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Sample records for allelic expression imbalances

  1. AllelicImbalance: An R/ bioconductor package for detecting, managing, and visualizing allele expression imbalance data from RNA sequencing

    DEFF Research Database (Denmark)

    Gådin, Jesper R.; van't Hooft, Ferdinand M.; Eriksson, Per;

    2015-01-01

    the possible biases. Results: We present AllelicImblance, a software program that is designed to detect, manage, and visualize allelic imbalances comprehensively. The purpose of this software is to allow users to pose genetic questions in any RNA sequencing experiment quickly, enhancing the general utility......-nucleotide polymorphisms. Allelic imbalance analysis is subject to technical biases, due to differences in the sequences of the measured alleles. Flexible bioinformatics tools are needed to ease the workflow while retaining as much RNA sequencing information as possible throughout the analysis to detect and address......, within the robust and versatile management class, ASEset....

  2. Tumor transcriptome sequencing reveals allelic expression imbalances associated with copy number alterations.

    Science.gov (United States)

    Tuch, Brian B; Laborde, Rebecca R; Xu, Xing; Gu, Jian; Chung, Christina B; Monighetti, Cinna K; Stanley, Sarah J; Olsen, Kerry D; Kasperbauer, Jan L; Moore, Eric J; Broomer, Adam J; Tan, Ruoying; Brzoska, Pius M; Muller, Matthew W; Siddiqui, Asim S; Asmann, Yan W; Sun, Yongming; Kuersten, Scott; Barker, Melissa A; De La Vega, Francisco M; Smith, David I

    2010-02-19

    Due to growing throughput and shrinking cost, massively parallel sequencing is rapidly becoming an attractive alternative to microarrays for the genome-wide study of gene expression and copy number alterations in primary tumors. The sequencing of transcripts (RNA-Seq) should offer several advantages over microarray-based methods, including the ability to detect somatic mutations and accurately measure allele-specific expression. To investigate these advantages we have applied a novel, strand-specific RNA-Seq method to tumors and matched normal tissue from three patients with oral squamous cell carcinomas. Additionally, to better understand the genomic determinants of the gene expression changes observed, we have sequenced the tumor and normal genomes of one of these patients. We demonstrate here that our RNA-Seq method accurately measures allelic imbalance and that measurement on the genome-wide scale yields novel insights into cancer etiology. As expected, the set of genes differentially expressed in the tumors is enriched for cell adhesion and differentiation functions, but, unexpectedly, the set of allelically imbalanced genes is also enriched for these same cancer-related functions. By comparing the transcriptomic perturbations observed in one patient to his underlying normal and tumor genomes, we find that allelic imbalance in the tumor is associated with copy number mutations and that copy number mutations are, in turn, strongly associated with changes in transcript abundance. These results support a model in which allele-specific deletions and duplications drive allele-specific changes in gene expression in the developing tumor.

  3. Tumor transcriptome sequencing reveals allelic expression imbalances associated with copy number alterations.

    Directory of Open Access Journals (Sweden)

    Brian B Tuch

    Full Text Available Due to growing throughput and shrinking cost, massively parallel sequencing is rapidly becoming an attractive alternative to microarrays for the genome-wide study of gene expression and copy number alterations in primary tumors. The sequencing of transcripts (RNA-Seq should offer several advantages over microarray-based methods, including the ability to detect somatic mutations and accurately measure allele-specific expression. To investigate these advantages we have applied a novel, strand-specific RNA-Seq method to tumors and matched normal tissue from three patients with oral squamous cell carcinomas. Additionally, to better understand the genomic determinants of the gene expression changes observed, we have sequenced the tumor and normal genomes of one of these patients. We demonstrate here that our RNA-Seq method accurately measures allelic imbalance and that measurement on the genome-wide scale yields novel insights into cancer etiology. As expected, the set of genes differentially expressed in the tumors is enriched for cell adhesion and differentiation functions, but, unexpectedly, the set of allelically imbalanced genes is also enriched for these same cancer-related functions. By comparing the transcriptomic perturbations observed in one patient to his underlying normal and tumor genomes, we find that allelic imbalance in the tumor is associated with copy number mutations and that copy number mutations are, in turn, strongly associated with changes in transcript abundance. These results support a model in which allele-specific deletions and duplications drive allele-specific changes in gene expression in the developing tumor.

  4. Analysis of APC allelic imbalance/loss of heterozygosity and APC protein expression in cutaneous squamous cell carcinomas.

    LENUS (Irish Health Repository)

    Gray, Sarah E

    2012-02-01

    BACKGROUND: The adenomatous polyposis coli (APC) gene is a tumor suppressor gene which is mutated in the hereditary disease, familial adenomatous polyposis (FAP). Somatic mutations of the APC gene have also been identified in the majority of sporadic colorectal carcinomas, and mutation of the APC gene appears to be an early step in the initiation of colon cancer. Loss of heterozygosity (LOH) of APC has been described in a variety of other cancer types, including renal cell carcinoma, gastric cancer, non-small cell lung cancer, endometrial cancer and oral squamous cell carcinomas (SCC). AIM: To determine the role played by APC gene in the genesis of cutaneous SCC. MATERIALS AND METHODS: Allelic imbalance\\/loss of heterozygosity (AI\\/LOH) was examined in twenty-two histologically confirmed cutaneous squamous cell carcinomas (SCC) using microsatellite markers, proximal to the APC gene. Immunohistochemical analysis of APC protein expression was also examined in the cutaneous SCC. RESULTS: AI\\/LOH was detected in 60% of the SCC samples using D5S346 marker (proximal to the APC gene). Ninty-five percent of the SCC samples showed positive reduced APC expression, however the localization of the APC protein was abnormal. CONCLUSION: The abnormal expression of APC suggests that APC gene may play a role in cutaneous SCC development.

  5. Allelic imbalance in hereditary and sporadic prostate cancer.

    NARCIS (Netherlands)

    Verhage, B.; Houwelingen, K.P. van; Ruijter, T.E.G.; Kiemeney, L.A.L.M.; Schalken, J.A.

    2003-01-01

    BACKGROUND: In this study, we evaluate the pattern of allelic imbalance (AI) in both sporadic prostate cancer (SPC) and hereditary prostate cancer (HPC) at loci that frequently show allelic imbalance in sporadic prostate cancer, or are believed to have a putative role in the disease. METHODS: DNA ob

  6. Frequent allelic imbalance but infrequent microsatellite instability in gastric lymphoma

    NARCIS (Netherlands)

    Hoeve, M A; Ferreira Mota, S C; Schuuring, E; de Leeuw, W J; Chott, A; Meijerink, J P; Kluin, P M; van Krieken, J H

    1999-01-01

    Specific defects in DNA repair pathways are reflected by DNA microsatellite instability (MSI) and play an important role in carcinogenesis. Reported frequencies in gastric non-Hodgkin's lymphomas (NHL) vary from 14% to as high as 90%. Another form of genetic instability in tumours is allelic imbalan

  7. Prostate Cancer Aggressiveness Locus on Chromosome 7832-q33 Identified by Linkage and Allelic Imbalance Studies

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    Phillippa J. Neville

    2002-01-01

    Full Text Available The biologic aggressiveness of prostate tumors is an important indicator of prognosis. Chromosome 7g32-q33 was recently reported to show linkage to more aggressive prostate cancer, based on Gleason score, in a large sibling pair study. We report confirmation and narrowing of the linked region using finer-scale genotyping. We also report a high frequency of allelic imbalance. (AI defined within this locus in a series of 48 primary prostate tumors from men unselected for family history or disease status. The highest frequency of AI was observed with adjacent markers D7S2531. (52% and D7S1804. (36%. These two markers delineated a common region of AI, with 24 tumors exhibiting interstitial AI involving one or both markers. The 1.1-Mb candidate region contains relatively few transcripts. Additionally, we observed positive associations between interstitial AI at D7S1804 and early age at diagnosis. (P=.03 as well as a high combined Gleason score and tumor stage. (P=.06. Interstitial AI at D7S2531 was associated with a positive family history of prostate cancer. (P=.05. These data imply that we have localized a prostate cancer tumor aggressiveness loci to chromosome 7832-q33 that is involved in familial and nonfamilial forms of prostate cancer.

