver genes. Our analyses identified HNF4A, a novel candidate driver gene in tumors with chromosome 20q amplifications. Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords novel insights into cancer biology.« less

Word-of-Mouth Innovation: Hypothesis Generation for Supplement Repurposing based on Consumer Reviews.

PubMed

Fan, Jung-Wei; Lussier, Yves A

2017-01-01

Dietary supplements remain a relatively underexplored source for drug repurposing. A systematic approach to soliciting responses from a large consumer population is desirable to speed up innovation. We tested a workflow that mines unexpected benefits of dietary supplements from massive consumer reviews. A (non-exhaustive) list of regular expressions was used to screen over 2 million reviews on health and personal care products. The matched reviews were manually analyzed, and one supplement-disease pair was linked to biological databases for enriching the hypothesized association. The regular expressions found 169 candidate reviews, of which 45.6% described unexpected benefits of certain dietary supplements. The manual analysis showed some of the supplement-disease associations to be novel or in agreement with evidence published later in the literature. The hypothesis enrichment was able to identify meaningful function similarity between the supplement and the disease. The results demonstrated value of the workflow in identifying candidates for supplement repurposing.

BATSE imaging survey of the Galactic plane

NASA Technical Reports Server (NTRS)

Grindlay, J. E.; Barret, D.; Bloser, P. F.; Zhang, S. N.; Robinson, C.; Harmon, B. A.

1997-01-01

The burst and transient source experiment (BATSE) onboard the Compton Gamma Ray Observatory (CGRO) provides all sky monitoring capability, occultation analysis and occultation imaging which enables new and fainter sources to be searched for in relatively crowded fields. The occultation imaging technique is used in combination with an automated BATSE image scanner, allowing an analysis of large data sets of occultation images for detections of candidate sources and for the construction of source catalogs and data bases. This automated image scanner system is being tested on archival data in order to optimize the search and detection thresholds. The image search system, its calibration results and preliminary survey results on archival data are reported on. The aim of the survey is to identify a complete sample of black hole candidates in the galaxy and constrain the number of black hole systems and neutron star systems.

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

PubMed

Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T; Edwards, Robert P; Eilber, Ursula; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kruger Kjaer, Susanne; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schildkraut, Joellen M; Schwaab, Ira; Sellers, Thomas A; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston, Lara; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; van Altena, Anne M; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D; Gayther, Simon A; Freedman, Matthew L

2015-09-22

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

PubMed Central

Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J.; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bowtell, David; Webb, Penelope M.; deFazio, Anna; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kruger Kjaer, Susanne; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F. A. G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Sellers, Thomas A.; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D.; Gayther, Simon A.; Freedman, Matthew L.

2015-01-01

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

Development and analysis of insulation constructions for aerospace wiring applications

NASA Astrophysics Data System (ADS)

Slenski, George A.; Woodford, Lynn M.

1993-03-01

The Wright Laboratory Materials Directorate at WPAFB, Ohio recently completed a research and development program under contract with the McDonnell Douglas Aerospace Company, St. Louis, Missouri. Program objectives were to develop wire insulation performance requirements, evaluate candidate insulations, and prepare preliminary specification sheets on the most promising candidates. Aircraft wiring continues to be a high maintenance item and a major contributor to electrically-related aircraft mishaps. Mishap data on aircraft show that chafing of insulation is the most common mode of wire failure. Improved wiring constructions are expected to increase aircraft performance and decrease costs by reducing maintenance actions. In the laboratory program, new insulation constructions were identified that had overall improved performance in evaluation tests when compared to currently available MIL-W-81381 and MIL-W-22759 wiring. These insulations are principally aromatic polyimide and crosslinked ethylene tetrafluoroethylene (ETFE), respectively. Candidate insulations identified in preliminary specification sheets were principally fluoropolymers with a polyimide inner layer. Examples of insulation properties evaluated included flammability, high temperature mechanical and electrical performance, fluid immersion, and susceptibility to arc propagation under applied power chafing conditions. Potential next generation wire insulation materials are also reviewed.

Global analysis of WRKY transcription factor superfamily in Setaria identifies potential candidates involved in abiotic stress signaling

PubMed Central

Muthamilarasan, Mehanathan; Bonthala, Venkata S.; Khandelwal, Rohit; Jaishankar, Jananee; Shweta, Shweta; Nawaz, Kashif; Prasad, Manoj

2015-01-01

Transcription factors (TFs) are major players in stress signaling and constitute an integral part of signaling networks. Among the major TFs, WRKY proteins play pivotal roles in regulation of transcriptional reprogramming associated with stress responses. In view of this, genome- and transcriptome-wide identification of WRKY TF family was performed in the C4model plants, Setaria italica (SiWRKY) and S. viridis (SvWRKY), respectively. The study identified 105 SiWRKY and 44 SvWRKY proteins that were computationally analyzed for their physicochemical properties. Sequence alignment and phylogenetic analysis classified these proteins into three major groups, namely I, II, and III with majority of WRKY proteins belonging to group II (53 SiWRKY and 23 SvWRKY), followed by group III (39 SiWRKY and 11 SvWRKY) and group I (10 SiWRKY and 6 SvWRKY). Group II proteins were further classified into 5 subgroups (IIa to IIe) based on their phylogeny. Domain analysis showed the presence of WRKY motif and zinc finger-like structures in these proteins along with additional domains in a few proteins. All SiWRKY genes were physically mapped on the S. italica genome and their duplication analysis revealed that 10 and 8 gene pairs underwent tandem and segmental duplications, respectively. Comparative mapping of SiWRKY and SvWRKY genes in related C4 panicoid genomes demonstrated the orthologous relationships between these genomes. In silico expression analysis of SiWRKY and SvWRKY genes showed their differential expression patterns in different tissues and stress conditions. Expression profiling of candidate SiWRKY genes in response to stress (dehydration and salinity) and hormone treatments (abscisic acid, salicylic acid, and methyl jasmonate) suggested the putative involvement of SiWRKY066 and SiWRKY082 in stress and hormone signaling. These genes could be potential candidates for further characterization to delineate their functional roles in abiotic stress signaling. PMID:26635818

Global analysis of WRKY transcription factor superfamily in Setaria identifies potential candidates involved in abiotic stress signaling.

PubMed

Muthamilarasan, Mehanathan; Bonthala, Venkata S; Khandelwal, Rohit; Jaishankar, Jananee; Shweta, Shweta; Nawaz, Kashif; Prasad, Manoj

2015-01-01

Transcription factors (TFs) are major players in stress signaling and constitute an integral part of signaling networks. Among the major TFs, WRKY proteins play pivotal roles in regulation of transcriptional reprogramming associated with stress responses. In view of this, genome- and transcriptome-wide identification of WRKY TF family was performed in the C4model plants, Setaria italica (SiWRKY) and S. viridis (SvWRKY), respectively. The study identified 105 SiWRKY and 44 SvWRKY proteins that were computationally analyzed for their physicochemical properties. Sequence alignment and phylogenetic analysis classified these proteins into three major groups, namely I, II, and III with majority of WRKY proteins belonging to group II (53 SiWRKY and 23 SvWRKY), followed by group III (39 SiWRKY and 11 SvWRKY) and group I (10 SiWRKY and 6 SvWRKY). Group II proteins were further classified into 5 subgroups (IIa to IIe) based on their phylogeny. Domain analysis showed the presence of WRKY motif and zinc finger-like structures in these proteins along with additional domains in a few proteins. All SiWRKY genes were physically mapped on the S. italica genome and their duplication analysis revealed that 10 and 8 gene pairs underwent tandem and segmental duplications, respectively. Comparative mapping of SiWRKY and SvWRKY genes in related C4 panicoid genomes demonstrated the orthologous relationships between these genomes. In silico expression analysis of SiWRKY and SvWRKY genes showed their differential expression patterns in different tissues and stress conditions. Expression profiling of candidate SiWRKY genes in response to stress (dehydration and salinity) and hormone treatments (abscisic acid, salicylic acid, and methyl jasmonate) suggested the putative involvement of SiWRKY066 and SiWRKY082 in stress and hormone signaling. These genes could be potential candidates for further characterization to delineate their functional roles in abiotic stress signaling.

An Infrared Search for Young Stellar Objects in IC 1396

NASA Astrophysics Data System (ADS)

Johnson, Chelen H.; Linahan, Marcella; Gibbs, John; Rebull, Luisa M.; Archibald, Andrew R.; Dickmann, Samantha Rose; Hart, Erica A.; Hedlund, Audrey R.; Hilfer, Shannon L.; Lacher, Thomas; McKernan, John T.; Medeiros, Emma M.; Nelson, Samantha Brooks; O'Leary, Harrison; Peña, Nicholas D.; Peterson, Alexis; Reader, Livia K.; Ropinski, Brandi Lucia; Scarpa, Gabriella; Sundeen, Kiera A.; Takara, Amber L.; Thiel, Theresa

2017-01-01

About 700 parsecs away from Earth, IC1396 lies along the galactic plane, in the direction of the constellation Cepheus, and includes many dark nebulae, including the Elephant’s Trunk Nebula. IC 1396A has been examined with a variety of telescopes, including Spitzer, 2MASS, IPHAS, Chandra, and WISE. The YSOVAR project (Rebull et al. 2014) also has Spitzer monitoring data in this region at 3.6 and 4.5 microns. Our team has merged these catalogs and identified candidate YSOs using IR color selection, X-ray detection, and variability metrics. In order to interpret the YSOVAR light curves, it is critical to understand which of the 700+ YSO candidates in this region are likely YSOs, and which are foreground/background stars or are extragalactic objects. As a first attempt to confirm these candidate YSOs, we have created spectral energy distributions (SEDs) for wavelengths from IPHAS r band to 24 microns, which we use, coupled with image inspection, to confirm (or refute) YSO candidates from this list of identified YSO candidates. We will then compare our vetted list of YSO candidates to the lists of YSO candidates already identified in the literature in this region. The goal of this study is to identify candidate YSO sources, as well as support the greater understanding of the variety, evolution and variability of young stars. This project is a collaborative effort of high school students from three states. They analyzed data individually and later collaborated online to compare results. This project is the result of many years of work with the NASA/IPAC Teacher Archive Research Program (NITARP).

Sleeping Beauty transposon mutagenesis identifies genes that cooperate with mutant Smad4 in gastric cancer development

PubMed Central

Takeda, Haruna; Rust, Alistair G.; Ward, Jerrold M.; Yew, Christopher Chin Kuan; Jenkins, Nancy A.; Copeland, Neal G.

2016-01-01

Mutations in SMAD4 predispose to the development of gastrointestinal cancer, which is the third leading cause of cancer-related deaths. To identify genes driving gastric cancer (GC) development, we performed a Sleeping Beauty (SB) transposon mutagenesis screen in the stomach of Smad4+/− mutant mice. This screen identified 59 candidate GC trunk drivers and a much larger number of candidate GC progression genes. Strikingly, 22 SB-identified trunk drivers are known or candidate cancer genes, whereas four SB-identified trunk drivers, including PTEN, SMAD4, RNF43, and NF1, are known human GC trunk drivers. Similar to human GC, pathway analyses identified WNT, TGF-β, and PI3K-PTEN signaling, ubiquitin-mediated proteolysis, adherens junctions, and RNA degradation in addition to genes involved in chromatin modification and organization as highly deregulated pathways in GC. Comparative oncogenomic filtering of the complete list of SB-identified genes showed that they are highly enriched for genes mutated in human GC and identified many candidate human GC genes. Finally, by comparing our complete list of SB-identified genes against the list of mutated genes identified in five large-scale human GC sequencing studies, we identified LDL receptor-related protein 1B (LRP1B) as a previously unidentified human candidate GC tumor suppressor gene. In LRP1B, 129 mutations were found in 462 human GC samples sequenced, and LRP1B is one of the top 10 most deleted genes identified in a panel of 3,312 human cancers. SB mutagenesis has, thus, helped to catalog the cooperative molecular mechanisms driving SMAD4-induced GC growth and discover genes with potential clinical importance in human GC. PMID:27006499

Sleeping Beauty transposon mutagenesis identifies genes that cooperate with mutant Smad4 in gastric cancer development.

PubMed

Takeda, Haruna; Rust, Alistair G; Ward, Jerrold M; Yew, Christopher Chin Kuan; Jenkins, Nancy A; Copeland, Neal G

2016-04-05

Mutations in SMAD4 predispose to the development of gastrointestinal cancer, which is the third leading cause of cancer-related deaths. To identify genes driving gastric cancer (GC) development, we performed a Sleeping Beauty (SB) transposon mutagenesis screen in the stomach of Smad4(+/-) mutant mice. This screen identified 59 candidate GC trunk drivers and a much larger number of candidate GC progression genes. Strikingly, 22 SB-identified trunk drivers are known or candidate cancer genes, whereas four SB-identified trunk drivers, including PTEN, SMAD4, RNF43, and NF1, are known human GC trunk drivers. Similar to human GC, pathway analyses identified WNT, TGF-β, and PI3K-PTEN signaling, ubiquitin-mediated proteolysis, adherens junctions, and RNA degradation in addition to genes involved in chromatin modification and organization as highly deregulated pathways in GC. Comparative oncogenomic filtering of the complete list of SB-identified genes showed that they are highly enriched for genes mutated in human GC and identified many candidate human GC genes. Finally, by comparing our complete list of SB-identified genes against the list of mutated genes identified in five large-scale human GC sequencing studies, we identified LDL receptor-related protein 1B (LRP1B) as a previously unidentified human candidate GC tumor suppressor gene. In LRP1B, 129 mutations were found in 462 human GC samples sequenced, and LRP1B is one of the top 10 most deleted genes identified in a panel of 3,312 human cancers. SB mutagenesis has, thus, helped to catalog the cooperative molecular mechanisms driving SMAD4-induced GC growth and discover genes with potential clinical importance in human GC.

Identification of downy mildew resistance gene candidates by positional cloning in maize (Zea mays subsp. mays; Poaceae)1

PubMed Central

Kim, Jae Yoon; Moon, Jun-Cheol; Kim, Hyo Chul; Shin, Seungho; Song, Kitae; Kim, Kyung-Hee; Lee, Byung-Moo

2017-01-01

Premise of the study: Positional cloning in combination with phenotyping is a general approach to identify disease-resistance gene candidates in plants; however, it requires several time-consuming steps including population or fine mapping. Therefore, in the present study, we suggest a new combined strategy to improve the identification of disease-resistance gene candidates. Methods and Results: Downy mildew (DM)–resistant maize was selected from five cultivars using a spreader row technique. Positional cloning and bioinformatics tools were used to identify the DM-resistance quantitative trait locus marker (bnlg1702) and 47 protein-coding gene annotations. Eventually, five DM-resistance gene candidates, including bZIP34, Bak1, and Ppr, were identified by quantitative reverse-transcription PCR (RT-PCR) without fine mapping of the bnlg1702 locus. Conclusions: The combined protocol with the spreader row technique, quantitative trait locus positional cloning, and quantitative RT-PCR was effective for identifying DM-resistance candidate genes. This cloning approach may be applied to other whole-genome-sequenced crops or resistance to other diseases. PMID:28224059

Ariadne: a database search engine for identification and chemical analysis of RNA using tandem mass spectrometry data.

PubMed

Nakayama, Hiroshi; Akiyama, Misaki; Taoka, Masato; Yamauchi, Yoshio; Nobe, Yuko; Ishikawa, Hideaki; Takahashi, Nobuhiro; Isobe, Toshiaki

2009-04-01

We present here a method to correlate tandem mass spectra of sample RNA nucleolytic fragments with an RNA nucleotide sequence in a DNA/RNA sequence database, thereby allowing tandem mass spectrometry (MS/MS)-based identification of RNA in biological samples. Ariadne, a unique web-based database search engine, identifies RNA by two probability-based evaluation steps of MS/MS data. In the first step, the software evaluates the matches between the masses of product ions generated by MS/MS of an RNase digest of sample RNA and those calculated from a candidate nucleotide sequence in a DNA/RNA sequence database, which then predicts the nucleotide sequences of these RNase fragments. In the second step, the candidate sequences are mapped for all RNA entries in the database, and each entry is scored for a function of occurrences of the candidate sequences to identify a particular RNA. Ariadne can also predict post-transcriptional modifications of RNA, such as methylation of nucleotide bases and/or ribose, by estimating mass shifts from the theoretical mass values. The method was validated with MS/MS data of RNase T1 digests of in vitro transcripts. It was applied successfully to identify an unknown RNA component in a tRNA mixture and to analyze post-transcriptional modification in yeast tRNA(Phe-1).

QTLs for Seed Vigor-Related Traits Identified in Maize Seeds Germinated under Artificial Aging Conditions

PubMed Central

Han, Zanping; Ku, Lixia; Zhang, Zhenzhen; Zhang, Jun; Guo, ShuLei; Liu, Haiying; Zhao, Ruifang; Ren, Zhenzhen; Zhang, Liangkun; Su, Huihui; Dong, Lei; Chen, Yanhui

2014-01-01

High seed vigor is important for agricultural production due to the associated potential for increased growth and productivity. However, a better understanding of the underlying molecular mechanisms is required because the genetic basis for seed vigor remains unknown. We used single-nucleotide polymorphism (SNP) markers to map quantitative trait loci (QTLs) for four seed vigor traits in two connected recombinant inbred line (RIL) maize populations under four treatment conditions during seed germination. Sixty-five QTLs distributed between the two populations were identified and a meta-analysis was used to integrate genetic maps. Sixty-one initially identified QTLs were integrated into 18 meta-QTLs (mQTLs). Initial QTLs with contribution to phenotypic variation values of R2>10% were integrated into mQTLs. Twenty-three candidate genes for association with seed vigor traits coincided with 13 mQTLs. The candidate genes had functions in the glycolytic pathway and in protein metabolism. QTLs with major effects (R2>10%) were identified under at least one treatment condition for mQTL2, mQTL3-2, and mQTL3-4. Candidate genes included a calcium-dependent protein kinase gene (302810918) involved in signal transduction that mapped in the mQTL3-2 interval associated with germination energy (GE) and germination percentage (GP), and an hsp20/alpha crystallin family protein gene (At5g51440) that mapped in the mQTL3-4 interval associated with GE and GP. Two initial QTLs with a major effect under at least two treatment conditions were identified for mQTL5-2. A cucumisin-like Ser protease gene (At5g67360) mapped in the mQTL5-2 interval associated with GP. The chromosome regions for mQTL2, mQTL3-2, mQTL3-4, and mQTL5-2 may be hot spots for QTLs related to seed vigor traits. The mQTLs and candidate genes identified in this study provide valuable information for the identification of additional quantitative trait genes. PMID:24651614

QTLs for seed vigor-related traits identified in maize seeds germinated under artificial aging conditions.

PubMed

Han, Zanping; Ku, Lixia; Zhang, Zhenzhen; Zhang, Jun; Guo, Shulei; Liu, Haiying; Zhao, Ruifang; Ren, Zhenzhen; Zhang, Liangkun; Su, Huihui; Dong, Lei; Chen, Yanhui

2014-01-01

High seed vigor is important for agricultural production due to the associated potential for increased growth and productivity. However, a better understanding of the underlying molecular mechanisms is required because the genetic basis for seed vigor remains unknown. We used single-nucleotide polymorphism (SNP) markers to map quantitative trait loci (QTLs) for four seed vigor traits in two connected recombinant inbred line (RIL) maize populations under four treatment conditions during seed germination. Sixty-five QTLs distributed between the two populations were identified and a meta-analysis was used to integrate genetic maps. Sixty-one initially identified QTLs were integrated into 18 meta-QTLs (mQTLs). Initial QTLs with contribution to phenotypic variation values of R(2)>10% were integrated into mQTLs. Twenty-three candidate genes for association with seed vigor traits coincided with 13 mQTLs. The candidate genes had functions in the glycolytic pathway and in protein metabolism. QTLs with major effects (R(2)>10%) were identified under at least one treatment condition for mQTL2, mQTL3-2, and mQTL3-4. Candidate genes included a calcium-dependent protein kinase gene (302810918) involved in signal transduction that mapped in the mQTL3-2 interval associated with germination energy (GE) and germination percentage (GP), and an hsp20/alpha crystallin family protein gene (At5g51440) that mapped in the mQTL3-4 interval associated with GE and GP. Two initial QTLs with a major effect under at least two treatment conditions were identified for mQTL5-2. A cucumisin-like Ser protease gene (At5g67360) mapped in the mQTL5-2 interval associated with GP. The chromosome regions for mQTL2, mQTL3-2, mQTL3-4, and mQTL5-2 may be hot spots for QTLs related to seed vigor traits. The mQTLs and candidate genes identified in this study provide valuable information for the identification of additional quantitative trait genes.

Utilization of gene mapping and candidate gene mutation screening for diagnosing clinically equivocal conditions: a Norrie disease case study.

PubMed

Chini, Vasiliki; Stambouli, Danai; Nedelea, Florina Mihaela; Filipescu, George Alexandru; Mina, Diana; Kambouris, Marios; El-Shantil, Hatem

2014-06-01

Prenatal diagnosis was requested for an undiagnosed eye disease showing X-linked inheritance in a family. No medical records existed for the affected family members. Mapping of the X chromosome and candidate gene mutation screening identified a c.C267A[p.F89L] mutation in NPD previously described as possibly causing Norrie disease. The detection of the c.C267A[p.F89L] variant in another unrelated family confirms the pathogenic nature of the mutation for the Norrie disease phenotype. Gene mapping, haplotype analysis, and candidate gene screening have been previously utilized in research applications but were applied here in a diagnostic setting due to the scarcity of available clinical information. The clinical diagnosis and mutation identification were critical for providing proper genetic counseling and prenatal diagnosis for this family.

Computational exploration of cis-regulatory modules in rhythmic expression data using the "Exploration of Distinctive CREs and CRMs" (EDCC) and "CRM Network Generator" (CNG) programs.

PubMed

Bekiaris, Pavlos Stephanos; Tekath, Tobias; Staiger, Dorothee; Danisman, Selahattin

2018-01-01

Understanding the effect of cis-regulatory elements (CRE) and clusters of CREs, which are called cis-regulatory modules (CRM), in eukaryotic gene expression is a challenge of computational biology. We developed two programs that allow simple, fast and reliable analysis of candidate CREs and CRMs that may affect specific gene expression and that determine positional features between individual CREs within a CRM. The first program, "Exploration of Distinctive CREs and CRMs" (EDCC), correlates candidate CREs and CRMs with specific gene expression patterns. For pairs of CREs, EDCC also determines positional preferences of the single CREs in relation to each other and to the transcriptional start site. The second program, "CRM Network Generator" (CNG), prioritizes these positional preferences using a neural network and thus allows unbiased rating of the positional preferences that were determined by EDCC. We tested these programs with data from a microarray study of circadian gene expression in Arabidopsis thaliana. Analyzing more than 1.5 million pairwise CRE combinations, we found 22 candidate combinations, of which several contained known clock promoter elements together with elements that had not been identified as relevant to circadian gene expression before. CNG analysis further identified positional preferences of these CRE pairs, hinting at positional information that may be relevant for circadian gene expression. Future wet lab experiments will have to determine which of these combinations confer daytime specific circadian gene expression.

The genetic basis of natural variation for iron homeostasis in the maize IBM population

PubMed Central

2014-01-01

Background Iron (Fe) deficiency symptoms in maize (Zea mays subsp. mays) express as leaf chlorosis, growth retardation, as well as yield reduction and are typically observed when plants grow in calcareous soils at alkaline pH. To improve our understanding of genotypical variability in the tolerance to Fe deficiency-induced chlorosis, the objectives of this study were to (i) determine the natural genetic variation of traits related to Fe homeostasis in the maize intermated B73 × Mo17 (IBM) population, (ii) to identify quantitative trait loci (QTLs) for these traits, and (iii) to analyze expression levels of genes known to be involved in Fe homeostasis as well as of candidate genes obtained from the QTL analysis. Results In hydroponically-grown maize, a total of 47 and 39 QTLs were detected for the traits recorded under limited and adequate supply of Fe, respectively. Conclusions From the QTL results, we were able to identify new putative candidate genes involved in Fe homeostasis under a deficient or adequate Fe nutritional status, like Ferredoxin class gene, putative ferredoxin PETF, metal tolerance protein MTP4, and MTP8. Furthermore, our expression analysis of candidate genes suggested the importance of trans-acting regulation for 2’-deoxymugineic acid synthase 1 (DMAS1), nicotianamine synthase (NAS3, NAS1), formate dehydrogenase 1 (FDH1), methylthioribose-1-phosphate isomerase (IDI2), aspartate/tyrosine/aromatic aminotransferase (IDI4), and methylthioribose kinase (MTK). PMID:24400634

Computational exploration of cis-regulatory modules in rhythmic expression data using the “Exploration of Distinctive CREs and CRMs” (EDCC) and “CRM Network Generator” (CNG) programs

PubMed Central

Staiger, Dorothee

2018-01-01

Understanding the effect of cis-regulatory elements (CRE) and clusters of CREs, which are called cis-regulatory modules (CRM), in eukaryotic gene expression is a challenge of computational biology. We developed two programs that allow simple, fast and reliable analysis of candidate CREs and CRMs that may affect specific gene expression and that determine positional features between individual CREs within a CRM. The first program, “Exploration of Distinctive CREs and CRMs” (EDCC), correlates candidate CREs and CRMs with specific gene expression patterns. For pairs of CREs, EDCC also determines positional preferences of the single CREs in relation to each other and to the transcriptional start site. The second program, “CRM Network Generator” (CNG), prioritizes these positional preferences using a neural network and thus allows unbiased rating of the positional preferences that were determined by EDCC. We tested these programs with data from a microarray study of circadian gene expression in Arabidopsis thaliana. Analyzing more than 1.5 million pairwise CRE combinations, we found 22 candidate combinations, of which several contained known clock promoter elements together with elements that had not been identified as relevant to circadian gene expression before. CNG analysis further identified positional preferences of these CRE pairs, hinting at positional information that may be relevant for circadian gene expression. Future wet lab experiments will have to determine which of these combinations confer daytime specific circadian gene expression. PMID:29298348

Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30) on rat chromosome 12: identification of fry as a candidate Mcs gene.

PubMed

Ren, Xuefeng; Graham, Jessica C; Jing, Lichen; Mikheev, Andrei M; Gao, Yuan; Lew, Jenny Pan; Xie, Hong; Kim, Andrea S; Shang, Xiuling; Friedman, Cynthia; Vail, Graham; Fang, Ming Zhu; Bromberg, Yana; Zarbl, Helmut

2013-01-01

Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop) and susceptible Fischer 344 (F344) strains, we mapped a novel mammary carcinoma susceptibility (Mcs30) locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker). The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs), one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression.

Soil environment is a key driver of adaptation in Medicago truncatula: new insights from landscape genomics.

PubMed

Guerrero, Jimena; Andrello, Marco; Burgarella, Concetta; Manel, Stephanie

2018-07-01

Spatial differences in environmental selective pressures interact with the genomes of organisms, ultimately leading to local adaptation. Landscape genomics is an emergent research area that uncovers genome-environment associations, thus allowing researchers to identify candidate loci for adaptation to specific environmental variables. In the present study, we used latent factor mixed models (LFMMs) and Moran spectral outlier detection/randomization (MSOD-MSR) to identify candidate loci for adaptation to 10 environmental variables (climatic, soil and atmospheric) among 43 515 single nucleotide polymorphisms (SNPs) from 202 accessions of the model legume Medicago truncatula. Soil variables were associated with a large number of candidate loci identified through both LFMMs and MSOD-MSR. Genes tagged by candidate loci associated with drought and salinity are involved in the response to biotic and abiotic stresses, while those tagged by candidates associated with soil nitrogen and atmospheric nitrogen, participate in the legume-rhizobia symbiosis. Candidate SNPs identified through both LFMMs and MSOD-MSR explained up to 56% of variance in flowering traits. Our findings highlight the importance of soil in driving adaptation in the system and elucidate the basis of evolutionary potential of M. truncatula to respond to global climate change and anthropogenic disruption of the nitrogen cycle. © 2018 The Authors New Phytologist © 2018 New Phytologist Trust.

Safety Guided Design of Crew Return Vehicle in Concept Design Phase Using STAMP/STPA

NASA Astrophysics Data System (ADS)

Nakao, H.; Katahira, M.; Miyamoto, Y.; Leveson, N.

2012-01-01

In the concept development and design phase of a new space system, such as a Crew Vehicle, designers tend to focus on how to implement new technology. Designers also consider the difficulty of using the new technology and trade off several system design candidates. Then they choose an optimal design from the candidates. Safety should be a key aspect driving optimal concept design. However, in past concept design activities, safety analysis such as FTA has not used to drive the design because such analysis techniques focus on component failure and component failure cannot be considered in the concept design phase. The solution to these problems is to apply a new hazard analysis technique, called STAMP/STPA. STAMP/STPA defines safety as a control problem rather than a failure problem and identifies hazardous scenarios and their causes. Defining control flow is the essential in concept design phase. Therefore STAMP/STPA could be a useful tool to assess the safety of system candidates and to be part of the rationale for choosing a design as the baseline of the system. In this paper, we explain our case study of safety guided concept design using STPA, the new hazard analysis technique, and model-based specification technique on Crew Return Vehicle design and evaluate benefits of using STAMP/STPA in concept development phase.

Application of Shuttle EVA Systems to Payloads. Volume 2: Payload EVA Task Completion Plans

NASA Technical Reports Server (NTRS)

1976-01-01

Candidate payload tasks for EVA application were identified and selected, based on an analysis of four representative space shuttle payloads, and typical EVA scenarios with supporting crew timelines and procedures were developed. The EVA preparations and post EVA operations, as well as the timelines emphasizing concurrent payload support functions, were also summarized.

Candid Reflections on the Departure of Black Women Faculty from Academe in the United States

ERIC Educational Resources Information Center

Chambers, Crystal Renee

2012-01-01

Critical content analysis is used to identify content within blogs, exposing views within academe that reinforce and normalize racist, sexist, and interactively racist and sexist perspectives. The two themes explored here are unfairness and subjectivities within personnel processes and the qualifications of Black women faculty, as raised through a…

The Effects of Program Structure on Dissertation Writing in "Online Academia": A Qualitative Analysis of Online Doctoral Student Experiences

ERIC Educational Resources Information Center

Goodwin-Lee, Regina

2010-01-01

Writing the dissertation can be one of the most stressful experiences in the doctoral education experience. Previous research findings indicate that traditional psychology doctoral candidates (PDC) identify the graduate school experience, and the dissertation process in particular as stress-inducing, isolating and key obstacles to graduation.…

Manned maneuvering unit mission definition study. Volume 3: MMU ancillary support equipment and attachment concepts

NASA Technical Reports Server (NTRS)

1975-01-01

An analysis of Manned Maneuvering Units (MMU) ancillary support equipment and attachment concepts is presented. The major objectives of the study are defined as: (1) identifying MMU applications which would supplement space shuttle safety and effectiveness, (2) to define general MMU performance and control requirements to satisfy candidate shuttle applications, (3) to develop concepts for attaching MMUs to various worksites and equipment, and (4) to identify requirements and develop concepts for MMU ancillary equipment.