  8. Identification of allelic imbalance with a statistical model for subtle genomic mosaicism.

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    Rui Xia

    2014-08-01

    Full Text Available Genetic heterogeneity in a mixed sample of tumor and normal DNA can confound characterization of the tumor genome. Numerous computational methods have been proposed to detect aberrations in DNA samples from tumor and normal tissue mixtures. Most of these require tumor purities to be at least 10-15%. Here, we present a statistical model to capture information, contained in the individual's germline haplotypes, about expected patterns in the B allele frequencies from SNP microarrays while fully modeling their magnitude, the first such model for SNP microarray data. Our model consists of a pair of hidden Markov models--one for the germline and one for the tumor genome--which, conditional on the observed array data and patterns of population haplotype variation, have a dependence structure induced by the relative imbalance of an individual's inherited haplotypes. Together, these hidden Markov models offer a powerful approach for dealing with mixtures of DNA where the main component represents the germline, thus suggesting natural applications for the characterization of primary clones when stromal contamination is extremely high, and for identifying lesions in rare subclones of a tumor when tumor purity is sufficient to characterize the primary lesions. Our joint model for germline haplotypes and acquired DNA aberration is flexible, allowing a large number of chromosomal alterations, including balanced and imbalanced losses and gains, copy-neutral loss-of-heterozygosity (LOH and tetraploidy. We found our model (which we term J-LOH to be superior for localizing rare aberrations in a simulated 3% mixture sample. More generally, our model provides a framework for full integration of the germline and tumor genomes to deal more effectively with missing or uncertain features, and thus extract maximal information from difficult scenarios where existing methods fail.

  9. Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI frequently occur together in tumor cells.

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    Junichi Soh

    Full Text Available BACKGROUND: Activating mutations in one allele of an oncogene (heterozygous mutations are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI has been observed in tumors and cell lines harboring mutations of oncogenes. METHODOLOGY/PRINCIPAL FINDINGS: We determined 1 mutational status, 2 copy number gains (CNGs and 3 relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20% in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1 MASI with CNG, either complete or partial; and 2 MASI without CNG (uniparental disomy; UPD, due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75% and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58%, was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival. CONCLUSIONS: MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.

  10. FREQUENT ALLELIC IMBALANCE AND CYTOGENETIC DELETION ON THE SHORT ARM OF CHROMOSOME 1 IN NASOPHARYNGEAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    黄铁军; 黄必军; 张林杰; 梁启万; 方燕

    2004-01-01

    Objective: To construct a fine map of the loss of chromosome lpter-p36.11 region in nasopharyngeal carcinoma (NPC) using PCR-LOH technique. Methods:DNA extracted from separated cancerous cells and their mated noncancerous lymphocytes from 47 cases of NPC biopsies were analyzed by means of PCR-LOH to detect 20loci spanning chromosome lpter-p36.11 region in NPC.Results: In 47 NPC cases, 37 (82.2%) cases showed at least one loci LOH. The highest frequency of less of heterozygosity (LOH) at all 20 loci was found at loci DIS234(50. 0%) on lp36.13 and loci DIS2644 (37.5%) on lp36.22.There was a statistically significant difference betweenDIS234 LOH frequency (60%, 9/15) in early stage and that (50. 0%, 8/16) in advanced stage (P>0.05). Of all 20 STSs (sequence tqgged-site, STS), DIS243 (37.5%) and DIS199(30.2%) showed the highest frequency of MI (microsatellite instability) on lp36.33 and lp36.21, respectively. In addition,several cases showed a contiguous stretch of allelic loss in a different level. Conclusion: Two minimal deletion regions (MDR) on the short arm of chromosome 1 were seated at lp36.13 (DIS234, 2.0 cm) and lp36.22 (DIS436-DIS2644, 6.3cm) respectively, indicating that one or more candidate tumor suppressor gene (TSG) in the two regions may be involved in NPC pathogenesis in an early clinical stage.

  11. Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents

    DEFF Research Database (Denmark)

    Birkbak, Nicolai J.; Wang, Zhigang C.; Kim, Ji-Young

    2012-01-01

    with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of NtAI forecast a better initial response. We found an inverse relationship between BRCA1 expression and NtAI in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation...

  12. DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status

    DEFF Research Database (Denmark)

    Weiner Lachmi, Karin; Lin, Ling; Kornum, Birgitte Rahbek;

    2012-01-01

    The association of narcolepsy-cataplexy, a sleep disorder caused by the loss of hypocretin/orexin neurons in the hypothalamus, with DQA1*01:02-DQB1*06:02 is one of the tightest known single-allele human leukocyte antigen (HLA) associations. In this study, we explored genome-wide expression...... in peripheral white blood cells of 50 narcolepsy versus 47 controls (half of whom were DQB1*06:02 positive) and observed the largest differences between the groups in the signal from HLA probes. Further studies of HLA-DQ expression (mRNA and protein in a subset) in 125 controls and 147 narcolepsy cases did...... indicate that allelic dosage is transmitted into changes in heterodimer availability, a phenomenon that may explain the increased risk for narcolepsy in DQB1*06:02 homozygotes versus heterozygotes....

  13. How the Number of Alleles Influences Gene Expression

    Science.gov (United States)

    Hat, Beata; Paszek, Pawel; Kimmel, Marek; Piechor, Kazimierz; Lipniacki, Tomasz

    2007-07-01

    The higher organisms, eukaryotes, are diploid and most of their genes have two homological copies (alleles). However, the number of alleles in a cell is not constant. In the S phase of the cell cycle all the genome is duplicated and then in the G2 phase and mitosis, which together last for several hours, most of the genes have four copies instead of two. Cancer development is, in many cases, associated with a change in allele number. Several genetic diseases are caused by haploinsufficiency: Lack of one of the alleles or its improper functioning. In the paper we consider the stochastic expression of a gene having a variable number of copies. We applied our previously developed method in which the reaction channels are split into slow (connected with change of gene state) and fast (connected with mRNA/protein synthesis/decay), the later being approximated by deterministic reaction rate equations. As a result we represent gene expression as a piecewise deterministic time-continuous Markov process, which is further related with a system of partial differential hyperbolic equations for probability density functions (pdfs) of protein distribution. The stationary pdfs are calculated analytically for haploidal gene or numerically for diploidal and tetraploidal ones. We distinguished nine classes of simultaneous activation of haploid, diploid and tetraploid genes. This allows for analysis of potential consequences of gene duplication or allele loss. We show that when gene activity is autoregulated by a positive feedback, the change in number of gene alleles may have dramatic consequences for its regulation and may not be compensated by the change of efficiency of mRNA synthesis per allele.

  14. Germline allele-specific expression of DAPK1 in chronic lymphocytic leukemia.

    Directory of Open Access Journals (Sweden)

    Quan-Xiang Wei

    Full Text Available We previously reported a rare germline variant (c.1-6531 that resulted in allele-specific expression (ASE of death-associated protein kinase 1 (DAPK1 and predisposition to chronic lymphocytic leukemia (CLL. We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of DAPK1. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE with MALDI-TOF mass spectrometry, and detected germline DAPK1 ASE in 17 out of 120 (14.2% CLL patients associated with a trend towards younger age at diagnosis. ASE was absent in 63 healthy controls. Germline cells of CLL patients with ASE showed increased levels of DNA methylation in the promoter region, however, neither genetic nor further epigenetic aberrations could be identified in the DAPK1 5' upstream regulatory region, within distinct exons or in the 3'-UTR. We identified B-lymphoid malignancy related cell line models harboring allelic imbalance and found that allele-specific methylation in DAPK1 is associated with ASE. Our data indicate that ASE at the DAPK1 gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL.

  15. RNA-FISH to analyze allele-specific expression.

    Science.gov (United States)

    Braidotti, G

    2001-01-01

    One of the difficulties associated with the analysis of imprinted gene expression is the need to distinguish RNA synthesis occurring at the maternal vs the paternally inherited copy of the gene. Most of the techniques used to examine allele-specific expression exploit naturally occurring polymorphisms and measure steady-state levels of RNA isolated from a pool of cells. Hence, a restriction fragment length polymorphism (RFLP) an be exploited in a heterozygote, by a reverse transcriptase polymerase chain reaction (RT-PCR)- based procedure, to analyze maternal vs paternal gene expression. The human IGF2R gene was analyzed in this way. Smrzka et al. (1) were thus able to show that the IGF2R gene possesses a hemimethylated, intronic CpG island analogous to the mouse imprinting box. However, IGF2R mRNA was detected that possessed the RFLP from both the maternal and paternal alleles in all but one of the 70 lymphoblastoid samples. (The one monoallelic sample reactivated its paternal allele with continued cell culturing.) It was concluded that monoallelic expression of the human gene is a polymorphic trait occurring in a small minority of all tested samples (reviewed in refs. 2,3). Although this is a sound conclusion, the question remains: Is the human IGF2R gene imprinted?