Use of a Novel Embryonic Mammary Stem Cell Gene Signature to Improve Human Breast Cancer Diagnostics and Therapeutic Decision Making

DTIC Science & Technology

2013-10-01

the fMaSC population into its component cell types. Based on in vitro sphere formation and in vivo limiting dilution transplantation functional...vivo transplantation . This approach will not only enable us to identify biomarkers useful for prospectively identifying fMaSCs, but should also...capture wells containing candidate fMaSC cells. green=live (Calcein-AM), red= dead (Ethidium Bromide). (B) RT-PCR analysis of prepared cDNA libraries

YSO jets in the Galactic plane from UWISH2 - V. Jets and outflows in M17

NASA Astrophysics Data System (ADS)

Samal, M. R.; Chen, W. P.; Takami, M.; Jose, J.; Froebrich, D.

2018-07-01

Jets and outflows are the first signposts of stellar birth. Emission in the H2 1-0 S(1) line at 2.122- μm is a powerful tracer of shock excitation in these objects. Here we present the analysis of 2.0 × 0.8 deg2 data from the UK Wide-field Infrared Survey for H2 (UWISH2) in the 1-0 S(1) line to identify and characterize the outflows of the M17 complex. We uncover 48 probable outflows, of which 93 per cent are new discoveries. We identified driving source candidates for 60 per cent of outflows. Among the driving source candidate young stellar objects (YSOs), 90 per cent are protostars and the remaining 10 per cent are Class II YSOs. In comparison with results from other surveys, we suggest that H2 emission fades very quickly as the objects evolve from protostars to pre-main-sequence stars. We fit spectral energy distribution (SED) models to 14 candidate outflow-driving sources and conclude that the outflows of our sample are mostly driven by moderate-mass YSOs that are still actively accreting from their protoplanetary disc. We examined the spatial distribution of the outflows with the gas and dust distribution of the complex and observed that the filamentary dark cloud M17SWex, located on the south-western side of the complex, is associated with a greater number of outflows. We find that our results corroborate previous suggestions that, in the M17 complex, M17SWex is the most active site of star formation. Several of our newly identified outflow candidates are excellent targets for follow-up studies to understand better the very early phase of protostellar evolution.

Restriction site polymorphism-based candidate gene mapping for seedling drought tolerance in cowpea [Vigna unguiculata (L.) Walp.].

PubMed

Muchero, Wellington; Ehlers, Jeffrey D; Roberts, Philip A

2010-02-01

Quantitative trait loci (QTL) studies provide insight into the complexity of drought tolerance mechanisms. Molecular markers used in these studies also allow for marker-assisted selection (MAS) in breeding programs, enabling transfer of genetic factors between breeding lines without complete knowledge of their exact nature. However, potential for recombination between markers and target genes limit the utility of MAS-based strategies. Candidate gene mapping offers an alternative solution to identify trait determinants underlying QTL of interest. Here, we used restriction site polymorphisms to investigate co-location of candidate genes with QTL for seedling drought stress-induced premature senescence identified previously in cowpea. Genomic DNA isolated from 113 F(2:8) RILs of drought-tolerant IT93K503-1 and drought susceptible CB46 genotypes was digested with combinations of EcoR1 and HpaII, Mse1, or Msp1 restriction enzymes and amplified with primers designed from 13 drought-responsive cDNAs. JoinMap 3.0 and MapQTL 4.0 software were used to incorporate polymorphic markers onto the AFLP map and to analyze their association with the drought response QTL. Seven markers co-located with peaks of previously identified QTL. Isolation, sequencing, and blast analysis of these markers confirmed their significant homology with drought or other abiotic stress-induced expressed sequence tags (EST) from cowpea and other plant systems. Further, homology with coding sequences for a multidrug resistance protein 3 and a photosystem I assembly protein ycf3 was revealed in two of these candidates. These results provide a platform for the identification and characterization of genetic trait determinants underlying seedling drought tolerance in cowpea.

Novel Genes Affecting the Interaction between the Cabbage Whitefly and Arabidopsis Uncovered by Genome-Wide Association Mapping

PubMed Central

Broekgaarden, Colette; Bucher, Johan; Bac-Molenaar, Johanna; Keurentjes, Joost J. B.; Kruijer, Willem; Voorrips, Roeland E.; Vosman, Ben

2015-01-01

Plants have evolved a variety of ways to defend themselves against biotic attackers. This has resulted in the presence of substantial variation in defense mechanisms among plants, even within a species. Genome-wide association (GWA) mapping is a useful tool to study the genetic architecture of traits, but has so far only had limited exploitation in studies of plant defense. Here, we study the genetic architecture of defense against the phloem-feeding insect cabbage whitefly (Aleyrodes proletella) in Arabidopsis thaliana. We determined whitefly performance, i.e. the survival and reproduction of whitefly females, on 360 worldwide selected natural accessions and subsequently performed GWA mapping using 214,051 SNPs. Substantial variation for whitefly adult survival and oviposition rate (number of eggs laid per female per day) was observed between the accessions. We identified 39 candidate SNPs for either whitefly adult survival or oviposition rate, all with relatively small effects, underpinning the complex architecture of defense traits. Among the corresponding candidate genes, i.e. genes in linkage disequilibrium (LD) with candidate SNPs, none have previously been identified as a gene playing a role in the interaction between plants and phloem-feeding insects. Whitefly performance on knock-out mutants of a number of candidate genes was significantly affected, validating the potential of GWA mapping for novel gene discovery in plant-insect interactions. Our results show that GWA analysis is a very useful tool to gain insight into the genetic architecture of plant defense against herbivorous insects, i.e. we identified and validated several genes affecting whitefly performance that have not previously been related to plant defense against herbivorous insects. PMID:26699853

Filling gaps in PPAR-alpha signaling through comparative nutrigenomics analysis.

PubMed

Cavalieri, Duccio; Calura, Enrica; Romualdi, Chiara; Marchi, Emmanuela; Radonjic, Marijana; Van Ommen, Ben; Müller, Michael

2009-12-11

The application of high-throughput genomic tools in nutrition research is a widespread practice. However, it is becoming increasingly clear that the outcome of individual expression studies is insufficient for the comprehensive understanding of such a complex field. Currently, the availability of the large amounts of expression data in public repositories has opened up new challenges on microarray data analyses. We have focused on PPARalpha, a ligand-activated transcription factor functioning as fatty acid sensor controlling the gene expression regulation of a large set of genes in various metabolic organs such as liver, small intestine or heart. The function of PPARalpha is strictly connected to the function of its target genes and, although many of these have already been identified, major elements of its physiological function remain to be uncovered. To further investigate the function of PPARalpha, we have applied a cross-species meta-analysis approach to integrate sixteen microarray datasets studying high fat diet and PPARalpha signal perturbations in different organisms. We identified 164 genes (MDEGs) that were differentially expressed in a constant way in response to a high fat diet or to perturbations in PPARs signalling. In particular, we found five genes in yeast which were highly conserved and homologous of PPARalpha targets in mammals, potential candidates to be used as models for the equivalent mammalian genes. Moreover, a screening of the MDEGs for all known transcription factor binding sites and the comparison with a human genome-wide screening of Peroxisome Proliferating Response Elements (PPRE), enabled us to identify, 20 new potential candidate genes that show, both binding site, both change in expression in the condition studied. Lastly, we found a non random localization of the differentially expressed genes in the genome. The results presented are potentially of great interest to resume the currently available expression data, exploiting the power of in silico analysis filtered by evolutionary conservation. The analysis enabled us to indicate potential gene candidates that could fill in the gaps with regards to the signalling of PPARalpha and, moreover, the non-random localization of the differentially expressed genes in the genome, suggest that epigenetic mechanisms are of importance in the regulation of the transcription operated by PPARalpha.

Characterization of the 3p12.3-pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transfer.

PubMed

Cody, Neal A L; Shen, Zhen; Ripeau, Jean-Sebastien; Provencher, Diane M; Mes-Masson, Anne-Marie; Chevrette, Mario; Tonin, Patricia N

2009-12-01

The genetic analysis of nontumorigenic radiation hybrids generated by transfer of chromosome 3 fragments into the tumorigenic OV-90 ovarian cancer cell line identified the 3p12.3-pcen region as a candidate tumor suppressor gene (TSG) locus. In the present study, polymorphic microsatellite repeat analysis of the hybrids further defined the 3p12.3-pcen interval to a 16.1 Mb common region containing 12 known or hypothetical genes: 3ptel-ROBO2-ROBO1-GBE1-CADM2-VGLL3-CHMP2B-POU1F1-HTR1F-CGGBP1-ZNF654-C3orf38-EPHA3-3pcen. Seven of these genes, ROBO1, GBE1, VGLL3, CHMP2B, CGGBP1, ZNF654, and C3orf38, exhibited gene expression in the hybrids, placing them as top TSG candidates for further analysis. The expression of all but one (VGLL3) of these genes was also detected in the parental OV-90 cell line. Mutations were not identified in a comparative sequence analysis of the predicted protein coding regions of these candidates in OV-90 and donor normal chromosome 3 contig. However, the nondeleterious sequence variants identified in the transcribed regions distinguished parent of origin alleles for ROBO1, VGLL3, CHMP2B, and CGGBP1 and cDNA sequencing of the hybrids revealed biallelic expression of these genes. Interestingly, underexpression of VGLL3 and ZNF654 were observed in malignant ovarian tumor samples as compared with primary cultures of normal ovarian surface epithelial cells or benign ovarian tumors, and this occurred regardless of allelic content of 3p12.3-pcen. The results taken together suggest that dysregulation of VGLL3 and/or ZNF654 expression may have affected pathways important in ovarian tumorigenesis which was offset by the transfer of chromosome 3 fragments in OV-90, a cell line hemizygous for 3p.

Proteomic analysis of bronchoalveolar lavage fluid (BALF) from lung cancer patients using label-free mass spectrometry.

PubMed

Hmmier, Abduladim; O'Brien, Michael Emmet; Lynch, Vincent; Clynes, Martin; Morgan, Ross; Dowling, Paul

2017-06-01

Lung cancer is the leading cause of cancer-related mortality in both men and women throughout the world. The need to detect lung cancer at an early, potentially curable stage, is essential and may reduce mortality by 20%. The aim of this study was to identify distinct proteomic profiles in bronchoalveolar fluid (BALF) and plasma that are able to discriminate individuals with benign disease from those with non-small cell lung cancer (NSCLC). Using label-free mass spectrometry analysis of BALF during discovery-phase analysis, a significant number of proteins were found to have different abundance levels when comparing control to adenocarcinoma (AD) or squamous cell lung carcinoma (SqCC). Validation of candidate biomarkers identified in BALF was performed in a larger cohort of plasma samples by detection with enzyme-linked immunoassay. Four proteins (Cystatin-C, TIMP-1, Lipocalin-2 and HSP70/HSPA1A) were selected as a representative group from discovery phase mass spectrometry BALF analysis. Plasma levels of TIMP-1, Lipocalin-2 and Cystatin-C were found to be significantly elevated in AD and SqCC compared to control. The results presented in this study indicate that BALF is an important proximal biofluid for the discovery and identification of candidate lung cancer biomarkers. There is good correlation between the trend of protein abundance levels in BALF and that of plasma which validates this approach to develop a blood biomarker to aid lung cancer diagnosis, particularly in the era of lung cancer screening. The protein signatures identified also provide insight into the molecular mechanisms associated with lung malignancy.

Four Interstellar Dust Candidates from the Stardust Interstellar Dust Collector

NASA Astrophysics Data System (ADS)

Westphal, A. J.; Allen, C.; Bajt, S.; Bechtel, H. A.; Borg, J.; Brenker, F.; Bridges, J.; Brownlee, D. E.; Burchell, M.; Burghammer, M.; Butterworth, A. L.; Cloetens, P.; Davis, A. M.; Floss, C.; Flynn, G. J.; Fougeray, P.; Frank, D.; Gainsforth, Z.; Grün, E.; Heck, P. R.; Hillier, J. K.; Hoppe, P.; Howard, L.; Hudson, B.; Huss, G. R.; Huth, J.; Kearsley, A.; King, A. J.; Lai, B.; Leitner, J.; Lemelle, L.; Leroux, H.; Lettieri, R.; Marchant, W.; Nittler, L. R.; Ogliore, R. C.; Postberg, F.; Price, M. C.; Sandford, S. A.; Sans Tresseras, J. A.; Schmitz, S.; Schoonjans, T.; Silversmit, G.; Simionovici, A.; Srama, R.; Stadermann, F. J.; Stephan, T.; Stodolna, J.; Stroud, R. M.; Sutton, S. R.; Toucoulou, R.; Trieloff, M.; Tsou, P.; Tsuchiyama, A.; Tyliczszak, T.; Vekemans, B.; Vincze, L.; Wordsworth, N.; Zevin, D.; Zolensky, M. E.; 29,000 Stardust@Home Dusters

2011-03-01

We report the discovery of two new interstellar dust candidates in the aerogel collectors of the Stardust Interstellar Dust Collector, and the analyses of these and two previously identified candidates.

Identifying Individual Differences among Doctoral Candidates: A Framework for Understanding Problematic Candidature

ERIC Educational Resources Information Center

Cantwell, Robert H.; Scevak, Jill J.; Bourke, Sid; Holbrook, Allyson

2012-01-01

Understanding how candidates cope with the demands of PhD candidature is important for institutions, supervisors and candidates. Individual differences in affective and metacognitive disposition were explored in 263 PhD candidates from two Australian universities. Several questionnaires relating to affective and metacognitive beliefs were…

Views on Values Education: From Teacher Candidates to Experienced Teachers

ERIC Educational Resources Information Center

Iscan, Canay Demirhan

2015-01-01

This study aimed to identify the views of experienced class teachers and class teacher candidates on values education. It conducted standard open-ended interviews with experienced class teachers and teacher candidates. The study group comprised 9 experienced class teachers from different socio-economic levels and 9 teacher candidates with…

Identification of reference genes for RT-qPCR in the Antarctic moss Sanionia uncinata under abiotic stress conditions

PubMed Central

Park, Mira; Hong, Soon Gyu; Park, Hyun; Lee, Byeong-ha

2018-01-01

Sanionia uncinata is a dominant moss species in the maritime Antarctic. Due to its high adaptability to harsh environments, this extremophile plant has been considered a good target for studying the molecular adaptation mechanisms of plants to a variety of environmental stresses. Despite the importance of S. uncinata as a representative Antarctic plant species for the identification and characterization of genes associated with abiotic stress tolerance, suitable reference genes, which are critical for RT-qPCR analyses, have not yet been identified. In this report, 11 traditionally used and 6 novel candidate reference genes were selected from transcriptome data of S. uncinata and the expression stability of these genes was evaluated under various abiotic stress conditions using three statistical algorithms; geNorm, NormFinder, and BestKeeper. The stability ranking analysis selected the best reference genes depending on the stress conditions. Among the 17 candidates, the most stable references were POB1 and UFD2 for cold stress, POB1 and AKB for drought treatment, and UFD2 and AKB for the field samples from a different water contents in Antarctica. Overall, novel genes POB1 and AKB were the most reliable references across all samples, irrespective of experimental conditions. In addition, 6 novel candidate genes including AKB, POB1 and UFD2, were more stable than the housekeeping genes traditionally used for internal controls, indicating that transcriptome data can be useful for identifying novel robust normalizers. The reference genes validated in this study will be useful for improving the accuracy of RT-qPCR analysis for gene expression studies of S. uncinata in Antarctica and for further functional genomic analysis of bryophytes. PMID:29920565

Genetic Architecture of Local Adaptation in Lunar and Diurnal Emergence Times of the Marine Midge Clunio marinus (Chironomidae, Diptera)

PubMed Central

Kaiser, Tobias S.; Heckel, David G.

2012-01-01

Circadian rhythms pre-adapt the physiology of most organisms to predictable daily changes in the environment. Some marine organisms also show endogenous circalunar rhythms. The genetic basis of the circalunar clock and its interaction with the circadian clock is unknown. Both clocks can be studied in the marine midge Clunio marinus (Chironomidae, Diptera), as different populations have different local adaptations in their lunar and diurnal rhythms of adult emergence, which can be analyzed by crossing experiments. We investigated the genetic basis of population variation in clock properties by constructing the first genetic linkage map for this species, and performing quantitative trait locus (QTL) analysis on variation in both lunar and diurnal timing. The genome has a genetic length of 167–193 centimorgans based on a linkage map using 344 markers, and a physical size of 95–140 megabases estimated by flow cytometry. Mapping the sex determining locus shows that females are the heterogametic sex, unlike most other Chironomidae. We identified two QTL each for lunar emergence time and diurnal emergence time. The distribution of QTL confirms a previously hypothesized genetic basis to a correlation of lunar and diurnal emergence times in natural populations. Mapping of clock genes and light receptors identified ciliary opsin 2 (cOps2) as a candidate to be involved in both lunar and diurnal timing; cryptochrome 1 (cry1) as a candidate gene for lunar timing; and two timeless (tim2, tim3) genes as candidate genes for diurnal timing. This QTL analysis of lunar rhythmicity, the first in any species, provides a unique entree into the molecular analysis of the lunar clock. PMID:22384150

Genetic architecture of local adaptation in lunar and diurnal emergence times of the marine midge Clunio marinus (Chironomidae, Diptera).

PubMed

Kaiser, Tobias S; Heckel, David G

2012-01-01

Circadian rhythms pre-adapt the physiology of most organisms to predictable daily changes in the environment. Some marine organisms also show endogenous circalunar rhythms. The genetic basis of the circalunar clock and its interaction with the circadian clock is unknown. Both clocks can be studied in the marine midge Clunio marinus (Chironomidae, Diptera), as different populations have different local adaptations in their lunar and diurnal rhythms of adult emergence, which can be analyzed by crossing experiments. We investigated the genetic basis of population variation in clock properties by constructing the first genetic linkage map for this species, and performing quantitative trait locus (QTL) analysis on variation in both lunar and diurnal timing. The genome has a genetic length of 167-193 centimorgans based on a linkage map using 344 markers, and a physical size of 95-140 megabases estimated by flow cytometry. Mapping the sex determining locus shows that females are the heterogametic sex, unlike most other Chironomidae. We identified two QTL each for lunar emergence time and diurnal emergence time. The distribution of QTL confirms a previously hypothesized genetic basis to a correlation of lunar and diurnal emergence times in natural populations. Mapping of clock genes and light receptors identified ciliary opsin 2 (cOps2) as a candidate to be involved in both lunar and diurnal timing; cryptochrome 1 (cry1) as a candidate gene for lunar timing; and two timeless (tim2, tim3) genes as candidate genes for diurnal timing. This QTL analysis of lunar rhythmicity, the first in any species, provides a unique entree into the molecular analysis of the lunar clock.

Magnetic Resonance Lymphography Findings in Patients With Biochemical Recurrence After Prostatectomy and the Relation With the Stephenson Nomogram

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meijer, Hanneke J.M., E-mail: H.Meijer@rther.umcn.nl; Debats, Oscar A.; Roach, Mack

2012-12-01

Purpose: To estimate the occurrence of positive lymph nodes on magnetic resonance lymphography (MRL) in patients with a prostate-specific antigen (PSA) recurrence after prostatectomy and to investigate the relation between score on the Stephenson nomogram and lymph node involvement on MRL. Methods and Materials: Sixty-five candidates for salvage radiation therapy were referred for an MRL to determine their lymph node status. Clinical and histopathologic features were recorded. For 49 patients, data were complete to calculate the Stephenson nomogram score. Receiver operating characteristic (ROC) analysis was performed to determine how well this nomogram related to the MRL result. Analysis was donemore » for the whole group and separately for patients with a PSA <1.0 ng/mL to determine the situation in candidates for early salvage radiation therapy, and for patients without pathologic lymph nodes at initial lymph node dissection. Results: MRL detected positive lymph nodes in 47 patients. ROC analysis for the Stephenson nomogram yielded an area under the curve (AUC) of 0.78 (95% confidence interval, 0.61-0.93). Of 29 patients with a PSA <1.0 ng/mL, 18 had a positive MRL. Of 37 patients without lymph node involvement at initial lymph node dissection, 25 had a positive MRL. ROC analysis for the Stephenson nomogram showed AUCs of 0.84 and 0.74, respectively, for these latter groups. Conclusion: MRL detected positive lymph nodes in 72% of candidates for salvage radiation therapy, in 62% of candidates for early salvage radiation therapy, and in 68% of initially node-negative patients. The Stephenson nomogram showed a good correlation with the MRL result and may thus be useful for identifying patients with a PSA recurrence who are at high risk for lymph node involvement.« less

Identification and Comparison of Candidate Olfactory Genes in the Olfactory and Non-Olfactory Organs of Elm Pest Ambrostoma quadriimpressum (Coleoptera: Chrysomelidae) Based on Transcriptome Analysis.

PubMed

Wang, Yinliang; Chen, Qi; Zhao, Hanbo; Ren, Bingzhong

2016-01-01

The leaf beetle Ambrostoma quadriimpressum (Coleoptera: Chrysomelidae) is a predominant forest pest that causes substantial damage to the lumber industry and city management. However, no effective and environmentally friendly chemical method has been discovered to control this pest. Until recently, the molecular basis of the olfactory system in A. quadriimpressum was completely unknown. In this study, antennae and leg transcriptomes were analyzed and compared using deep sequencing data to identify the olfactory genes in A. quadriimpressum. Moreover, the expression profiles of both male and female candidate olfactory genes were analyzed and validated by bioinformatics, motif analysis, homology analysis, semi-quantitative RT-PCR and RT-qPCR experiments in antennal and non-olfactory organs to explore the candidate olfactory genes that might play key roles in the life cycle of A. quadriimpressum. As a result, approximately 102.9 million and 97.3 million clean reads were obtained from the libraries created from the antennas and legs, respectively. Annotation led to 34344 Unigenes, which were matched to known proteins. Annotation data revealed that the number of genes in antenna with binding functions and receptor activity was greater than that of legs. Furthermore, many pathway genes were differentially expressed in the two organs. Sixteen candidate odorant binding proteins (OBPs), 10 chemosensory proteins (CSPs), 34 odorant receptors (ORs), 20 inotropic receptors [1] and 2 sensory neuron membrane proteins (SNMPs) and their isoforms were identified. Additionally, 15 OBPs, 9 CSPs, 18 ORs, 6 IRs and 2 SNMPs were predicted to be complete ORFs. Using RT-PCR, RT-qPCR and homology analysis, AquaOBP1/2/4/7/C1/C6, AquaCSP3/9, AquaOR8/9/10/14/15/18/20/26/29/33, AquaIR8a/13/25a showed olfactory-specific expression, indicating that these genes might play a key role in olfaction-related behaviors in A. quadriimpressum such as foraging and seeking. AquaOBP4/C5, AquaOBP4/C5, AquaCSP7/9/10, AquaOR17/24/32 and AquaIR4 were highly expressed in the antenna of males, suggesting that these genes were related to sex-specific behaviors, and expression trends that were male specific were observed for most candidate olfactory genes, which supported the existence of a female-produced sex pheromone in A. quadriimpressum. All of these results could provide valuable information and guidance for future functional studies on these genes and provide better molecular knowledge regarding the olfactory system in A. quadriimpressum.

Automated microaneurysm detection in diabetic retinopathy using curvelet transform

NASA Astrophysics Data System (ADS)

Ali Shah, Syed Ayaz; Laude, Augustinus; Faye, Ibrahima; Tang, Tong Boon

2016-10-01

Microaneurysms (MAs) are known to be the early signs of diabetic retinopathy (DR). An automated MA detection system based on curvelet transform is proposed for color fundus image analysis. Candidates of MA were extracted in two parallel steps. In step one, blood vessels were removed from preprocessed green band image and preliminary MA candidates were selected by local thresholding technique. In step two, based on statistical features, the image background was estimated. The results from the two steps allowed us to identify preliminary MA candidates which were also present in the image foreground. A collection set of features was fed to a rule-based classifier to divide the candidates into MAs and non-MAs. The proposed system was tested with Retinopathy Online Challenge database. The automated system detected 162 MAs out of 336, thus achieved a sensitivity of 48.21% with 65 false positives per image. Counting MA is a means to measure the progression of DR. Hence, the proposed system may be deployed to monitor the progression of DR at early stage in population studies.

Automated microaneurysm detection in diabetic retinopathy using curvelet transform.

PubMed

Ali Shah, Syed Ayaz; Laude, Augustinus; Faye, Ibrahima; Tang, Tong Boon

2016-10-01

Microaneurysms (MAs) are known to be the early signs of diabetic retinopathy (DR). An automated MA detection system based on curvelet transform is proposed for color fundus image analysis. Candidates of MA were extracted in two parallel steps. In step one, blood vessels were removed from preprocessed green band image and preliminary MA candidates were selected by local thresholding technique. In step two, based on statistical features, the image background was estimated. The results from the two steps allowed us to identify preliminary MA candidates which were also present in the image foreground. A collection set of features was fed to a rule-based classifier to divide the candidates into MAs and non-MAs. The proposed system was tested with Retinopathy Online Challenge database. The automated system detected 162 MAs out of 336, thus achieved a sensitivity of 48.21% with 65 false positives per image. Counting MA is a means to measure the progression of DR. Hence, the proposed system may be deployed to monitor the progression of DR at early stage in population studies.

Candidate genes and molecular markers associated with heat tolerance in colonial Bentgrass.

PubMed

Jespersen, David; Belanger, Faith C; Huang, Bingru

2017-01-01

Elevated temperature is a major abiotic stress limiting the growth of cool-season grasses during the summer months. The objectives of this study were to determine the genetic variation in the expression patterns of selected genes involved in several major metabolic pathways regulating heat tolerance for two genotypes contrasting in heat tolerance to confirm their status as potential candidate genes, and to identify PCR-based markers associated with candidate genes related to heat tolerance in a colonial (Agrostis capillaris L.) x creeping bentgrass (Agrostis stolonifera L.) hybrid backcross population. Plants were subjected to heat stress in controlled-environmental growth chambers for phenotypic evaluation and determination of genetic variation in candidate gene expression. Molecular markers were developed for genes involved in protein degradation (cysteine protease), antioxidant defense (catalase and glutathione-S-transferase), energy metabolism (glyceraldehyde-3-phosphate dehydrogenase), cell expansion (expansin), and stress protection (heat shock proteins HSP26, HSP70, and HSP101). Kruskal-Wallis analysis, a commonly used non-parametric test used to compare population individuals with or without the gene marker, found the physiological traits of chlorophyll content, electrolyte leakage, normalized difference vegetative index, and turf quality were associated with all candidate gene markers with the exception of HSP101. Differential gene expression was frequently found for the tested candidate genes. The development of candidate gene markers for important heat tolerance genes may allow for the development of new cultivars with increased abiotic stress tolerance using marker-assisted selection.

Candidate genes and molecular markers associated with heat tolerance in colonial Bentgrass

PubMed Central

Jespersen, David; Belanger, Faith C.; Huang, Bingru

2017-01-01

Elevated temperature is a major abiotic stress limiting the growth of cool-season grasses during the summer months. The objectives of this study were to determine the genetic variation in the expression patterns of selected genes involved in several major metabolic pathways regulating heat tolerance for two genotypes contrasting in heat tolerance to confirm their status as potential candidate genes, and to identify PCR-based markers associated with candidate genes related to heat tolerance in a colonial (Agrostis capillaris L.) x creeping bentgrass (Agrostis stolonifera L.) hybrid backcross population. Plants were subjected to heat stress in controlled-environmental growth chambers for phenotypic evaluation and determination of genetic variation in candidate gene expression. Molecular markers were developed for genes involved in protein degradation (cysteine protease), antioxidant defense (catalase and glutathione-S-transferase), energy metabolism (glyceraldehyde-3-phosphate dehydrogenase), cell expansion (expansin), and stress protection (heat shock proteins HSP26, HSP70, and HSP101). Kruskal-Wallis analysis, a commonly used non-parametric test used to compare population individuals with or without the gene marker, found the physiological traits of chlorophyll content, electrolyte leakage, normalized difference vegetative index, and turf quality were associated with all candidate gene markers with the exception of HSP101. Differential gene expression was frequently found for the tested candidate genes. The development of candidate gene markers for important heat tolerance genes may allow for the development of new cultivars with increased abiotic stress tolerance using marker-assisted selection. PMID:28187136

A Proteomics View of the Molecular Mechanisms and Biomarkers of Glaucomatous Neurodegeneration

PubMed Central

Tezel, Gülgün

2013-01-01

Despite improving understanding of glaucoma, key molecular players of neurodegeneration that can be targeted for treatment of glaucoma, or molecular biomarkers that can be useful for clinical testing, remain unclear. Proteomics technology offers a powerful toolbox to accomplish these important goals of the glaucoma research and is increasingly being applied to identify molecular mechanisms and biomarkers of glaucoma. Recent studies of glaucoma using proteomics analysis techniques have resulted in the lists of differentially expressed proteins in human glaucoma and animal models. The global analysis of protein expression in glaucoma has been followed by cell-specific proteome analysis of retinal ganglion cells and astrocytes. The proteomics data have also guided targeted studies to identify post-translational modifications and protein-protein interactions during glaucomatous neurodegeneration. In addition, recent applications of proteomics have provided a number of potential biomarker candidates. Proteomics technology holds great promise to move glaucoma research forward toward new treatment strategies and biomarker discovery. By reviewing the major proteomics approaches and their applications in the field of glaucoma, this article highlights the power of proteomics in translational and clinical research related to glaucoma and also provides a framework for future research to functionally test the importance of specific molecular pathways and validate candidate biomarkers. PMID:23396249

Genome-wide scan reveals LEMD3 and WIF1 on SSC5 as the candidates for porcine ear size.

PubMed

Zhang, Longchao; Liang, Jing; Luo, Weizhen; Liu, Xin; Yan, Hua; Zhao, Kebin; Shi, Huibi; Zhang, Yuebo; Wang, Ligang; Wang, Lixian

2014-01-01

The quantitative trait loci (QTL) for porcine ear size was previously reported to mainly focus on SSC5 and SSC7. Recently, a missense mutation, G32E, in PPARD in the QTL interval on SSC7 was identified as the causative mutation for ear size. However, on account of the large interval of QTL, the responsible gene on SSC5 has not been identified. In this study, an intercross population was constructed from the large-eared Minzhu, an indigenous Chinese pig breed, and the Western commercial Large White pig to examine the genetic basis of ear size diversity. A GWAS was performed to detect SNPs significantly associated with ear size. Thirty-five significant SNPs defined a 10.78-Mb (30.14-40.92 Mb) region on SSC5. Further, combining linkage disequilibrium and haplotype sharing analysis, a reduced region of 3.07-Mb was obtained. Finally, by using a selective sweep analysis, a critical region of about 450-kb interval containing two annotated genes LEMD3 and WIF1 was refined in this work. Functional analysis indicated that both represent biological candidates for porcine ear size, with potential application in breeding programs. The two genes could also be used as novel references for further study of the mechanism underlying human microtia.