  16. High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta

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    Clark Taane G

    2010-04-01

    Full Text Available Abstract Background Imprinted genes show expression from one parental allele only and are important for development and behaviour. This extreme mode of allelic imbalance has been described for approximately 56 human genes. Imprinting status is often disrupted in cancer and dysmorphic syndromes. More subtle variation of gene expression, that is not parent-of-origin specific, termed 'allele-specific gene expression' (ASE is more common and may give rise to milder phenotypic differences. Using two allele-specific high-throughput technologies alongside bioinformatics predictions, normal term human placenta was screened to find new imprinted genes and to ascertain the extent of ASE in this tissue. Results Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted gene ZNF331 in human placenta. Two potential differentially methylated regions (DMRs were found in the vicinity of ZNF331. None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed for PHACTR2, a neighbour of the imprinted PLAGL1 gene. ASE was detected for two or more individuals in 39 candidate genes (18%. Conclusions Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes

  17. Allele specific expression in worker reproduction genes in the bumblebee Bombus terrestris

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    Harindra E. Amarasinghe

    2015-07-01

    Full Text Available Methylation has previously been associated with allele specific expression in ants. Recently, we found methylation is important in worker reproduction in the bumblebee Bombus terrestris. Here we searched for allele specific expression in twelve genes associated with worker reproduction in bees. We found allele specific expression in Ecdysone 20 monooxygenase and IMP-L2-like. Although we were unable to confirm a genetic or epigenetic cause for this allele specific expression, the expression patterns of the two genes match those predicted for imprinted genes.

  18. Imbalance between the expression dosages of X-chromosome and autosomal genes in mammalian oocytes.

    Science.gov (United States)

    Fukuda, Atsushi; Tanino, Motohiko; Matoba, Ryo; Umezawa, Akihiro; Akutsu, Hidenori

    2015-09-15

    Oocytes have unique characteristics compared with other cell types. In mouse and human oocytes, two X chromosomes are maintained in the active state. Previous microarray studies have shown that the balance of the expression state is maintained in haploid oocytes. Here, we investigated transcripts using RNA-sequence technology in mouse and human oocytes. The median expression ratio between X chromosome and autosomal genes (X:A) in immature mouse oocytes increased as the gene expression levels increased, reaching a value of 1. However, the ratio in mature oocytes was under 1 for all expression categories. Moreover, we observed a markedly low ratio resulting from the bimodal expression patterns of X-linked genes. The low X:A expression ratio in mature oocyte was independent of DNA methylation. While mature human oocytes exhibited a slightly low X:A expression ratio, this was the result of the skewed high frequency of lowly expressed X-linked genes rather than the bimodal state. We propose that this imbalance between the expression dosages of X-chromosome and autosomal genes is a feature of transcripts in mammalian oocytes lacking X-chromosome inactivation.

  19. Allelic-specific expression in relation to Bombyx mori resistance to Bt toxin.

    Science.gov (United States)

    Chen, Yazhou; Li, Muwang; Islam, Iftakher; You, Lang; Wang, Yueqiang; Li, Zhiqian; Ling, Lin; Zeng, Baosheng; Xu, Jun; Huang, Yongping; Tan, Anjiang

    2014-11-01

    Understanding the mechanism of Bt resistance is one of the key elements of the effective application of Bt in pest control. The lepidopteran model insect, the silkworm, demonstrates qualities that make it an ideal species to use in achieving this understanding. We screened 45 strains of silkworm (Bombyx mori) using a Cry1Ab toxin variant. The sensitivity levels of the strains varied over a wide range. A resistant strain (P50) and a phylogenetically related susceptible strain (Dazao) were selected to profile the expressions of 12 Bt resistance-related genes. The SNPs in these genes were detected based on EST analysis and were validated by allelic-specific PCR. A comparison of allelic-specific expression between P50 and Dazao showed that the transcript levels of heterozygous genes containing two alleles rather than an imbalanced allelic expression contribute more to the resistance of P50 against Bt. The responses of the allelic-specific expression to Bt in hybrid larvae were then investigated. The results showed that the gene expression pattern of an ATP-binding cassette transporter C2 (ABCC2) and an aminopeptidase N (APN3), changed in an allelic-specific manner, with the increase of the resistant allele expression correlated with larval survival. The results suggest that a trans-regulatory mechanism in ABCC2 and APN3 allelic-specific expression is involved in the insect's response to the Bt toxin. The potential role of allelic-specific gene regulation in insect resistance to Bt toxins is discussed.

  20. Expression and loss of alleles in cultured mouse embryonic fibroblasts and stem cells carrying allelic fluorescent protein genes

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    Stringer Saundra L

    2006-10-01

    Full Text Available Abstract Background Loss of heterozygosity (LOH contributes to many cancers, but the rate at which these events occur in normal cells of the body is not clear. LOH would be detectable in diverse cell types in the body if this event were to confer an obvious cellular phenotype. Mice that carry two different fluorescent protein genes as alleles of a locus would seem to be a useful tool for addressing this issue because LOH would change a cell's phenotype from dichromatic to monochromatic. In addition, LOH caused by mitotic crossing over might be discernable in tissues because this event produces a pair of neighboring monochromatic cells that are different colors. Results As a step in assessing the utility of this approach, we derived primary embryonic fibroblast populations and embryonic stem cell lines from mice that carried two different fluorescent protein genes as alleles at the chromosome 6 locus, ROSA26. Fluorescence activated cell sorting (FACS showed that the vast majority of cells in each line expressed the two marker proteins at similar levels, and that populations exhibited expression noise similar to that seen in bacteria and yeast. Cells with a monochromatic phenotype were present at frequencies on the order of 10-4 and appeared to be produced at a rate of approximately 10-5 variant cells per mitosis. 45 of 45 stably monochromatic ES cell clones exhibited loss of the expected allele at the ROSA26 locus. More than half of these clones retained heterozygosity at a locus between ROSA26 and the centromere. Other clones exhibited LOH near the centromere, but were disomic for chromosome 6. Conclusion Allelic fluorescent markers allowed LOH at the ROSA26 locus to be detected by FACS. LOH at this locus was usually not accompanied by LOH near the centromere, suggesting that mitotic recombination was the major cause of ROSA26 LOH. Dichromatic mouse embryonic cells provide a novel system for studying genetic/karyotypic stability and factors

  1. Quantification of allele-specific expression of a gene encoding strawberry polygalacturonase-inhibiting protein (PGIP) using Pyrosequencing((TM))

    NARCIS (Netherlands)

    Schaart, J.G.; Mehli, L.; Schouten, H.J.

    2005-01-01

    Recent studies indicate that allele-specific differences in gene expression are a common phenomenon. The extent to which differential allelic expression exists might be underestimated, due to the limited accuracy of the methods used so far. To demonstrate allele-specific expression, we investigated

  2. Accurate quantitation of allele-specific expression patterns by analysis of DNA melting

    OpenAIRE

    Jeong, Sangkyun; Hahn, Yoonsoo; Rong, Qi; Pfeifer, Karl

    2007-01-01

    Epigenetic and genetic mechanisms can result in large differences in expression levels of the two alleles in a diploid organism. Furthermore, these differences may be critical to phenotypic variations among individuals. In this study, we present a novel procedure and algorithm to precisely and accurately quantitate the relative expression of each allele. This method uses the differential melting properties of DNAs differing at even a single base pair. By referring to the melting characteristi...

  3. Reduced expression of the normal DMPK allele in a congenital DM patient

    Energy Technology Data Exchange (ETDEWEB)

    Funanage, V.L.; Carango, P.; Moses, R.M.; Marks, H.G. [Alfred I. duPont Institute, Wilmington, DE (United States)

    1994-09-01

    Both adult-onset and congenital myotonic dystrophy (DM) are autosomal dominant disorders caused by triplet repeat expansions within the 3{prime} untranslated region of the DM protein kinase (DMPK) gene. The size of the repeat region shows a positive correlation with disease severity; in general, the triplet repeat expansions in congenital DM patients are larger than those found in adult DM individuals. In an adult DM patient, the expanded allele of 133 repeats reduced both the synthesis and processing of DMPK mRNA, whereas expression from the unexpanded allele remained unaffected. However, in both muscle and skin tissues from a congenital DM individual, DMPK mRNA expression from the unexpanded allele was also reduced. This reduced expression was maintained in fibroblasts cultured from a skin biospy of the patient; however, normal expression of the unexpanded allele occurred in cultured myoblasts established from this patient`s muscle biopsy. To determine if the expanded repeat exerts a trans effect on DMPK gene expression, we have separated the normal and mutant DMPK alleles from the cogenital DM skin fibroblasts by somatic cell hybridization. Hybrid clones containing only the normal DMPK gene still produced reduced levels of DMPK mRNA, indicating that the reduced expression from the normal allele is due to a cis effect. Cultured skin fibroblasts from the congenital DM patient were exposed to 5-azacytidine to determine if demethylation of the DMPK gene could restore proper expression of the normal allele. We are currently analyzing DMPK mRNA levels in these cells and determining if a difference in the methylation patterns of the normal DMPK alleles from adult and congenital DM patients accounts for this effect.