The PhytoClust tool for metabolic gene clusters discovery in plant genomes

PubMed Central

Fuchs, Lisa-Maria

2017-01-01

Abstract The existence of Metabolic Gene Clusters (MGCs) in plant genomes has recently raised increased interest. Thus far, MGCs were commonly identified for pathways of specialized metabolism, mostly those associated with terpene type products. For efficient identification of novel MGCs, computational approaches are essential. Here, we present PhytoClust; a tool for the detection of candidate MGCs in plant genomes. The algorithm employs a collection of enzyme families related to plant specialized metabolism, translated into hidden Markov models, to mine given genome sequences for physically co-localized metabolic enzymes. Our tool accurately identifies previously characterized plant MGCs. An exhaustive search of 31 plant genomes detected 1232 and 5531 putative gene cluster types and candidates, respectively. Clustering analysis of putative MGCs types by species reflected plant taxonomy. Furthermore, enrichment analysis revealed taxa- and species-specific enrichment of certain enzyme families in MGCs. When operating through our web-interface, PhytoClust users can mine a genome either based on a list of known cluster types or by defining new cluster rules. Moreover, for selected plant species, the output can be complemented by co-expression analysis. Altogether, we envisage PhytoClust to enhance novel MGCs discovery which will in turn impact the exploration of plant metabolism. PMID:28486689

The PhytoClust tool for metabolic gene clusters discovery in plant genomes.

PubMed

Töpfer, Nadine; Fuchs, Lisa-Maria; Aharoni, Asaph

2017-07-07

The existence of Metabolic Gene Clusters (MGCs) in plant genomes has recently raised increased interest. Thus far, MGCs were commonly identified for pathways of specialized metabolism, mostly those associated with terpene type products. For efficient identification of novel MGCs, computational approaches are essential. Here, we present PhytoClust; a tool for the detection of candidate MGCs in plant genomes. The algorithm employs a collection of enzyme families related to plant specialized metabolism, translated into hidden Markov models, to mine given genome sequences for physically co-localized metabolic enzymes. Our tool accurately identifies previously characterized plant MGCs. An exhaustive search of 31 plant genomes detected 1232 and 5531 putative gene cluster types and candidates, respectively. Clustering analysis of putative MGCs types by species reflected plant taxonomy. Furthermore, enrichment analysis revealed taxa- and species-specific enrichment of certain enzyme families in MGCs. When operating through our web-interface, PhytoClust users can mine a genome either based on a list of known cluster types or by defining new cluster rules. Moreover, for selected plant species, the output can be complemented by co-expression analysis. Altogether, we envisage PhytoClust to enhance novel MGCs discovery which will in turn impact the exploration of plant metabolism. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY.

PubMed

Horikawa, Yukio; Hosomichi, Kazuyoshi; Enya, Mayumi; Ishiura, Hiroyuki; Suzuki, Yutaka; Tsuji, Shoji; Sugano, Sumio; Inoue, Ituro; Takeda, Jun

2018-07-01

MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.

Transcriptomic Analysis of the Regulation of Rhizome Formation in Temperate and Tropical Lotus (Nelumbo nucifera).

PubMed

Yang, Mei; Zhu, Lingping; Pan, Cheng; Xu, Liming; Liu, Yanling; Ke, Weidong; Yang, Pingfang

2015-08-17

Rhizome is the storage organ of lotus derived from modified stems. The development of rhizome is a complex process and depends on the balanced expression of the genes that is controlled by environmental and endogenous factors. However, little is known about the mechanism that regulates rhizome girth enlargement. In this study, using RNA-seq, transcriptomic analyses were performed at three rhizome developmental stages-the stolon, middle swelling and later swelling stage -in the cultivars 'ZO' (temperate lotus with enlarged rhizome) and 'RL' (tropical lotus with stolon). About 348 million high-quality reads were generated, and 88.5% of the data were mapped to the reference genome. Of 26783 genes identified, 24069 genes were previously predicted in the reference, and 2714 genes were novel transcripts. Moreover, 8821 genes were differentially expressed between the cultivars at the three stages. Functional analysis identified that these genes were significantly enriched in pathways carbohydrate metabolism and plant hormone signal transduction. Twenty-two genes involved in photoperiod pathway, starch metabolism and hormone signal transduction were candidate genes inducing rhizome girth enlargement. Comparative transcriptomic analysis detected several differentially expressed genes and potential candidate genes required for rhizome girth enlargement, which lay a foundation for future studies on molecular mechanisms underlying rhizome formation.

Transcriptomic Analysis of the Regulation of Rhizome Formation in Temperate and Tropical Lotus (Nelumbo nucifera)

PubMed Central

Yang, Mei; Zhu, Lingping; Pan, Cheng; Xu, Liming; Liu, Yanling; Ke, Weidong; Yang, Pingfang

2015-01-01

Rhizome is the storage organ of lotus derived from modified stems. The development of rhizome is a complex process and depends on the balanced expression of the genes that is controlled by environmental and endogenous factors. However, little is known about the mechanism that regulates rhizome girth enlargement. In this study, using RNA-seq, transcriptomic analyses were performed at three rhizome developmental stages—the stolon, middle swelling and later swelling stage —in the cultivars ‘ZO’ (temperate lotus with enlarged rhizome) and ‘RL’ (tropical lotus with stolon). About 348 million high-quality reads were generated, and 88.5% of the data were mapped to the reference genome. Of 26783 genes identified, 24069 genes were previously predicted in the reference, and 2714 genes were novel transcripts. Moreover, 8821 genes were differentially expressed between the cultivars at the three stages. Functional analysis identified that these genes were significantly enriched in pathways carbohydrate metabolism and plant hormone signal transduction. Twenty-two genes involved in photoperiod pathway, starch metabolism and hormone signal transduction were candidate genes inducing rhizome girth enlargement. Comparative transcriptomic analysis detected several differentially expressed genes and potential candidate genes required for rhizome girth enlargement, which lay a foundation for future studies on molecular mechanisms underlying rhizome formation. PMID:26279185

Analysis of Differentially Expressed Genes and Signaling Pathways Related to Intramuscular Fat Deposition in Skeletal Muscle of Sex-Linked Dwarf Chickens

PubMed Central

Ye, Yaqiong; Lin, Shumao; Mu, Heping; Tang, Xiaohong; Ou, Yangdan; Chen, Jian; Ma, Yongjiang; Li, Yugu

2014-01-01

Intramuscular fat (IMF) plays an important role in meat quality. However, the molecular mechanisms underlying IMF deposition in skeletal muscle have not been addressed for the sex-linked dwarf (SLD) chicken. In this study, potential candidate genes and signaling pathways related to IMF deposition in chicken leg muscle tissue were characterized using gene expression profiling of both 7-week-old SLD and normal chickens. A total of 173 differentially expressed genes (DEGs) were identified between the two breeds. Subsequently, 6 DEGs related to lipid metabolism or muscle development were verified in each breed based on gene ontology (GO) analysis. In addition, KEGG pathway analysis of DEGs indicated that some of them (GHR, SOCS3, and IGF2BP3) participate in adipocytokine and insulin signaling pathways. To investigate the role of the above signaling pathways in IMF deposition, the gene expression of pathway factors and other downstream genes were measured by using qRT-PCR and Western blot analyses. Collectively, the results identified potential candidate genes related to IMF deposition and suggested that IMF deposition in skeletal muscle of SLD chicken is regulated partially by pathways of adipocytokine and insulin and other downstream signaling pathways (TGF-β/SMAD3 and Wnt/catenin-β pathway). PMID:24757673

7TMRmine: a Web server for hierarchical mining of 7TMR proteins

PubMed Central

Lu, Guoqing; Wang, Zhifang; Jones, Alan M; Moriyama, Etsuko N

2009-01-01

Background Seven-transmembrane region-containing receptors (7TMRs) play central roles in eukaryotic signal transduction. Due to their biomedical importance, thorough mining of 7TMRs from diverse genomes has been an active target of bioinformatics and pharmacogenomics research. The need for new and accurate 7TMR/GPCR prediction tools is paramount with the accelerated rate of acquisition of diverse sequence information. Currently available and often used protein classification methods (e.g., profile hidden Markov Models) are highly accurate for identifying their membership information among already known 7TMR subfamilies. However, these alignment-based methods are less effective for identifying remote similarities, e.g., identifying proteins from highly divergent or possibly new 7TMR families. In this regard, more sensitive (e.g., alignment-free) methods are needed to complement the existing protein classification methods. A better strategy would be to combine different classifiers, from more specific to more sensitive methods, to identify a broader spectrum of 7TMR protein candidates. Description We developed a Web server, 7TMRmine, by integrating alignment-free and alignment-based classifiers specifically trained to identify candidate 7TMR proteins as well as transmembrane (TM) prediction methods. This new tool enables researchers to easily assess the distribution of GPCR functionality in diverse genomes or individual newly-discovered proteins. 7TMRmine is easily customized and facilitates exploratory analysis of diverse genomes. Users can integrate various alignment-based, alignment-free, and TM-prediction methods in any combination and in any hierarchical order. Sixteen classifiers (including two TM-prediction methods) are available on the 7TMRmine Web server. Not only can the 7TMRmine tool be used for 7TMR mining, but also for general TM-protein analysis. Users can submit protein sequences for analysis, or explore pre-analyzed results for multiple genomes. The server currently includes prediction results and the summary statistics for 68 genomes. Conclusion 7TMRmine facilitates the discovery of 7TMR proteins. By combining prediction results from different classifiers in a multi-level filtering process, prioritized sets of 7TMR candidates can be obtained for further investigation. 7TMRmine can be also used as a general TM-protein classifier. Comparisons of TM and 7TMR protein distributions among 68 genomes revealed interesting differences in evolution of these protein families among major eukaryotic phyla. PMID:19538753

A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12.

PubMed

Bianchi, Matteo; Dahlgren, Stina; Massey, Jonathan; Dietschi, Elisabeth; Kierczak, Marcin; Lund-Ziener, Martine; Sundberg, Katarina; Thoresen, Stein Istre; Kämpe, Olle; Andersson, Göran; Ollier, William E R; Hedhammar, Åke; Leeb, Tosso; Lindblad-Toh, Kerstin; Kennedy, Lorna J; Lingaas, Frode; Rosengren Pielberg, Gerli

2015-01-01

Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds--the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10(-11)). Further characterisation of the candidate region revealed a shared ~167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.

A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12

PubMed Central

Massey, Jonathan; Dietschi, Elisabeth; Kierczak, Marcin; Lund-Ziener, Martine; Sundberg, Katarina; Thoresen, Stein Istre; Kämpe, Olle; Andersson, Göran; Ollier, William E. R.; Hedhammar, Åke; Leeb, Tosso; Lindblad-Toh, Kerstin; Kennedy, Lorna J.; Lingaas, Frode; Rosengren Pielberg, Gerli

2015-01-01

Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds—the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10-11). Further characterisation of the candidate region revealed a shared ~167 kb risk haplotype (4,915,018–5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans. PMID:26261983

Identification of Microorganisms by High Resolution Tandem Mass Spectrometry with Accurate Statistical Significance

NASA Astrophysics Data System (ADS)

Alves, Gelio; Wang, Guanghui; Ogurtsov, Aleksey Y.; Drake, Steven K.; Gucek, Marjan; Suffredini, Anthony F.; Sacks, David B.; Yu, Yi-Kuo

2016-02-01

Correct and rapid identification of microorganisms is the key to the success of many important applications in health and safety, including, but not limited to, infection treatment, food safety, and biodefense. With the advance of mass spectrometry (MS) technology, the speed of identification can be greatly improved. However, the increasing number of microbes sequenced is challenging correct microbial identification because of the large number of choices present. To properly disentangle candidate microbes, one needs to go beyond apparent morphology or simple `fingerprinting'; to correctly prioritize the candidate microbes, one needs to have accurate statistical significance in microbial identification. We meet these challenges by using peptidome profiles of microbes to better separate them and by designing an analysis method that yields accurate statistical significance. Here, we present an analysis pipeline that uses tandem MS (MS/MS) spectra for microbial identification or classification. We have demonstrated, using MS/MS data of 81 samples, each composed of a single known microorganism, that the proposed pipeline can correctly identify microorganisms at least at the genus and species levels. We have also shown that the proposed pipeline computes accurate statistical significances, i.e., E-values for identified peptides and unified E-values for identified microorganisms. The proposed analysis pipeline has been implemented in MiCId, a freely available software for Microorganism Classification and Identification. MiCId is available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads.html.

Design criteria for payload workstation accommodations

NASA Technical Reports Server (NTRS)

Watters, H. H.; Stokes, J. W.

1975-01-01

Anticipated shuttle sortie payload man-system design criteria needs are investigated. Man-system interactions for the scientific disciplines are listed and the extent is assessed to which documented Skylab experience is expected to provide system design guidance for each of the identified interactions. Where the analysis revealed that the reduced Skylab data does not answer the anticipated needs candidate criteria, based on unreduced Skylab data, available prior research, original analysis, or related requirements derived from previous space programs, are provided.

Synteny analysis of genes and distribution of loci controlling oil content and fatty acid profile based on QTL alignment map in Brassica napus.

PubMed

Raboanatahiry, Nadia; Chao, Hongbo; Guo, Liangxing; Gan, Jianping; Xiang, Jun; Yan, Mingli; Zhang, Libin; Yu, Longjiang; Li, Maoteng

2017-10-12

Deciphering the genetic architecture of a species is a good way to understand its evolutionary history, but also to tailor its profile for breeding elite cultivars with desirable traits. Aligning QTLs from diverse population in one map and utilizing it for comparison, but also as a basis for multiple analyses assure a stronger evidence to understand the genetic system related to a given phenotype. In this study, 439 genes involved in fatty acid (FA) and triacylglycerol (TAG) biosyntheses were identified in Brassica napus. B. napus genome showed mixed gene loss and insertion compared to B. rapa and B. oleracea, and C genome had more inserted genes. Identified QTLs for oil (OC-QTLs) and fatty acids (FA-QTLs) from nine reported populations were projected on the physical map of the reference genome "Darmor-bzh" to generate a map. Thus, 335 FA-QTLs and OC-QTLs could be highlighted and 82 QTLs were overlapping. Chromosome C3 contained 22 overlapping QTLs with all trait studied except for C18:3. In total, 218 candidate genes which were potentially involved in FA and TAG were identified in 162 QTLs confidence intervals and some of them might affect many traits. Also, 76 among these candidate genes were found inside 57 overlapping QTLs, and candidate genes for oil content were in majority (61/76 genes). Then, sixteen genes were found in overlapping QTLs involving three populations, and the remaining 60 genes were found in overlapping QTLs of two populations. Interaction network and pathway analysis of these candidate genes indicated ten genes that might have strong influence over the other genes that control fatty acids and oil formation. The present results provided new information for genetic basis of FA and TAG formation in B. napus. A map including QTLs from numerous populations was built, which could serve as reference to study the genome profile of B. napus, and new potential genes emerged which might affect seed oil. New useful tracks were showed for the selection of population or/and selection of interesting genes for breeding improvement purpose.

Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis

PubMed Central

Tsuboi, Masaya; Watanabe, Manabu; Nibe, Kazumi; Yoshimi, Natsuko; Kato, Akihisa; Sakaguchi, Masahiro; Yamato, Osamu; Tanaka, Miyuu; Kuwamura, Mitsuru; Kushida, Kazuya; Harada, Tomoyuki; Chambers, James Kenn; Sugano, Sumio; Uchida, Kazuyuki; Nakayama, Hiroyuki

2017-01-01

Whole exome sequencing (WES) has become a common tool for identifying genetic causes of human inherited disorders, and it has also recently been applied to canine genome research. We conducted WES analysis of neuroaxonal dystrophy (NAD), a neurodegenerative disease that sporadically occurs worldwide in Papillon dogs. The disease is considered an autosomal recessive monogenic disease, which is histopathologically characterized by severe axonal swelling, known as “spheroids,” throughout the nervous system. By sequencing all eleven DNA samples from one NAD-affected Papillon dog and her parents, two unrelated NAD-affected Papillon dogs, and six unaffected control Papillon dogs, we identified 10 candidate mutations. Among them, three candidates were determined to be “deleterious” by in silico pathogenesis evaluation. By subsequent massive screening by TaqMan genotyping analysis, only the PLA2G6 c.1579G>A mutation had an association with the presence or absence of the disease, suggesting that it may be a causal mutation of canine NAD. As a human homologue of this gene is a causative gene for infantile neuroaxonal dystrophy, this canine phenotype may serve as a good animal model for human disease. The results of this study also indicate that WES analysis is a powerful tool for exploring canine hereditary diseases, especially in rare monogenic hereditary diseases. PMID:28107443

Machine Learning–Based Differential Network Analysis: A Study of Stress-Responsive Transcriptomes in Arabidopsis[W

PubMed Central

Ma, Chuang; Xin, Mingming; Feldmann, Kenneth A.; Wang, Xiangfeng

2014-01-01

Machine learning (ML) is an intelligent data mining technique that builds a prediction model based on the learning of prior knowledge to recognize patterns in large-scale data sets. We present an ML-based methodology for transcriptome analysis via comparison of gene coexpression networks, implemented as an R package called machine learning–based differential network analysis (mlDNA) and apply this method to reanalyze a set of abiotic stress expression data in Arabidopsis thaliana. The mlDNA first used a ML-based filtering process to remove nonexpressed, constitutively expressed, or non-stress-responsive “noninformative” genes prior to network construction, through learning the patterns of 32 expression characteristics of known stress-related genes. The retained “informative” genes were subsequently analyzed by ML-based network comparison to predict candidate stress-related genes showing expression and network differences between control and stress networks, based on 33 network topological characteristics. Comparative evaluation of the network-centric and gene-centric analytic methods showed that mlDNA substantially outperformed traditional statistical testing–based differential expression analysis at identifying stress-related genes, with markedly improved prediction accuracy. To experimentally validate the mlDNA predictions, we selected 89 candidates out of the 1784 predicted salt stress–related genes with available SALK T-DNA mutagenesis lines for phenotypic screening and identified two previously unreported genes, mutants of which showed salt-sensitive phenotypes. PMID:24520154

Identification of Linkages between EDCs in Personal Care Products and Breast Cancer through Data Integration Combined with Gene Network Analysis

PubMed Central

Kim, Jongwoon

2017-01-01

Approximately 1000 chemicals have been reported to possibly have endocrine disrupting effects, some of which are used in consumer products, such as personal care products (PCPs) and cosmetics. We conducted data integration combined with gene network analysis to: (i) identify causal molecular mechanisms between endocrine disrupting chemicals (EDCs) used in PCPs and breast cancer; and (ii) screen candidate EDCs associated with breast cancer. Among EDCs used in PCPs, four EDCs having correlation with breast cancer were selected, and we curated 27 common interacting genes between those EDCs and breast cancer to perform the gene network analysis. Based on the gene network analysis, ESR1, TP53, NCOA1, AKT1, and BCL6 were found to be key genes to demonstrate the molecular mechanisms of EDCs in the development of breast cancer. Using GeneMANIA, we additionally predicted 20 genes which could interact with the 27 common genes. In total, 47 genes combining the common and predicted genes were functionally grouped with the gene ontology and KEGG pathway terms. With those genes, we finally screened candidate EDCs for their potential to increase breast cancer risk. This study highlights that our approach can provide insights to understand mechanisms of breast cancer and identify potential EDCs which are in association with breast cancer. PMID:28973975

Proteomics, bioinformatics and targeted gene expression analysis reveals up-regulation of cochlin and identifies other potential biomarkers in the mouse model for deafness in usher syndrome type 1F

PubMed Central

Chance, Mark R.; Chang, Jinsook; Liu, Shuqing; Gokulrangan, Giridharan; Chen, Daniel H.-C.; Lindsay, Aaron; Geng, Ruishuang; Zheng, Qing Y.; Alagramam, Kumar

2010-01-01

Proteins and protein networks associated with cochlear pathogenesis in the Ames waltzer (av) mouse, a model for deafness in Usher syndrome 1F (USH1F), were identified. Cochlear protein from wild-type and av mice at postnatal day 30, a time point in which cochlear pathology is well established, was analyzed by quantitative 2D gel electrophoresis followed by mass spectrometry (MS). The analytic gel resolved 2270 spots; 69 spots showed significant changes in intensity in the av cochlea compared with the control. The cochlin protein was identified in 20 peptide spots, most of which were up-regulated, while a few were down-regulated. Analysis of MS sequence data showed that, in the av cochlea, a set of full-length isoforms of cochlin was up-regulated, while isoforms missing the N-terminal FCH/LCCL domain were down-regulated. Protein interaction network analysis of all differentially expressed proteins was performed with Metacore software. That analysis revealed a number of statistically significant candidate protein networks predicted to be altered in the affected cochlea. Quantitative PCR (qPCR) analysis of select candidates from the proteomic and bioinformatic investigations showed up-regulation of Coch mRNA and those of p53, Brn3a and Nrf2, transcription factors linked to stress response and survival. Increased mRNA of Brn3a and Nrf2 has previously been associated with increased expression of cochlin in human glaucomatous trabecular meshwork. Our report strongly suggests that increased level of cochlin is an important etiologic factor leading to the degeneration of cochlear neuroepithelia in the USH1F model. PMID:20097680

OVA: integrating molecular and physical phenotype data from multiple biomedical domain ontologies with variant filtering for enhanced variant prioritization.

PubMed

Antanaviciute, Agne; Watson, Christopher M; Harrison, Sally M; Lascelles, Carolina; Crinnion, Laura; Markham, Alexander F; Bonthron, David T; Carr, Ian M

2015-12-01

Exome sequencing has become a de facto standard method for Mendelian disease gene discovery in recent years, yet identifying disease-causing mutations among thousands of candidate variants remains a non-trivial task. Here we describe a new variant prioritization tool, OVA (ontology variant analysis), in which user-provided phenotypic information is exploited to infer deeper biological context. OVA combines a knowledge-based approach with a variant-filtering framework. It reduces the number of candidate variants by considering genotype and predicted effect on protein sequence, and scores the remainder on biological relevance to the query phenotype.We take advantage of several ontologies in order to bridge knowledge across multiple biomedical domains and facilitate computational analysis of annotations pertaining to genes, diseases, phenotypes, tissues and pathways. In this way, OVA combines information regarding molecular and physical phenotypes and integrates both human and model organism data to effectively prioritize variants. By assessing performance on both known and novel disease mutations, we show that OVA performs biologically meaningful candidate variant prioritization and can be more accurate than another recently published candidate variant prioritization tool. OVA is freely accessible at http://dna2.leeds.ac.uk:8080/OVA/index.jsp. Supplementary data are available at Bioinformatics online. umaan@leeds.ac.uk. © The Author 2015. Published by Oxford University Press.

Meta-QTL analysis of seed iron and zinc concentration and content in common bean (Phaseolus vulgaris L.).

PubMed

Izquierdo, Paulo; Astudillo, Carolina; Blair, Matthew W; Iqbal, Asif M; Raatz, Bodo; Cichy, Karen A

2018-05-11

Twelve meta-QTL for seed Fe and Zn concentration and/or content were identified from 87 QTL originating from seven population grown in sixteen field trials. These meta-QTL include 2 specific to iron, 2 specific to zinc and 8 that co-localize for iron and zinc concentrations and/or content. Common bean (Phaseolus vulgaris L.) is the most important legume for human consumption worldwide and it is an important source of microelements, especially iron and zinc. Bean biofortification breeding programs develop new varieties with high levels of Fe and Zn targeted for countries with human micronutrient deficiencies. Biofortification efforts thus far have relied on phenotypic selection of raw seed mineral concentrations in advanced generations. While numerous quantitative trait loci (QTL) studies have been conducted to identify genomic regions associated with increased Fe and Zn concentration in seeds, these results have yet to be employed for marker-assisted breeding. The objective of this study was to conduct a meta-analysis from seven QTL studies in Andean and Middle American intra- and inter-gene pool populations to identify the regions in the genome that control the Fe and Zn levels in seeds. Two meta-QTL specific to Fe and two meta-QTL specific to Zn were identified. Additionally, eight Meta QTL that co-localized for Fe and Zn concentration and/or content were identified across seven chromosomes. The Fe and Zn shared meta-QTL could be useful candidates for marker-assisted breeding to simultaneously increase seed Fe and Zn. The physical positions for 12 individual meta-QTL were identified and within five of the meta-QTL, candidate genes were identified from six gene families that have been associated with transport of iron and zinc in plants.

Analysis of candidates for interacting galaxy clusters. I. A1204 and A2029/A2033

NASA Astrophysics Data System (ADS)

Gonzalez, Elizabeth Johana; de los Rios, Martín; Oio, Gabriel A.; Lang, Daniel Hernández; Tagliaferro, Tania Aguirre; Domínguez R., Mariano J.; Castellón, José Luis Nilo; Cuevas L., Héctor; Valotto, Carlos A.

2018-04-01

Context. Merging galaxy clusters allow for the study of different mass components, dark and baryonic, separately. Also, their occurrence enables to test the ΛCDM scenario, which can be used to put constraints on the self-interacting cross-section of the dark-matter particle. Aim. It is necessary to perform a homogeneous analysis of these systems. Hence, based on a recently presented sample of candidates for interacting galaxy clusters, we present the analysis of two of these cataloged systems. Methods: In this work, the first of a series devoted to characterizing galaxy clusters in merger processes, we perform a weak lensing analysis of clusters A1204 and A2029/A2033 to derive the total masses of each identified interacting structure together with a dynamical study based on a two-body model. We also describe the gas and the mass distributions in the field through a lensing and an X-ray analysis. This is the first of a series of works which will analyze these type of system in order to characterize them. Results: Neither merging cluster candidate shows evidence of having had a recent merger event. Nevertheless, there is dynamical evidence that these systems could be interacting or could interact in the future. Conclusions: It is necessary to include more constraints in order to improve the methodology of classifying merging galaxy clusters. Characterization of these clusters is important in order to properly understand the nature of these systems and their connection with dynamical studies.

Screening key candidate genes and pathways involved in insulinoma by microarray analysis.

PubMed

Zhou, Wuhua; Gong, Li; Li, Xuefeng; Wan, Yunyan; Wang, Xiangfei; Li, Huili; Jiang, Bin

2018-06-01

Insulinoma is a rare type tumor and its genetic features remain largely unknown. This study aimed to search for potential key genes and relevant enriched pathways of insulinoma.The gene expression data from GSE73338 were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified between insulinoma tissues and normal pancreas tissues, followed by pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. The expressions of candidate key genes were validated by quantitative real-time polymerase chain reaction (RT-PCR) in insulinoma tissues.A total of 1632 DEGs were obtained, including 1117 upregulated genes and 514 downregulated genes. Pathway enrichment results showed that upregulated DEGs were significantly implicated in insulin secretion, and downregulated DEGs were mainly enriched in pancreatic secretion. PPI network analysis revealed 7 hub genes with degrees more than 10, including GCG (glucagon), GCGR (glucagon receptor), PLCB1 (phospholipase C, beta 1), CASR (calcium sensing receptor), F2R (coagulation factor II thrombin receptor), GRM1 (glutamate metabotropic receptor 1), and GRM5 (glutamate metabotropic receptor 5). DEGs involved in the significant modules were enriched in calcium signaling pathway, protein ubiquitination, and platelet degranulation. Quantitative RT-PCR data confirmed that the expression trends of these hub genes were similar to the results of bioinformatic analysis.The present study demonstrated that candidate DEGs and enriched pathways were the potential critical molecule events involved in the development of insulinoma, and these findings were useful for better understanding of insulinoma genesis.

Mutational Landscape of Candidate Genes in Familial Prostate Cancer

PubMed Central

Johnson, Anna M.; Zuhlke, Kimberly A.; Plotts, Chris; McDonnell, Shannon K.; Middha, Sumit; Riska, Shaun M.; Thibodeau, Stephen N.; Douglas, Julie A.; Cooney, Kathleen A.

2014-01-01

Background Family history is a major risk factor for prostate cancer (PCa), suggesting a genetic component to the disease. However, traditional linkage and association studies have failed to fully elucidate the underlying genetic basis of familial PCa. Methods Here we use a candidate gene approach to identify potential PCa susceptibility variants in whole exome sequencing data from familial PCa cases. Six hundred ninety-seven candidate genes were identified based on function, location near a known chromosome 17 linkage signal, and/or previous association with prostate or other cancers. Single nucleotide variants (SNVs) in these candidate genes were identified in whole exome sequence data from 33 PCa cases from 11 multiplex PCa families (3 cases/family). Results Overall, 4856 candidate gene SNVs were identified, including 1052 missense and 10 nonsense variants. Twenty missense variants were shared by all 3 family members in each family in which they were observed. Additionally, 15 missense variants were shared by 2 of 3 family members and predicted to be deleterious by 5 different algorithms. Four missense variants, BLM Gln123Arg, PARP2 Arg283Gln, LRCC46 Ala295Thr and KIF2B Pro91Leu, and 1 nonsense variant, CYP3A43 Arg441Ter, showed complete co-segregation with PCa status. Twelve additional variants displayed partial co-segregation with PCa. Conclusions Forty-three nonsense and shared, missense variants were identified in our candidate genes. Further research is needed to determine the contribution of these variants to PCa susceptibility. PMID:25111073

A Novel Candidate Region for Genetic Adaptation to High Altitude in Andean Populations

PubMed Central

Lippold, Sebastian; de Filippo, Cesare; Tang, Kun; López Herráez, David; Li, Jing; Stoneking, Mark

2015-01-01

Humans living at high altitude (≥2,500 meters above sea level) have acquired unique abilities to survive the associated extreme environmental conditions, including hypoxia, cold temperature, limited food availability and high levels of free radicals and oxidants. Long-term inhabitants of the most elevated regions of the world have undergone extensive physiological and/or genetic changes, particularly in the regulation of respiration and circulation, when compared to lowland populations. Genome scans have identified candidate genes involved in altitude adaption in the Tibetan Plateau and the Ethiopian highlands, in contrast to populations from the Andes, which have not been as intensively investigated. In the present study, we focused on three indigenous populations from Bolivia: two groups of Andean natives, Aymara and Quechua, and the low-altitude control group of Guarani from the Gran Chaco lowlands. Using pooled samples, we identified a number of SNPs exhibiting large allele frequency differences over 900,000 genotyped SNPs. A region in chromosome 10 (within the cytogenetic bands q22.3 and q23.1) was significantly differentiated between highland and lowland groups. We resequenced ~1.5 Mb surrounding the candidate region and identified strong signals of positive selection in the highland populations. A composite of multiple signals like test localized the signal to FAM213A and a related enhancer; the product of this gene acts as an antioxidant to lower oxidative stress and may help to maintain bone mass. The results suggest that positive selection on the enhancer might increase the expression of this antioxidant, and thereby prevent oxidative damage. In addition, the most significant signal in a relative extended haplotype homozygosity analysis was localized to the SFTPD gene, which encodes a surfactant pulmonary-associated protein involved in normal respiration and innate host defense. Our study thus identifies two novel candidate genes and associated pathways that may be involved in high-altitude adaptation in Andean populations. PMID:25961286

A novel method for transient detection in high-cadence optical surveys. Its application for a systematic search for novae in M 31

NASA Astrophysics Data System (ADS)

Soraisam, Monika D.; Gilfanov, Marat; Kupfer, Thomas; Masci, Frank; Shafter, Allen W.; Prince, Thomas A.; Kulkarni, Shrinivas R.; Ofek, Eran O.; Bellm, Eric

2017-03-01

Context. In the present era of large-scale surveys in the time domain, the processing of data, from procurement up to the detection of sources, is generally automated. One of the main challenges in the astrophysical analysis of their output is contamination by artifacts, especially in the regions of high surface brightness of unresolved emission. Aims: We present a novel method for identifying candidates for variable and transient sources from the outputs of optical time-domain survey data pipelines. We use the method to conduct a systematic search for novae in the intermediate Palomar Transient Factory (iPTF) observations of the bulge part of M 31 during the second half of 2013. Methods: We demonstrate that a significant fraction of artifacts produced by the iPTF pipeline form a locally uniform background of false detections approximately obeying Poissonian statistics, whereas genuine variable and transient sources, as well as artifacts associated with bright stars, result in clusters of detections whose spread is determined by the source localization accuracy. This makes the problem analogous to source detection on images produced by grazing incidence X-ray telescopes, enabling one to utilize the arsenal of powerful tools developed in X-ray astronomy. In particular, we use a wavelet-based source detection algorithm from the Chandra data analysis package CIAO. Results: Starting from 2.5 × 105 raw detections made by the iPTF data pipeline, we obtain approximately 4000 unique source candidates. Cross-matching these candidates with the source-catalog of a deep reference image of the same field, we find counterparts for 90% of the candidates. These sources are either artifacts due to imperfect PSF matching or genuine variable sources. The remaining approximately 400 detections are transient sources. We identify novae among these candidates by applying selection cuts to their lightcurves based on the expected properties of novae. Thus, we recovered all 12 known novae (not counting one that erupted toward the end of the survey) registered during the time span of the survey and discovered three nova candidates. Our method is generic and can be applied to mining any target out of the artifacts in optical time-domain data. As it is fully automated, its incompleteness can be accurately computed and corrected for.