  4. SYSTEMIC IMBALANCE OF ESSENTIAL METALS AND CARDIAC GENE EXPRESSION IN RATS FOLLOWING ACUTE PULMONARY ZINC EXPOSURE

    Science.gov (United States)

    We have recently demonstrated that PM containing water-soluble zinc may cause cardiac injury following pulmonary exposure. To investigate if pulmonary zinc exposure causes systemic metal imbalance and direct cardiac effects, we intratracheally (IT) instilled male Wistar Kyoto (WK...

  5. Analysis of FBN1 allele expression by dermal fibroblasts from Marfan syndrome patients

    Energy Technology Data Exchange (ETDEWEB)

    Putman, E.A.; Cao, S.N.; Milewicz, D.M. [Univ. of Texas Medical School, Houston, TX (United States)

    1994-09-01

    Screening for mutations in the FBN1 cDNA from Marfan patient cell strains has detected mutations in only 10-15% of patients. In an attempt to explain this poor detection rate, we examined FBN1 allele expression and fibrillin synthesis by 26 cell strains from Marfan patients. DNA from the patients and 10 controls was assessed for the presence of a polymorphic Rsa I restriction site in the 3{prime} untranslated region of the FBN1 gene. Twelve of 26 patient and 5 of 10 control DNAs were heterozygous. Fibroblast RNA from the heterozygous cell strains was reverse-transcribed and subsequently PCR amplified using a [{sup 32}P]-labelled primer, digested with Rsa I and analyzed. Although 3 samples showed no transcript from one allele by ethidium bromide staining, a Betagen scanner detected low levels (10-15%) of that allele. In addition, there was unequal expression of the two alleles in three other patients; for example, only 30% expression from one allele. The remaining patients and the controls had equal expression of each allele. Fibrillin protein synthesis by fibroblasts from these heterozygous patients was also examined. After a 30 minute pulse with [{sup 35}S]-cysteine, cell lysates were collected and proteins analyzed by SDS-PAGE. The amount of fibrillin produced relative to a reference protein was determined using a Betagen scanner. Fibrillin protein synthesis was reduced in 2 of the 3 patients with very low RNA production from one of the FBN1 alleles. All other Marfan and control cell strains showed normal amounts of fibrillin synthesized. The low expression levels from one allele may contribute to, but not fully account for, the low detection rate of FBN1 mutations. Interestingly, protein synthesis levels were not affected in 4 of 6 cell strains demonstrating low levels of RNA expression.

  6. Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2

    Directory of Open Access Journals (Sweden)

    Sinilnikova Olga

    2011-05-01

    Full Text Available Abstract Background The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether CHEK2 was subject to DAE in lymphoblastoid cell lines (LCLs from high-risk breast cancer patients for whom no mutation in BRCA1 or BRCA2 had been identified. Methods We implemented an assay based on high-resolution melting (HRM curve analysis and developed an analysis tool for DAE assessment. Results We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs. Conclusions Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.

  7. Low and high expressing alleles of the LMNA gene: implications for laminopathy disease development.

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    Sofía Rodríguez

    Full Text Available Today, there are at least a dozen different genetic disorders caused by mutations within the LMNA gene, and collectively, they are named laminopathies. Interestingly, the same mutation can cause phenotypes with different severities or even different disorders and might, in some cases, be asymptomatic. We hypothesized that one possible contributing mechanism for this phenotypic variability could be the existence of high and low expressing alleles in the LMNA locus. To investigate this hypothesis, we developed an allele-specific absolute quantification method for lamin A and lamin C transcripts using the polymorphic rs4641(C/TLMNA coding SNP. The contribution of each allele to the total transcript level was investigated in nine informative human primary dermal fibroblast cultures from Hutchinson-Gilford progeria syndrome (HGPS and unaffected controls. Our results show differential expression of the two alleles. The C allele is more frequently expressed and accounts for ∼70% of the lamin A and lamin C transcripts. Analysis of samples from six patients with Hutchinson-Gilford progeria syndrome showed that the c.1824C>T, p.G608G mutation is located in both the C and the T allele, which might account for the variability in phenotype seen among HGPS patients. Our method should be useful for further studies of human samples with mutations in the LMNA gene and to increase the understanding of the link between genotype and phenotype in laminopathies.

  8. Myotonic Dystrophy: Increased expression of the normal allele in CDM infants muscle

    Energy Technology Data Exchange (ETDEWEB)

    Radvanyi, H.H.; Gourdon, G.; Junien, C. [Inserm U, Paris (France)]|[Universite Rene Descartes, Paris (France)

    1994-09-01

    Myotonic dystrophy (DM) is an autosomal dominant multisystemic disorder characterized by a highly variable clinical phenotype. The mutation has been identified as an unstable trinucleotide CTG repeat in the 3{prime} untranslated region of the myotonin-protein kinase (MT-PK) gene. Congenital myotonic dystrophy (CDM), which represents the most severe phenotype, is exclusively maternally inherited. Recent studies, analysis by Northern blots and RT-PCR provided apparently conflicting results on the mutated allele expression in samples from congenitally affected children. The level of expression of the mutant allele depends on the extent of the repeat in the adult form and is no longer expressed when over 800-1300 repeats, whether in adult forms or in CDM. Could this decrease account for the late onset forms? However, the differences between the two phenotypes cannot be explained by the same mechanism. Alternatively, these differences could be due to differences in expression of the normal allele. We analyzed by quantitative RT-PCR the expression of the MT-PK gene in muscle samples from four CDM infants and two aged-matched normal controls. In two of these, the mutant allele (3.3 and 8 kb) was undetectable on Northern blots. We observed an increased expression of the MT-PK gene (10- to 20-fold) in tissues of severely affected congenital patients which can be attributed to the normal allele. Since expression of the normal allele is either normal or slightly decreased in the adult form, the dramatic increase in the congenital form could reflect a disturbance in muscle differentiation. Expression studies of MT-PK at different stages of development and, especially after the 20th week, are therefore required.

  9. Parental genome dosage imbalance deregulates imprinting in Arabidopsis.

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    Pauline E Jullien

    2010-03-01

    Full Text Available In mammals and in plants, parental genome dosage imbalance deregulates embryo growth and might be involved in reproductive isolation between emerging new species. Increased dosage of maternal genomes represses growth while an increased dosage of paternal genomes has the opposite effect. These observations led to the discovery of imprinted genes, which are expressed by a single parental allele. It was further proposed in the frame of the parental conflict theory that parental genome imbalances are directly mirrored by antagonistic regulations of imprinted genes encoding maternal growth inhibitors and paternal growth enhancers. However these hypotheses were never tested directly. Here, we investigated the effect of parental genome imbalance on the expression of Arabidopsis imprinted genes FERTILIZATION INDEPENDENT SEED2 (FIS2 and FLOWERING WAGENINGEN (FWA controlled by DNA methylation, and MEDEA (MEA and PHERES1 (PHE1 controlled by histone methylation. Genome dosage imbalance deregulated the expression of FIS2 and PHE1 in an antagonistic manner. In addition increased dosage of inactive alleles caused a loss of imprinting of FIS2 and MEA. Although FIS2 controls histone methylation, which represses MEA and PHE1 expression, the changes of PHE1 and MEA expression could not be fully accounted for by the corresponding fluctuations of FIS2 expression. Our results show that parental genome dosage imbalance deregulates imprinting using mechanisms, which are independent from known regulators of imprinting. The complexity of the network of regulations between expressed and silenced alleles of imprinted genes activated in response to parental dosage imbalance does not support simple models derived from the parental conflict hypothesis.

  10. Upregulated Expression of microRNA-16 Correlates with Th17/Treg Cell Imbalance in Patients with Rheumatoid Arthritis.

    Science.gov (United States)

    Wu, Yuan-Hao; Liu, Wei; Xue, Bin; Zhang, Lei; Liu, Xiao-Ya; Liu, Bin; Wang, Yi; Cai, Yue; Duan, Ran

    2016-12-01

    To explore the correlation between miR-16 expression in T cells of peripheral blood mononuclear cells (PBMCs) and Th17/Treg imbalance in rheumatoid arthritis (RA) patients. Forty RA patients were recruited as the case group and further grouped as active RA and inactive RA groups; 21 healthy individuals were selected as the control group. Th17 and Treg were measured by flow cytometry, and their related cytokines were measured by FlowCytomix. RORγt, FoxP3 mRNA, and miR-16 expression in T cells was determined by real-time quantitative polymerase chain reaction. Western blotting was performed to measure RORγt and FoxP3 protein expression. RA patients showed upregulated Th17 and RORγt mRNA and protein expression compared with the controls (all p Treg and FoxP3 mRNA and protein expression compared with inactive RA patients and controls (all p Treg-related cytokines were lower in active RA patients than in controls (all p Treg cells of PBMCs (both p Treg cells was positively related with FoxP3 mRNA expression (both p Treg cells of PBMCs in RA patients was closely associated with the expression of RORγt and FoxP3. MiR-16 may be involved in Th17/Treg imbalance of RA patients by affecting the expression of RORγt and FoxP3.