Donations and dependence: Individual contributor strategies in house elections.

PubMed

Heerwig, Jennifer A

2016-11-01

Despite the importance of individual contributors to financing federal candidates, past work has largely neglected this crucial financial constituency in favor of research on corporate and trade political action committees (PACs). By contrast, in this study I offer the first analysis of aggregate contributions from the population of individual contributors to House candidates. Using an original big dataset constructed from over fifteen million Federal Election Commission (FEC) disclosure records, I identify individual contributors (rather than contributions) and trace the variation in their strategies across types of House candidates. I distinguish between frequent donors, who are theorized to have more contact with members of Congress, versus infrequent donors in these elections. I find evidence that the character of aggregate donations from repeat donors is more access-oriented even while controlling for other salient candidate characteristics. Funds from infrequent donors, in contrast, appear more ideologically motivated. By also examining the percentage of funds that House candidates receive from repeat donors, I show that the fundraising coalitions of candidates may reproduce reliance on more access-oriented, repeat donors despite the influx of dollars from infrequent donors. I suggest that my findings provide a persuasive case for re-evaluating the diversity of roles individual contributors play in the campaign finance system, and for systematically analyzing variation in contributor strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

The open cluster IC 4665

NASA Technical Reports Server (NTRS)

Prosser, Charles F.

1993-01-01

The results of a combined astrometric, photometric, and spectroscopic program to identify members of the open cluster IC 4665 are presented. Numerous new proper motion/photometric candidate members and at least 23 M dwarfs with H-alpha emission have been identified. A reanalysis of IC 4665 age using different methods yields conflicting results ranging from about 3 X 10 exp 7 yr to the age of the Pleiades. This study provides a list of candidate cluster members in the intermediate and low-mass regime of this cluster. Future spectroscopic observations of these candidates should eventually identify true cluster members.

BANYAN. V. A SYSTEMATIC ALL-SKY SURVEY FOR NEW VERY LATE-TYPE LOW-MASS STARS AND BROWN DWARFS IN NEARBY YOUNG MOVING GROUPS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gagné, Jonathan; Lafrenière, David; Doyon, René

2015-01-10

We present the BANYAN All-Sky Survey (BASS) catalog, consisting of 228 new late-type (M4-L6) candidate members of nearby young moving groups (YMGs) with an expected false-positive rate of ∼13%. This sample includes 79 new candidate young brown dwarfs and 22 planetary-mass objects. These candidates were identified through the first systematic all-sky survey for late-type low-mass stars and brown dwarfs in YMGs. We cross-matched the Two Micron All Sky Survey and AllWISE catalogs outside of the galactic plane to build a sample of 98,970 potential ≥M5 dwarfs in the solar neighborhood and calculated their proper motions with typical precisions of 5-15more » mas yr{sup –1}. We selected highly probable candidate members of several YMGs from this sample using the Bayesian Analysis for Nearby Young AssociatioNs II tool (BANYAN II). We used the most probable statistical distances inferred from BANYAN II to estimate the spectral type and mass of these candidate YMG members. We used this unique sample to show tentative signs of mass segregation in the AB Doradus moving group and the Tucana-Horologium and Columba associations. The BASS sample has already been successful in identifying several new young brown dwarfs in earlier publications, and will be of great interest in studying the initial mass function of YMGs and for the search of exoplanets by direct imaging; the input sample of potential close-by ≥M5 dwarfs will be useful to study the kinematics of low-mass stars and brown dwarfs and search for new proper motion pairs.« less

Discovery and characterization of antibody variants using mass spectrometry-based comparative analysis for biosimilar candidates of monoclonal antibody drugs.

PubMed

Li, Wenhua; Yang, Bin; Zhou, Dongmei; Xu, Jun; Ke, Zhi; Suen, Wen-Chen

2016-07-01

Liquid chromatography mass spectrometry (LC-MS) is the most commonly used technique for the characterization of antibody variants. MAb-X and mAb-Y are two approved IgG1 subtype monoclonal antibody drugs recombinantly produced in Chinese hamster ovary (CHO) cells. We report here that two unexpected and rare antibody variants have been discovered during cell culture process development of biosimilars for these two approved drugs through intact mass analysis. We then used comprehensive mass spectrometry-based comparative analysis including reduced light, heavy chains, and domain-specific mass as well as peptide mapping analysis to fully characterize the observed antibody variants. The "middle-up" mass comparative analysis demonstrated that the antibody variant from mAb-X biosimilar candidate was caused by mass variation of antibody crystalline fragment (Fc), whereas a different variant with mass variation in antibody antigen-binding fragment (Fab) from mAb-Y biosimilar candidate was identified. Endoproteinase Lys-C digested peptide mapping and tandem mass spectrometry analysis further revealed that a leucine to glutamine change in N-terminal 402 site of heavy chain was responsible for the generation of mAb-X antibody variant. Lys-C and trypsin coupled non-reduced and reduced peptide mapping comparative analysis showed that the formation of the light-heavy interchain trisulfide bond resulted in the mAb-Y antibody variant. These two cases confirmed that mass spectrometry-based comparative analysis plays a critical role for the characterization of monoclonal antibody variants, and biosimilar developers should start with a comprehensive structural assessment and comparative analysis to decrease the risk of the process development for biosimilars. Copyright © 2016 Elsevier B.V. All rights reserved.

Using Social Media Data to Identify Potential Candidates for Drug Repurposing: A Feasibility Study.

PubMed

Rastegar-Mojarad, Majid; Liu, Hongfang; Nambisan, Priya

2016-06-16

Drug repurposing (defined as discovering new indications for existing drugs) could play a significant role in drug development, especially considering the declining success rates of developing novel drugs. Typically, new indications for existing medications are identified by accident. However, new technologies and a large number of available resources enable the development of systematic approaches to identify and validate drug-repurposing candidates. Patients today report their experiences with medications on social media and reveal side effects as well as beneficial effects of those medications. Our aim was to assess the feasibility of using patient reviews from social media to identify potential candidates for drug repurposing. We retrieved patient reviews of 180 medications from an online forum, WebMD. Using dictionary-based and machine learning approaches, we identified disease names in the reviews. Several publicly available resources were used to exclude comments containing known indications and adverse drug effects. After manually reviewing some of the remaining comments, we implemented a rule-based system to identify beneficial effects. The dictionary-based system and machine learning system identified 2178 and 6171 disease names respectively in 64,616 patient comments. We provided a list of 10 common patterns that patients used to report any beneficial effects or uses of medication. After manually reviewing the comments tagged by our rule-based system, we identified five potential drug repurposing candidates. To our knowledge, this is the first study to consider using social media data to identify drug-repurposing candidates. We found that even a rule-based system, with a limited number of rules, could identify beneficial effect mentions in patient comments. Our preliminary study shows that social media has the potential to be used in drug repurposing.

Quantitative trait locus linkage analysis in a large Amish pedigree identifies novel candidate loci for erythrocyte traits

PubMed Central

Hinckley, Jesse D; Abbott, Diana; Burns, Trudy L; Heiman, Meadow; Shapiro, Amy D; Wang, Kai; Di Paola, Jorge

2013-01-01

We characterized a large Amish pedigree and, in 384 pedigree members, analyzed the genetic variance components with covariate screen as well as genome-wide quantitative trait locus (QTL) linkage analysis of red blood cell count (RBC), hemoglobin (HB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), platelet count (PLT), and white blood cell count (WBC) using SOLAR. Age and gender were found to be significant covariates in many CBC traits. We obtained significant heritability estimates for RBC, MCV, MCH, MCHC, RDW, PLT, and WBC. We report four candidate loci with Logarithm of the odds (LOD) scores above 2.0: 6q25 (MCH), 9q33 (WBC), 10p12 (RDW), and 20q13 (MCV). We also report eleven candidate loci with LOD scores between 1.5 and <2.0. Bivariate linkage analysis of MCV and MCH on chromosome 20 resulted in a higher maximum LOD score of 3.14. Linkage signals on chromosomes 4q28, 6p22, 6q25, and 20q13 are concomitant with previously reported QTL. All other linkage signals reported herein represent novel evidence of candidate QTL. Interestingly rs1800562, the most common causal variant of hereditary hemochromatosis in HFE (6p22) was associated with MCH and MCHC in this family. Linkage studies like the one presented here will allow investigators to focus the search for rare variants amidst the noise encountered in the large amounts of data generated by whole-genome sequencing. PMID:24058921

Differential Gene Expression Reveals Candidate Genes for Drought Stress Response in Abies alba (Pinaceae)

PubMed Central

Ziegenhagen, Birgit; Liepelt, Sascha

2015-01-01

Increasing drought periods as a result of global climate change pose a threat to many tree species by possibly outpacing their adaptive capabilities. Revealing the genetic basis of drought stress response is therefore implemental for future conservation strategies and risk assessment. Access to informative genomic regions is however challenging, especially for conifers, partially due to their large genomes, which puts constraints on the feasibility of whole genome scans. Candidate genes offer a valuable tool to reduce the complexity of the analysis and the amount of sequencing work and costs. For this study we combined an improved drought stress phenotyping of needles via a novel terahertz water monitoring technique with Massive Analysis of cDNA Ends to identify candidate genes for drought stress response in European silver fir (Abies alba Mill.). A pooled cDNA library was constructed from the cotyledons of six drought stressed and six well-watered silver fir seedlings, respectively. Differential expression analyses of these libraries revealed 296 candidate genes for drought stress response in silver fir (247 up- and 49 down-regulated) of which a subset was validated by RT-qPCR of the twelve individual cotyledons. A majority of these genes code for currently uncharacterized proteins and hint on new genomic resources to be explored in conifers. Furthermore, we could show that some traditional reference genes from model plant species (GAPDH and eIF4A2) are not suitable for differential analysis and we propose a new reference gene, TPC1, for drought stress expression profiling in needles of conifer seedlings. PMID:25924061

Identification of KCNJ11 as a functional candidate gene for bovine meat tenderness.

PubMed

Tizioto, Polyana C; Gasparin, Gustavo; Souza, Marcela M; Mudadu, Mauricio A; Coutinho, Luiz L; Mourão, Gerson B; Tholon, Patricia; Meirelles, Sarah L C; Tullio, Rymer R; Rosa, Antônio N; Alencar, Maurício M; Medeiros, Sérgio R; Siqueira, Fabiane; Feijó, Gelson L D; Nassu, Renata T; Regitano, Luciana C A

2013-12-15

The potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene was investigated as a candidate for meat tenderness based on the effects reported on muscle for KCNJ11 gene knockout in rat models and its position in a quantitative trait locus (QTL) for meat tenderness in the bovine genome. Sequence variations in the KCNJ11 gene were described by sequencing six amplified fragments, covering almost the entire gene. We identified single nucleotide polymorphisms (SNP) and validated them by different approaches, taking advantage of simultaneous projects that are being developed with the same Nelore population. By sequencing the KCNJ11 in Nelore steers representing extreme phenotypes for Warner-Bratzler shear force (WBSF), it was possible to identify 22 SNPs. We validated two of the identified markers by genotyping the whole population (n = 460). Analysis of association between genotypes and WBSF values revealed a significant additive effect of a SNP at different meat aging times (P ≤ 0.05). In addition, an association between the expression levels of KCNJ11 and WBSF was found, with lower expression levels of KCNJ11 associated with more tender meat (P ≤ 0.05). The results showed that the KCNJ11 gene is a candidate mapped to a QTL for meat tenderness previously identified on BTA15 and may be useful to identify animals with genetic potential to produce tender meat. The effect of KCNJ11 observed on muscle is potentially due to changes in activity of KATP channels, which in turn influence the flow of potassium in the intracellular space, allowing establishment of the membrane potential necessary for muscle contraction.

Mining biological databases for candidate disease genes

NASA Astrophysics Data System (ADS)

Braun, Terry A.; Scheetz, Todd; Webster, Gregg L.; Casavant, Thomas L.

2001-07-01

The publicly-funded effort to sequence the complete nucleotide sequence of the human genome, the Human Genome Project (HGP), has currently produced more than 93% of the 3 billion nucleotides of the human genome into a preliminary `draft' format. In addition, several valuable sources of information have been developed as direct and indirect results of the HGP. These include the sequencing of model organisms (rat, mouse, fly, and others), gene discovery projects (ESTs and full-length), and new technologies such as expression analysis and resources (micro-arrays or gene chips). These resources are invaluable for the researchers identifying the functional genes of the genome that transcribe and translate into the transcriptome and proteome, both of which potentially contain orders of magnitude more complexity than the genome itself. Preliminary analyses of this data identified approximately 30,000 - 40,000 human `genes.' However, the bulk of the effort still remains -- to identify the functional and structural elements contained within the transcriptome and proteome, and to associate function in the transcriptome and proteome to genes. A fortuitous consequence of the HGP is the existence of hundreds of databases containing biological information that may contain relevant data pertaining to the identification of disease-causing genes. The task of mining these databases for information on candidate genes is a commercial application of enormous potential. We are developing a system to acquire and mine data from specific databases to aid our efforts to identify disease genes. A high speed cluster of Linux of workstations is used to analyze sequence and perform distributed sequence alignments as part of our data mining and processing. This system has been used to mine GeneMap99 sequences within specific genomic intervals to identify potential candidate disease genes associated with Bardet-Biedle Syndrome (BBS).

Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor.

PubMed

Bime, Christian; Pouladi, Nima; Sammani, Saad; Batai, Ken; Casanova, Nancy; Zhou, Tong; Kempf, Carrie L; Sun, Xiaoguang; Camp, Sara M; Wang, Ting; Kittles, Rick A; Lussier, Yves A; Jones, Tiffanie K; Reilly, John P; Meyer, Nuala J; Christie, Jason D; Karnes, Jason H; Gonzalez-Garay, Manuel; Christiani, David C; Yates, Charles R; Wurfel, Mark M; Meduri, Gianfranco U; Garcia, Joe G N

2018-06-01

Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches. To identify genetic susceptibility targets for ARDS. A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort. Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg -/- mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation. These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.

Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

PubMed Central

Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

2016-01-01

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

Statistical Methods for Rapid Aerothermal Analysis and Design Technology: Validation

NASA Technical Reports Server (NTRS)

DePriest, Douglas; Morgan, Carolyn

2003-01-01

The cost and safety goals for NASA s next generation of reusable launch vehicle (RLV) will require that rapid high-fidelity aerothermodynamic design tools be used early in the design cycle. To meet these requirements, it is desirable to identify adequate statistical models that quantify and improve the accuracy, extend the applicability, and enable combined analyses using existing prediction tools. The initial research work focused on establishing suitable candidate models for these purposes. The second phase is focused on assessing the performance of these models to accurately predict the heat rate for a given candidate data set. This validation work compared models and methods that may be useful in predicting the heat rate.

Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes.

PubMed

Di Gregorio, E; Riberi, E; Belligni, E F; Biamino, E; Spielmann, M; Ala, U; Calcia, A; Bagnasco, I; Carli, D; Gai, G; Giordano, M; Guala, A; Keller, R; Mandrile, G; Arduino, C; Maffè, A; Naretto, V G; Sirchia, F; Sorasio, L; Ungari, S; Zonta, A; Zacchetti, G; Talarico, F; Pappi, P; Cavalieri, S; Giorgio, E; Mancini, C; Ferrero, M; Brussino, A; Savin, E; Gandione, M; Pelle, A; Giachino, D F; De Marchi, M; Restagno, G; Provero, P; Cirillo Silengo, M; Grosso, E; Buxbaum, J D; Pasini, B; De Rubeis, S; Brusco, A; Ferrero, G B

2017-10-01

Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). Identification of genomic disorders in DD/ID. We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The 'permeome' of the malaria parasite: an overview of the membrane transport proteins of Plasmodium falciparum

PubMed Central

Martin, Rowena E; Henry, Roselani I; Abbey, Janice L; Clements, John D; Kirk, Kiaran

2005-01-01

Background The uptake of nutrients, expulsion of metabolic wastes and maintenance of ion homeostasis by the intraerythrocytic malaria parasite is mediated by membrane transport proteins. Proteins of this type are also implicated in the phenomenon of antimalarial drug resistance. However, the initial annotation of the genome of the human malaria parasite Plasmodium falciparum identified only a limited number of transporters, and no channels. In this study we have used a combination of bioinformatic approaches to identify and attribute putative functions to transporters and channels encoded by the malaria parasite, as well as comparing expression patterns for a subset of these. Results A computer program that searches a genome database on the basis of the hydropathy plots of the corresponding proteins was used to identify more than 100 transport proteins encoded by P. falciparum. These include all the transporters previously annotated as such, as well as a similar number of candidate transport proteins that had escaped detection. Detailed sequence analysis enabled the assignment of putative substrate specificities and/or transport mechanisms to all those putative transport proteins previously without. The newly-identified transport proteins include candidate transporters for a range of organic and inorganic nutrients (including sugars, amino acids, nucleosides and vitamins), and several putative ion channels. The stage-dependent expression of RNAs for 34 candidate transport proteins of particular interest are compared. Conclusion The malaria parasite possesses substantially more membrane transport proteins than was originally thought, and the analyses presented here provide a range of novel insights into the physiology of this important human pathogen. PMID:15774027

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

PubMed

Li, Yafang; Xiao, Xiangjun; Han, Younghun; Gorlova, Olga; Qian, David; Leighl, Natasha; Johansen, Jakob S; Barnett, Matt; Chen, Chu; Goodman, Gary; Cox, Angela; Taylor, Fiona; Woll, Penella; Wichmann, H-Erich; Manz, Judith; Muley, Thomas; Risch, Angela; Rosenberger, Albert; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Houlston, Richard; Soler Artigas, María; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Liu, Geoffrey; Bojesen, Stig E; Wu, Xifeng; Marchand, Loic Le; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Bertazzi, Pier Alberto; Pesatori, Angela C; Christiani, David C; Caporaso, Neil; Johansson, Mattias; McKay, James D; Brennan, Paul; Hung, Rayjean J; Amos, Christopher I

2018-03-08

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

Evaluation and Validation of Housekeeping Genes as Reference for Gene Expression Studies in Pigeonpea (Cajanus cajan) Under Drought Stress Conditions

PubMed Central

Sinha, Pallavi; Singh, Vikas K.; Suryanarayana, V.; Krishnamurthy, L.; Saxena, Rachit K.; Varshney, Rajeev K.

2015-01-01

Gene expression analysis using quantitative real-time PCR (qRT-PCR) is a very sensitive technique and its sensitivity depends on the stable performance of reference gene(s) used in the study. A number of housekeeping genes have been used in various expression studies in many crops however, their expression were found to be inconsistent under different stress conditions. As a result, species specific housekeeping genes have been recommended for different expression studies in several crop species. However, such specific housekeeping genes have not been reported in the case of pigeonpea (Cajanus cajan) despite the fact that genome sequence has become available for the crop. To identify the stable housekeeping genes in pigeonpea for expression analysis under drought stress conditions, the relative expression variations of 10 commonly used housekeeping genes (EF1α, UBQ10, GAPDH, 18SrRNA, 25SrRNA, TUB6, ACT1, IF4α, UBC and HSP90) were studied on root, stem and leaves tissues of Asha (ICPL 87119). Three statistical algorithms geNorm, NormFinder and BestKeeper were used to define the stability of candidate genes. geNorm analysis identified IF4α and TUB6 as the most stable housekeeping genes however, NormFinder analysis determined IF4α and HSP90 as the most stable housekeeping genes under drought stress conditions. Subsequently validation of the identified candidate genes was undertaken in qRT-PCR based gene expression analysis of uspA gene which plays an important role for drought stress conditions in pigeonpea. The relative quantification of the uspA gene varied according to the internal controls (stable and least stable genes), thus highlighting the importance of the choice of as well as validation of internal controls in such experiments. The identified stable and validated housekeeping genes will facilitate gene expression studies in pigeonpea especially under drought stress conditions. PMID:25849964

Evaluation and validation of housekeeping genes as reference for gene expression studies in pigeonpea (Cajanus cajan) under drought stress conditions.

PubMed

Sinha, Pallavi; Singh, Vikas K; Suryanarayana, V; Krishnamurthy, L; Saxena, Rachit K; Varshney, Rajeev K

2015-01-01

Gene expression analysis using quantitative real-time PCR (qRT-PCR) is a very sensitive technique and its sensitivity depends on the stable performance of reference gene(s) used in the study. A number of housekeeping genes have been used in various expression studies in many crops however, their expression were found to be inconsistent under different stress conditions. As a result, species specific housekeeping genes have been recommended for different expression studies in several crop species. However, such specific housekeeping genes have not been reported in the case of pigeonpea (Cajanus cajan) despite the fact that genome sequence has become available for the crop. To identify the stable housekeeping genes in pigeonpea for expression analysis under drought stress conditions, the relative expression variations of 10 commonly used housekeeping genes (EF1α, UBQ10, GAPDH, 18SrRNA, 25SrRNA, TUB6, ACT1, IF4α, UBC and HSP90) were studied on root, stem and leaves tissues of Asha (ICPL 87119). Three statistical algorithms geNorm, NormFinder and BestKeeper were used to define the stability of candidate genes. geNorm analysis identified IF4α and TUB6 as the most stable housekeeping genes however, NormFinder analysis determined IF4α and HSP90 as the most stable housekeeping genes under drought stress conditions. Subsequently validation of the identified candidate genes was undertaken in qRT-PCR based gene expression analysis of uspA gene which plays an important role for drought stress conditions in pigeonpea. The relative quantification of the uspA gene varied according to the internal controls (stable and least stable genes), thus highlighting the importance of the choice of as well as validation of internal controls in such experiments. The identified stable and validated housekeeping genes will facilitate gene expression studies in pigeonpea especially under drought stress conditions.

Gene Network Construction from Microarray Data Identifies a Key Network Module and Several Candidate Hub Genes in Age-Associated Spatial Learning Impairment

PubMed Central

Uddin, Raihan; Singh, Shiva M.

2017-01-01

As humans age many suffer from a decrease in normal brain functions including spatial learning impairments. This study aimed to better understand the molecular mechanisms in age-associated spatial learning impairment (ASLI). We used a mathematical modeling approach implemented in Weighted Gene Co-expression Network Analysis (WGCNA) to create and compare gene network models of young (learning unimpaired) and aged (predominantly learning impaired) brains from a set of exploratory datasets in rats in the context of ASLI. The major goal was to overcome some of the limitations previously observed in the traditional meta- and pathway analysis using these data, and identify novel ASLI related genes and their networks based on co-expression relationship of genes. This analysis identified a set of network modules in the young, each of which is highly enriched with genes functioning in broad but distinct GO functional categories or biological pathways. Interestingly, the analysis pointed to a single module that was highly enriched with genes functioning in “learning and memory” related functions and pathways. Subsequent differential network analysis of this “learning and memory” module in the aged (predominantly learning impaired) rats compared to the young learning unimpaired rats allowed us to identify a set of novel ASLI candidate hub genes. Some of these genes show significant repeatability in networks generated from independent young and aged validation datasets. These hub genes are highly co-expressed with other genes in the network, which not only show differential expression but also differential co-expression and differential connectivity across age and learning impairment. The known function of these hub genes indicate that they play key roles in critical pathways, including kinase and phosphatase signaling, in functions related to various ion channels, and in maintaining neuronal integrity relating to synaptic plasticity and memory formation. Taken together, they provide a new insight and generate new hypotheses into the molecular mechanisms responsible for age associated learning impairment, including spatial learning. PMID:29066959

Gene Network Construction from Microarray Data Identifies a Key Network Module and Several Candidate Hub Genes in Age-Associated Spatial Learning Impairment.

PubMed

Uddin, Raihan; Singh, Shiva M

2017-01-01

As humans age many suffer from a decrease in normal brain functions including spatial learning impairments. This study aimed to better understand the molecular mechanisms in age-associated spatial learning impairment (ASLI). We used a mathematical modeling approach implemented in Weighted Gene Co-expression Network Analysis (WGCNA) to create and compare gene network models of young (learning unimpaired) and aged (predominantly learning impaired) brains from a set of exploratory datasets in rats in the context of ASLI. The major goal was to overcome some of the limitations previously observed in the traditional meta- and pathway analysis using these data, and identify novel ASLI related genes and their networks based on co-expression relationship of genes. This analysis identified a set of network modules in the young, each of which is highly enriched with genes functioning in broad but distinct GO functional categories or biological pathways. Interestingly, the analysis pointed to a single module that was highly enriched with genes functioning in "learning and memory" related functions and pathways. Subsequent differential network analysis of this "learning and memory" module in the aged (predominantly learning impaired) rats compared to the young learning unimpaired rats allowed us to identify a set of novel ASLI candidate hub genes. Some of these genes show significant repeatability in networks generated from independent young and aged validation datasets. These hub genes are highly co-expressed with other genes in the network, which not only show differential expression but also differential co-expression and differential connectivity across age and learning impairment. The known function of these hub genes indicate that they play key roles in critical pathways, including kinase and phosphatase signaling, in functions related to various ion channels, and in maintaining neuronal integrity relating to synaptic plasticity and memory formation. Taken together, they provide a new insight and generate new hypotheses into the molecular mechanisms responsible for age associated learning impairment, including spatial learning.

Outcomes of Multiple Listing for Adult Heart Transplantation in the United States: Analysis of OPTN Data from 2000 to 2013

PubMed Central

Givens, Raymond C.; Dardas, Todd; Clerkin, Kevin J.; Restaino, Susan; Schulze, P. Christian; Mancini, Donna M.

2015-01-01

Background Heart transplant (HT) candidates in the U.S. may register at multiple centers. Not all candidates have the resources and mobility needed for multiple-listing; thus this policy may advantage wealthier and less sick patients. Objectives We assessed the association of multiple-listing with waitlist outcomes and post-HT survival. Methods We identified 33,928 adult candidates for a first single-organ HT between January 1, 2000 and December 31, 2013 in the OPTN database. Results We identified 679 multiple-listed candidates (ML, 2.0%), who were younger (median age 53 years [IQR 43–60] vs. 55 [45–61], p <0.0001), more often white (76.4% vs 70.7%, p =0.0010) and privately insured (65.5% vs 56.3%, p <0.0001), and lived in ZIP codes with higher median incomes (90,153 [25,471-253,831] vs 68,986 [19,471-219,702], p =0.0015). Likelihood of ML increased with the primary center’s median waiting time. ML candidates had lower initial priority (39.0% 1A or 1B vs 55.1%, p <0.0001) and predicted 90-day waitlist mortality (2.9% [2.3–4.7] vs 3.6% [2.3–6.0], p <0.0001), but were frequently upgraded at secondary centers (58.2% 1A/1B; p <0.0001 vs ML primary listing). ML candidates had a higher HT rate (74.4% vs 70.2%, p =0.0196) and lower waitlist mortality (8.1% vs 12.2%, p =0.0011). Compared to a propensity-matched cohort, the relative ML HT rate was 3.02 (95% CI 2.59–3.52, p <0.0001). There were no post-HT survival differences. Conclusions Multiple-listing is a rational response to organ shortage but may advantage patients with the means to participate rather than the most medically needy. The multiple-listing policy should be overturned. PMID:26577617

Identifying Exosome-Derived MicroRNAs as Candidate Biomarkers of Frailty.

PubMed

Ipson, B R; Fletcher, M B; Espinoza, S E; Fisher, A L

2018-01-01

Frailty is a geriatric syndrome associated with progressive physical decline and significantly increases risk for falls, disability, hospitalizations, and death. However, much remains unknown regarding the biological mechanisms that contribute to aging and frailty, and to date, there are no clinically used prognostic or diagnostic molecular biomarkers. The present study profiled exosome-derived microRNAs isolated from the plasma of young, robust older, and frail older individuals and identified eight miRNAs that are uniquely enriched in frailty: miR-10a-3p, miR-92a-3p, miR-185-3p, miR-194-5p, miR-326, miR-532-5p, miR-576-5p, and miR-760. Furthermore, since exosomes can deliver miRNAs to alter cellular activity and behavior, these miRNAs may also provide insights into the biological mechanisms underlying frailty; KEGG analysis of their target genes revealed multiple pathways implicated in aging and age-related processes. Although further validation and research studies are warranted, our study identified eight novel candidate biomarkers of frailty that may help to elucidate the multifactorial pathogenesis of frailty.

A Multi-layered Quantitative In Vivo Expression Atlas of the Podocyte Unravels Kidney Disease Candidate Genes.

PubMed

Rinschen, Markus M; Gödel, Markus; Grahammer, Florian; Zschiedrich, Stefan; Helmstädter, Martin; Kretz, Oliver; Zarei, Mostafa; Braun, Daniela A; Dittrich, Sebastian; Pahmeyer, Caroline; Schroder, Patricia; Teetzen, Carolin; Gee, HeonYung; Daouk, Ghaleb; Pohl, Martin; Kuhn, Elisa; Schermer, Bernhard; Küttner, Victoria; Boerries, Melanie; Busch, Hauke; Schiffer, Mario; Bergmann, Carsten; Krüger, Marcus; Hildebrandt, Friedhelm; Dengjel, Joern; Benzing, Thomas; Huber, Tobias B

2018-05-22

Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. Moreover, in vivo stable isotope labeling by amino acids uncovered surprisingly rapid synthesis of mitochondrial proteins under steady-state conditions that was perturbed under autophagy-deficient, disease-susceptible conditions. Integration of acquired omics dimensions suggested FARP1 as a candidate essential for podocyte function, which could be substantiated by genetic analysis in humans and knockdown experiments in zebrafish. This work exemplifies how the integration of multi-omics datasets can identify a framework of cell-type-specific features relevant for organ health and disease. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.