  11. Allelic imbalance and cytogenetic deletion of 1p in colorectal adenomas: a target region identified between DIS199 and DIS234

    DEFF Research Database (Denmark)

    Bomme, L; Heim, S; Bardi, G;

    1998-01-01

    centromere 1 signals were invariably found. In the cases hybridized with the 1p-telomeric probe, we found the same frequencies of telomeric and centromeric signals, in agreement with the interpretation that the deletions were interstitial. One of the 53 adenomas had genomic instability, seen as new alleles...

  12. Allelic expression analysis of the osteoarthritis susceptibility locus that maps to MICAL3

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    Ratnayake Madhushika

    2012-03-01

    Full Text Available Abstract Background A genome-wide association scan with subsequent replication study that involved over 67,000 individuals of European ancestry has produced evidence of association of single nucleotide polymorphism rs2277831 to primary osteoarthritis (OA with a P-value of 2.9 × 10-5. rs2277831, an A/G transition, is located in an intron of MICAL3. This gene is located on chromosome 22q11.21 and the association signal encompasses two additional genes, BCL2L13 and BID. It is becoming increasingly apparent that many common complex traits are mediated by cis-acting regulatory polymorphisms that influence, in a tissue-specific manner, gene expression or transcript stability. Methods We used total and allelic expression analysis to assess whether the OA association to rs2277831 is mediated by an influence on MICAL3, BCL2L13 or BID expression. Using RNA extracted from joint tissues of 60 patients who had undergone elective joint replacement surgery, we assessed whether rs2277831 correlated with allelic expression of either of the three genes by: 1 measuring the expression of each gene by quantitative PCR and then stratifying the data by genotype at rs2277831 and 2 accurately discriminating and quantifying the mRNA synthesised from the alleles of OA patients using allelic-quantitative PCR. Results We found no evidence for a correlation between gene expression and genotype at rs2277831, with P-values of 0.09 for BCL2L13, 0.07 for BID and 0.33 for MICAL3. In the allelic expression analysis we observed several examples of significant (p BCL2L13 (P = 0.004, 2.09 at BID (P = 0.001 and the most extreme case being at MICAL3, with an allelic expression ratio of 5.47 (P = 0.001. However, there was no correlation observed between the pattern of allelic expression and the genotype at rs2277831. Conclusions In the tissues that we have studied, our data do not support our hypothesis that the association between rs2277831 and OA is due to the effect this SNP has on

  13. High-resolution analysis of parent-of-origin allelic expression in the Arabidopsis Endosperm.

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    Philip Wolff

    2011-06-01

    Full Text Available Genomic imprinting is an epigenetic phenomenon leading to parent-of-origin specific differential expression of maternally and paternally inherited alleles. In plants, genomic imprinting has mainly been observed in the endosperm, an ephemeral triploid tissue derived after fertilization of the diploid central cell with a haploid sperm cell. In an effort to identify novel imprinted genes in Arabidopsis thaliana, we generated deep sequencing RNA profiles of F1 hybrid seeds derived after reciprocal crosses of Arabidopsis Col-0 and Bur-0 accessions. Using polymorphic sites to quantify allele-specific expression levels, we could identify more than 60 genes with potential parent-of-origin specific expression. By analyzing the distribution of DNA methylation and epigenetic marks established by Polycomb group (PcG proteins using publicly available datasets, we suggest that for maternally expressed genes (MEGs repression of the paternally inherited alleles largely depends on DNA methylation or PcG-mediated repression, whereas repression of the maternal alleles of paternally expressed genes (PEGs predominantly depends on PcG proteins. While maternal alleles of MEGs are also targeted by PcG proteins, such targeting does not cause complete repression. Candidate MEGs and PEGs are enriched for cis-proximal transposons, suggesting that transposons might be a driving force for the evolution of imprinted genes in Arabidopsis. In addition, we find that MEGs and PEGs are significantly faster evolving when compared to other genes in the genome. In contrast to the predominant location of mammalian imprinted genes in clusters, cluster formation was only detected for few MEGs and PEGs, suggesting that clustering is not a major requirement for imprinted gene regulation in Arabidopsis.

  14. Allele-specific down-regulation of RPTOR expression induced by retinoids contributes to climate adaptations.

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    Chang Sun

    2010-10-01

    Full Text Available The mechanistic target of rapamycin (MTOR pathway regulates cell growth, energy homeostasis, apoptosis, and immune response. The regulatory associated protein of MTOR encoded by the RPTOR gene is a key component of this pathway. A previous survey of candidate genes found that RPTOR contains multiple SNPs with strong correlations between allele frequencies and climate variables, consistent with the action of selective pressures that vary across environments. Using data from a recent genome scan for selection signals, we honed in on a SNP (rs11868112 26 kb upstream to the transcription start site of RPTOR that exhibits the strongest association with temperature variables. Transcription factor motif scanning and mining of recently mapped transcription factor binding sites identified a binding site for POU class 2 homeobox 1 (POU2F1 spanning the SNP and an adjacent retinoid acid receptor (RAR binding site. Using expression quantification, chromatin immunoprecipitation (ChIP, and reporter gene assays, we demonstrate that POU2F1 and RARA do bind upstream of the RPTOR gene to regulate its expression in response to retinoids; this regulation is affected by the allele status at rs11868112 with the derived allele resulting in lower expression levels. We propose a model in which the derived allele influences thermogenesis or immune response by altering MTOR pathway activity and thereby increasing fitness in colder climates. Our results show that signatures of genetic adaptations can identify variants with functional effects, consistent with the idea that selection signals may be used for SNP annotation.

  15. Phenylalanine hydroxylase activity and expression in chicks subjected to phenylalanine imbalance or phenylalanine toxicity.

    Science.gov (United States)

    Lartey, F M; Austic, R E

    2009-04-01

    Experiments were performed to investigate the activity of hepatic Phe hydroxylase (PAH) and plasma amino acid concentrations under conditions of Phe imbalance or toxicity in chicks fed on experimental diets from 7 to 14 or 16 d of age. In experiment 1, Phe imbalance was created by adding 10% of a mixture of indispensable amino acids lacking Phe (IAA - Phe) to a basal diet containing 0.46% Phe. The activity of PAH was not significantly affected by the imbalance. Correcting the imbalance by adding 1.12% Phe to the diet prevented the growth impairment and increased the activity of PAH. In experiment 2, growth was reduced by the addition of excess (2%) Phe to the basal diet. Correcting the excess by adding the IAA - Phe to the diet prevented the growth reduction. The activity of PAH was not significantly affected by 2% Phe, but it increased in chicks fed the corrected diet. The levels of PAH mRNA were not affected by the dietary treatments. A factorial arrangement of treatments with 3 dietary levels of Phe (0.46, 1.58, and 2.46%) with or without the IAA - Phe was used in experiment 3. The effects on growth were similar to those of the same treatments in experiments 1 and 2. The addition of Phe significantly increased hepatic PAH activity, but there was no detectable main effect of the IAA - Phe and no interaction. Plasma Phe concentration was increased by dietary Phe and decreased by the IAA - Phe mixture. We conclude that hepatic PAH activity in chicks variably increases in response to Phe or a 10% dietary supplement of indispensable amino acids including Phe but does not increase in response to IAA - Phe when the amino acids are added to a diet that is marginally adequate in Phe. The increased activity does not involve changes in PAH mRNA. The effects of IAA - Phe on plasma Phe concentrations appear to be independent of hepatic PAH activity as measured in vitro.

  16. Identification of transcriptome SNPs for assessing allele-specific gene expression in a super-hybrid rice Xieyou9308.

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    Rongrong Zhai

    Full Text Available Hybridization, a common process in nature, can give rise to a vast reservoir of allelic variants. Combination of these allelic variants may result in novel patterns of gene action and is thought to contribute to heterosis. In this study, we analyzed genome-wide allele-specific gene expression (ASGE in the super-hybrid rice variety Xieyou9308 using RNA sequencing technology (RNA-Seq. We identified 9325 reliable single nucleotide polymorphisms (SNPs distributed throughout the genome. Nearly 68% of the identified polymorphisms were CT and GA SNPs between R9308 and Xieqingzao B, suggesting the existence of DNA methylation, a heritable epigenetic mark, in the parents and their F1 hybrid. Of 2793 identified transcripts with consistent allelic biases, only 480 (17% showed significant allelic biases during tillering and/or heading stages, implying that trans effects may mediate most transcriptional differences in hybrid offspring. Approximately 67% and 62% of the 480 transcripts showed R9308 allelic expression biases at tillering and heading stages, respectively. Transcripts with higher levels of gene expression in R9308 also exhibited R9308 allelic biases in the hybrid. In addition, 125 transcripts were identified with significant allelic expression biases at both stages, of which 74% showed R9308 allelic expression biases. R9308 alleles may tend to preserve their characteristic states of activity in the hybrid and may play important roles in hybrid vigor at both stages. The allelic expression of 355 transcripts was highly stage-specific, with divergent allelic expression patterns observed at different developmental stages. Many transcripts associated with stress resistance were differently regulated in the F1 hybrid. The results of this study may provide valuable insights into molecular mechanisms of heterosis.

  17. Ploidy mosaicism and allele-specific gene expression differences in the allopolyploid Squalius alburnoides

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    Matos Isa

    2011-12-01

    Full Text Available Abstract Background Squalius alburnoides is an Iberian cyprinid fish resulting from an interspecific hybridisation between Squalius pyrenaicus females (P genome and males of an unknown Anaecypris hispanica-like species (A genome. S. alburnoides is an allopolyploid hybridogenetic complex, which makes it a likely candidate for ploidy mosaicism occurrence, and is also an interesting model to address questions about gene expression regulation and genomic interactions. Indeed, it was previously suggested that in S. alburnoides triploids (PAA composition silencing of one of the three alleles (mainly of the P allele occurs. However, not a whole haplome is inactivated but a more or less random inactivation of alleles varying between individuals and even between organs of the same fish was seen. In this work we intended to correlate expression differences between individuals and/or between organs to the occurrence of mosaicism, evaluating if mosaics could explain previous observations and its impact on the assessment of gene expression patterns. Results To achieve our goal, we developed flow cytometry and cell sorting protocols for this system generating more homogenous cellular and transcriptional samples. With this set-up we detected 10% ploidy mosaicism within the S. alburnoides complex, and determined the allelic expression profiles of ubiquitously expressed genes (rpl8; gapdh and β-actin in cells from liver and kidney of mosaic and non-mosaic individuals coming from different rivers over a wide geographic range. Conclusions Ploidy mosaicism occurs sporadically within the S. alburnoides complex, but in a frequency significantly higher than reported for other organisms. Moreover, we could exclude the influence of this phenomenon on the detection of variable allelic expression profiles of ubiquitously expressed genes (rpl8; gapdh and β-actin in cells from liver and kidney of triploid individuals. Finally, we determined that the expression patterns

  18. Association of breast cancer risk with genetic variants showing differential allelic expression

    DEFF Research Database (Denmark)

    Hamdi, Yosr; Soucy, Penny; Adoue, Véronique

    2016-01-01

    in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage...... candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and....../or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating...

  19. Detection, Validation, and Downstream Analysis of Allelic Variation in Gene Expression

    Science.gov (United States)

    Ciobanu, Daniel C.; Lu, Lu; Mozhui, Khyobeni; Wang, Xusheng; Jagalur, Manjunatha; Morris, John A.; Taylor, William L.; Dietz, Klaus; Simon, Perikles; Williams, Robert W.

    2010-01-01

    Common sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control—or cis modulation—rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40–50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to ∼80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higher-order phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility. PMID:19884314

  20. Analysis of APC allelic imbalance/loss of heterozygosity and APC protein expression in cutaneous squamous cell carcinomas.

    LENUS (Irish Health Repository)

    Gray, Sarah E

    2011-05-01

    The adenomatous polyposis coli (APC) gene is a tumor suppressor gene which is mutated in the hereditary disease, familial adenomatous polyposis (FAP). Somatic mutations of the APC gene have also been identified in the majority of sporadic colorectal carcinomas, and mutation of the APC gene appears to be an early step in the initiation of colon cancer. Loss of heterozygosity (LOH) of APC has been described in a variety of other cancer types, including renal cell carcinoma, gastric cancer, non-small cell lung cancer, endometrial cancer and oral squamous cell carcinomas (SCC).

  1. Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs

    OpenAIRE

    Adoue, Veronique; Schiavi, Alicia; Light, Nicholas; Carlsson Almlöf, Jonas; Lundmark, Per; Ge, Bing; Kwan, Tony; Caron, Maxime; Rönnblom, Lars; Wang, Chuan; Chen, Shu-Huang; Goodall, Alison H; Cambien, Francois; Deloukas, Panos; Ouwehand, Willem H.

    2014-01-01

    Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified ...

  2. Allelic expression of mammalian imprinted genes in a matrotrophic lizard, Pseudemoia entrecasteauxii.

    Science.gov (United States)

    Griffith, Oliver W; Brandley, Matthew C; Belov, Katherine; Thompson, Michael B

    2016-03-01

    Genomic imprinting is a process that results in the differential expression of genes depending on their parent of origin. It occurs in both plants and live-bearing mammals, with imprinted genes typically regulating the ability of an embryo to manipulate the maternal provision of nutrients. Genomic imprinting increases the potential for selection to act separately on paternally and maternally expressed genes, which increases the number of opportunities that selection can facilitate embryonic control over maternal nutrient provision. By looking for imprinting in an independent matrotrophic lineage, the viviparous lizard Pseudemoia entrecasteauxii (Scincidae), we test the hypothesis that genomic imprinting facilitates the evolution of substantial placental nutrient transport to embryos (matrotrophy). We sequenced transcriptomes from the embryonic component of lizard placentae to determine whether there are parent-of-origin differences in expression of genes that are imprinted in mammals. Of these genes, 19 had sufficiently high expression in the lizard to identify polymorphisms in transcribed sequences. We identified bi-allelic expression in 17 genes (including insulin-like growth factor 2), indicating that neither allele was imprinted. These data suggest that either genomic imprinting has not evolved in this matrotrophic skink or, if it has, it has evolved in different genes to mammals. We outline how these hypotheses can be tested. This study highlights important differences between mammalian and reptile pregnancy and the absence of any shared imprinting genes reflects fundamental differences in the way that pregnancy has evolved in these two lineages.

  3. Allele-specific expression of the low density lipoprotein receptor gene

    Energy Technology Data Exchange (ETDEWEB)

    Minnich, A.; Lussier-Cacan, S.; Roy, M. [Clincial Research Institute of Montreal, Quebec (Canada)

    1994-09-01

    Approximately 60% of familial hypercholesterolemia (FH) in French Canadians is due to a > 10 kb deletion of the promoter region of the gene encoding the low density lipoprotein (LDL) receptor (LDL-R), allowing determination of the influence of a single LDL-R allele on phenotypic expression of FH. Normal allele haplotypes of approximately 250 heterozygotes were determined with 7 RFLPs. In vitro maximal LDL-R activity of blood lymphocytes from a subset of approximately 150 heterozygotes, measured by immunocytofluorometry, was significantly higher (20 to 30%) in subjects with LDL-R normal allele haplotype G (n=11), and O (n=7) compared to the most frequent haplotype F (n=43), while no differences were observed among F, E (n=11), and the 2 other most prevalent haplotypes (n=43). LDL-R mRNA in these lymphocytes was significantly elevated 2.3-, 1.7-, and 1.8- fold, in G, O, and E, respectively, compared to F, while no significant differences were apparent between F and the other two most frequent haplotyes. Large interindividual variability in lymphocyte LDL-R mRNA levels and activity was observed even among subjects with the same LDL-R normal allele haplotype. However, maximally induced lymphocyte LDL-R mRNA levels correlated poorly with levels measured in freshly isolated cells (n=14). Relative to haplotype F (n=47 women (W), 39 men (M)), mean plasma LDL cholesterol levels adjusted for age and apolipoprotein E genotype were 5-10% lower in men and women with haplotypes G (n=16 W, 12 M) and O (n=8 W, 6 M), and 20% lower in 7 W with haplotype E. These results suggest that (1) normal LDL-R allele haplotype G and O may contain sequence variations which confer relatively high gene expression and (2) environmental and genetic influences other than the LDL-R gene contribute substantially to variability in LDL-R expression and plasma LDL cholesterol levels in French Canadian FH heterozygotes.

  4. Recurrent RECQL4 Imbalance and Increased Gene Expression Levels Are Associated with Structural Chromosomal Instability in Sporadic Osteosarcoma

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    Georges Maire

    2009-03-01

    Full Text Available Osteosarcoma (OS is an aggressive bone tumor with complex abnormal karyotypes and a highly unstable genome, exhibiting both numerical- and structural-chromosomal instability (N- and S-CIN. Chromosomal rearrangements and genomic imbalances affecting 8q24 are frequent in OS. RECQL4 gene maps to this cytoband and encodes a putative helicase involved in the fidelity of DNA replication and repair. This protective genomic function of the protein is relevant because often patients with Rothmund-Thomson syndrome have constitutional mutations of RECQL4 and carry a very high risk of developing OS. To determine the relative level of expression of RECQL4 in OS, 18 sporadic tumors were studied by reverse transcription–polymerase chain reaction. All tumors overexpressed RECQL4 in comparison to control osteoblasts, and fluorescence in situ hybridization analysis of tumor DNA showed that expression levels were strongly copy number–dependent. Relative N- and S-CIN levels were determined by classifying copy number transitions within array comparative genomic hybridization profiles and by enumerating the frequency of break-apart fluorescence in situ hybridization within 8q24 using region-specific and control probes. Although there was no evidence that disruption of 8q24 in OS led to an elevated expression of RECQL4, there was a marked association between increased overall levels of S-CIN, determined by copy number transition frequency and higher levels of RECQL4.

  5. Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brain.

    Science.gov (United States)

    Perez, Julio D; Rubinstein, Nimrod D; Fernandez, Daniel E; Santoro, Stephen W; Needleman, Leigh A; Ho-Shing, Olivia; Choi, John J; Zirlinger, Mariela; Chen, Shau-Kwaun; Liu, Jun S; Dulac, Catherine

    2015-07-03

    The maternal and paternal genomes play different roles in mammalian brains as a result of genomic imprinting, an epigenetic regulation leading to differential expression of the parental alleles of some genes. Here we investigate genomic imprinting in the cerebellum using a newly developed Bayesian statistical model that provides unprecedented transcript-level resolution. We uncover 160 imprinted transcripts, including 41 novel and independently validated imprinted genes. Strikingly, many genes exhibit parentally biased--rather than monoallelic--expression, with different magnitudes according to age, organ, and brain region. Developmental changes in parental bias and overall gene expression are strongly correlated, suggesting combined roles in regulating gene dosage. Finally, brain-specific deletion of the paternal, but not maternal, allele of the paternally-biased Bcl-x, (Bcl2l1) results in loss of specific neuron types, supporting the functional significance of parental biases. These findings reveal the remarkable complexity of genomic imprinting, with important implications for understanding the normal and diseased brain.

  6. Identification of genes escaping X inactivation by allelic expression analysis in a novel hybrid mouse model.

    Science.gov (United States)

    Berletch, Joel B; Ma, Wenxiu; Yang, Fan; Shendure, Jay; Noble, William S; Disteche, Christine M; Deng, Xinxian

    2015-12-01

    X chromosome inactivation (XCI) is a female-specific mechanism that serves to balance gene dosage between the sexes whereby one X chromosome in females is inactivated during early development. Despite this silencing, a small portion of genes escape inactivation and remain expressed from the inactive X (Xi). Little is known about the distribution of escape from XCI in different tissues in vivo and about the mechanisms that control tissue-specific differences. Using a new binomial model in conjunction with a mouse model with identifiable alleles and skewed X inactivation we are able to survey genes that escape XCI in vivo. We show that escape from X inactivation can be a common feature of some genes, whereas others escape in a tissue specific manner. Furthermore, we characterize the chromatin environment of escape genes and show that expression from the Xi correlates with factors associated with open chromatin and that CTCF co-localizes with escape genes. Here, we provide a detailed description of the experimental design and data analysis pipeline we used to assay allele-specific expression and epigenetic characteristics of genes escaping X inactivation. The data is publicly available through the GEO database under ascension numbers GSM1014171, GSE44255, and GSE59779. Interpretation and discussion of these data are included in a previously published study (Berletch et al., 2015) [1].

  7. Association between high expression macrophage migration inhibitory factor (MIF) alleles and West Nile virus encephalitis.

    Science.gov (United States)

    Das, Rituparna; Loughran, Kerry; Murchison, Charles; Qian, Feng; Leng, Lin; Song, Yan; Montgomery, Ruth R; Loeb, Mark; Bucala, Richard

    2016-02-01

    Infection with mosquito-borne West Nile virus (WNV) is usually asymptomatic but can lead to severe WNV encephalitis. The innate cytokine, macrophage migration inhibitory factor (MIF), is elevated in patients with WNV encephalitis and promotes viral neuroinvasion and mortality in animal models. In a case-control study, we examined functional polymorphisms in the MIF locus in a cohort of 454 North American patients with neuroinvasive WNV disease and found patients homozygous for high-expression MIF alleles to be >20-fold (p=0.008) more likely to have WNV encephalitis. These data indicate that MIF is an important determinant of severity of WNV neuropathogenesis and may be a therapeutic target.

  8. Imbalances in prefrontal cortex CC-Homer1 versus CC-Homer2 expression promote cocaine preference.

    Science.gov (United States)

    Ary, Alexis W; Lominac, Kevin D; Wroten, Melissa G; Williams, Amy R; Campbell, Rianne R; Ben-Shahar, Osnat; von Jonquieres, Georg; Klugmann, Matthias; Szumlinski, Karen K

    2013-05-01

    Homer postsynaptic scaffolding proteins regulate forebrain glutamate transmission and thus, are likely molecular candidates mediating hypofrontality in addiction. Protracted withdrawal from cocaine experience increases the relative expression of Homer2 versus Homer1 isoforms within medial prefrontal cortex (mPFC). Thus, this study used virus-mediated gene transfer strategies to investigate the functional relevance of an imbalance in mPFC Homer1/2 expression as it relates to various measures of sensorimotor, cognitive, emotional and motivational processing, as well as accompanying alterations in extracellular glutamate in C57BL/6J mice. mPFC Homer2b overexpression elevated basal glutamate content and blunted cocaine-induced glutamate release within the mPFC, whereas Homer2b knockdown produced the opposite effects. Despite altering mPFC glutamate, Homer2b knockdown failed to influence cocaine-elicited conditioned place preferences, nor did it produce consistent effects on any other behavioral measures. In contrast, elevating the relative expression of Homer2b versus Homer1 within mPFC, by overexpressing Homer2b or knocking down Homer1c, shifted the dose-response function for cocaine-conditioned reward to the left, without affecting cocaine locomotion or sensitization. Intriguingly, both these transgenic manipulations produced glutamate anomalies within the nucleus accumbens (NAC) of cocaine-naive animals that are reminiscent of those observed in cocaine experienced animals, including reduced basal extracellular glutamate content, reduced Homer1/2 and glutamate receptor expression, and augmented cocaine-elicited glutamate release. Together, these data provide novel evidence in support of opposing roles for constitutively expressed Homer1 and Homer2 isoforms in regulating mPFC glutamate transmission in vivo and support the hypothesis that cocaine-elicited increases in the relative amount of mPFC Homer2 versus Homer1 signaling produces abnormalities in NAC glutamate

  9. DNA methylation and mRNA expression of HLA-DQA1 alleles in type 1 diabetes mellitus.

    Science.gov (United States)

    Cepek, Pavel; Zajacova, Marta; Kotrbova-Kozak, Anna; Silhova, Elena; Cerna, Marie

    2016-06-01

    Type 1 diabetes (T1D) belongs among polygenic multifactorial autoimmune diseases. The highest risk is associated with human leucocyte antigen (HLA) class II genes, including HLA-DQA1 gene. Our aim was to investigate DNA methylation of HLA-DQA1 promoter alleles (QAP) and correlate methylation status with individual HLA-DQA1 allele expression of patients with T1D and healthy controls. DNA methylation is one of the epigenetic modifications that regulate gene expression and is known to be shaped by the environment.Sixty one patients with T1D and 39 healthy controls were involved in this study. Isolated DNA was treated with sodium bisulphite and HLA-DQA1 promoter sequence was amplified using nested PCR. After sequencing, DNA methylation of HLA-DQA1 promoter alleles was analysed. Individual mRNA HLA-DQA1 relative allele expression was assessed using two different endogenous controls (PPIA, DRA). We have found statistically significant differences in HLA-DQA1 allele 02:01 expression (PPIA normalization, Pcorr = 0·041; DRA normalization, Pcorr = 0·052) between healthy controls and patients with T1D. The complete methylation profile of the HLA-DQA1 promoter was gained with the most methylated allele DQA1*02:01 and the least methylated DQA1*05:01 in both studied groups. Methylation profile observed in patients with T1D and healthy controls was similar, and no correlation between HLA-DQA1 allele expression and DNA methylation was found. Although we have not proved significant methylation differences between the two groups, detailed DNA methylation status and its correlation with expression of each HLA-DQA1 allele in patients with T1D have been described for the first time.

  10. Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression

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    Hanamura Ichiro

    2006-10-01

    Full Text Available Abstract Background A high proliferative capacity of tumor cells usually is associated with shortened patient survival. Disruption of the RB pathway, which is critically involved in regulating the G1 to S cell cycle transition, is a frequent target of oncogenic events that are thought to contribute to increased proliferation during tumor progression. Previously, we determined that p18INK4c, an essential gene for normal plasma cell differentiation, was bi-allelically deleted in five of sixteen multiple myeloma (MM cell lines. The present study was undertaken to investigate a possible role of p18INK4c in increased proliferation of myeloma tumors as they progress. Results Thirteen of 40 (33% human myeloma cell lines do not express normal p18INK4c, with bi-allelic deletion of p18 in twelve, and expression of a mutated p18 fragment in one. Bi-allelic deletion of p18, which appears to be a late progression event, has a prevalence of about 2% in 261 multiple myeloma (MM tumors, but the prevalence is 6 to10% in the 50 tumors with a high expression-based proliferation index. Paradoxically, 24 of 40 (60% MM cell lines, and 30 of 50 (60% MM tumors with a high proliferation index express an increased level of p18 RNA compared to normal bone marrow plasma cells, whereas this occurs in only five of the 151 (3% MM tumors with a low proliferation index. Tumor progression is often accompanied by increased p18 expression and an increased proliferation index. Retroviral-mediated expression of exogenous p18 results in marked growth inhibition in three MM cell lines that express little or no endogenous p18, but has no effect in another MM cell line that already expresses a high level of p18. Conclusion Paradoxically, although loss of p18 appears to contribute to increased proliferation of nearly 10% of MM tumors, most MM cell lines and proliferative MM tumors have increased expression of p18. Apart from a small fraction of cell lines and tumors that have inactivated

  11. Paramutation:A Heritable Change in Gene Expression by Allelic Interactions In Trans

    Institute of Scientific and Technical Information of China (English)

    Maike Stam

    2009-01-01

    Epigenetic gene regulation involves the stable propagation of gene activity states through mitotic,and sometimes even meiotic,cell divisions without changes in DNA sequence.Paramutation is an epigenetic phenomenon involving changes in gene expression that are stably transmitted through mitosis as well as meiosis.These heritable changes are mediated by in trans interactions between homologous DNA sequences on different chromosomes.During these in trans interactions,epigenetic information is transferred from one allele of a gene to another allele of the same gene,resulting in a change in gene expression.Although paramutation was initially discovered in plants,it has recently been observed in mammals as well,suggesting that the mechanisms underlying paramutation might be evolutionarily conserved.Recent findings point to a crucial role for small RNAs in the paramutation process.In mice,small RNAs appear sufficient to induce paramutation,whereas in maize,it seems not to be the only player in the process.In this review,potential mechanisms are discussed in relation to the various paramutation phenomena.

  12. Double Imbalance

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The government has been introducing a string of policies to stabilize the economy and cushion the impact of the global eco-nomic slowdown since October.These policies are generally deemed"timely"and"necessary,"but not a long-term cure for problems in China’s economy.Renowned economist Wu Jinglian says the country must address its"double imbalance"and further reform its economic growth mode.He made his comments at the First Annual Global Management Forum on December 6 in Shanghai.Excerptsf ollow:

  13. Assessing allele-specific expression across multiple tissues from RNA-seq read data

    Science.gov (United States)

    Pirinen, Matti; Lappalainen, Tuuli; Zaitlen, Noah A.; Dermitzakis, Emmanouil T.; Donnelly, Peter; McCarthy, Mark I.; Rivas, Manuel A.

    2015-01-01

    Motivation: RNA sequencing enables allele-specific expression (ASE) studies that complement standard genotype expression studies for common variants and, importantly, also allow measuring the regulatory impact of rare variants. The Genotype-Tissue Expression (GTEx) project is collecting RNA-seq data on multiple tissues of a same set of individuals and novel methods are required for the analysis of these data. Results: We present a statistical method to compare different patterns of ASE across tissues and to classify genetic variants according to their impact on the tissue-wide expression profile. We focus on strong ASE effects that we are expecting to see for protein-truncating variants, but our method can also be adjusted for other types of ASE effects. We illustrate the method with a real data example on a tissue-wide expression profile of a variant causal for lipoid proteinosis, and with a simulation study to assess our method more generally. Availability and implementation: http://www.well.ox.ac.uk/~rivas/mamba/. R-sources and data examples http://www.iki.fi/mpirinen/ Contact: matti.pirinen@helsinki.fi or rivas@well.ox.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25819081

  14. Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue

    Directory of Open Access Journals (Sweden)

    Broderick Gordon

    2012-09-01

    Full Text Available Abstract Background As Chronic Fatigue Syndrome (CFS has been known to follow Epstein-Bar virus (EBV and other systemic infections; our objective was to describe differences in immune activation in post-infective CFS (PI-CFS patients and recovered controls. We studied 301 adolescents prospectively over 24 months following the diagnosis of monospot-positive infectious mononucleosis (IM. We found an incidence of CFS at 6, 12 and 24 months of 13%, 7% and 4% respectively. Methods Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70, 13, 15, 17 and 23, IFN-γ, TNF-α and TNF-β in duplicate plasma samples available in bio-bank from 9 PI-CFS subjects and 12 recovered controls at 24 months post-infection. Results Standard comparative analysis indicated significant differences in IL-8 and 23 across subject groups. In constructing a linear classification model IL-6, 8 and 23 were selected by two different statistical approaches as discriminating features, with IL-1a, IL-2 and IFN-γ also selected in one model or the other. This supported an assignment accuracy of better than 80% at a confidence level of 0.95 into PI-CFS versus recovered controls. Conclusion These results suggest that co-expression patterns in as few as 5 cytokines associated with Th17 function may hold promise as a tool for the diagnosis of post-infectious CFS.

  15. Visualizing allele-specific expression in single cells reveals epigenetic mosaicism in an H19 loss-of-imprinting mutant.

    Science.gov (United States)

    Ginart, Paul; Kalish, Jennifer M; Jiang, Connie L; Yu, Alice C; Bartolomei, Marisa S; Raj, Arjun

    2016-03-01

    Imprinting is a classic mammalian epigenetic phenomenon that results in expression from a single parental allele. Imprinting defects can lead to inappropriate expression from the normally silenced allele, but it remains unclear whether every cell in a mutant organism follows the population average, which would have profound implications for human imprinting disorders. Here, we apply a new fluorescence in situ hybridization method that measures allele-specific expression in single cells to address this question in mutants exhibiting aberrant H19/Igf2 (insulin-like growth factor 2) imprinting. We show that mutant primary embryonic mouse fibroblasts are comprised of two subpopulations: one expressing both H19 alleles and another expressing only the maternal copy. Only in the latter cell population is Igf2 expression detected. Furthermore, the two subpopulations are stable in that cells do not interconvert between the two expression patterns. Combined small input methylation analysis and transcriptional imaging revealed that these two mutant subpopulations exhibit distinct methylation patterns at their imprinting control regions. Consistently, pharmacological inhibition of DNA methylation reduced the proportion of monoallelic cells. Importantly, we observed that the same two subpopulations are also present in vivo within murine cardiac tissue. Our results establish that imprinting disorders can display striking single-cell heterogeneity in their molecular phenotypes and suggest that such heterogeneity may underlie epigenetic mosaicism in human imprinting disorders.

  16. The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele.

    Science.gov (United States)

    Aubart, Mélodie; Gross, Marie-Sylvie; Hanna, Nadine; Zabot, Marie-Thérèse; Sznajder, Marc; Detaint, Delphine; Gouya, Laurent; Jondeau, Guillaume; Boileau, Catherine; Stheneur, Chantal

    2015-05-15

    Marfan syndrome is an autosomal dominant disorder mainly caused by mutations within FBN1 gene. The disease displays large variability in age of onset or severity and very poor phenotype/genotype correlations have been demonstrated. We investigated the hypothesis that phenotype severity could be related to the variable expression level of fibrillin-1 (FBN1) synthesized from the wild-type (WT) allele. Quantitative reverse-transcription and polymerase chain reaction was used to evaluate FBN1 levels in skin fibroblasts from 80 Marfan patients with premature termination codons and in skin fibroblasts from 80 controls. Results in controls showed a 3.9-fold variation in FBN1 mRNA synthesis level between subjects. A similar 4.4-fold variation was found in the Marfan population, but the mean level of FBN1 mRNA was a half of the control population. Differential allelic expression analysis in Marfan fibroblasts showed that over 90% of FBN1 mRNA was transcribed from the wild allele and the mutated allele was not detected. In the control population, independently of the expression level of FBN1, we observed steady-state equilibrium between the two allelic-mRNAs suggesting that FBN1 expression mainly depends on trans-acting regulators. Finally, we show that a low level of residual WT FBN1 mRNA accounts for a high risk of ectopia lentis and pectus abnormality and tends to increase the risk of aortic dilatation.

  17. A New Strategy to Reduce Allelic Bias in RNA-Seq Readmapping

    Science.gov (United States)

    2012-01-01

    Williams,B.A., McCue,K., Schaeffer,L. and Wold ,B. (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods, 5, 621–628. 2. Trapnell...Hunt,K.A., Bockett,N., Franke,L., Dubois,P.C., Mein,C.A., Dobson,R.J. et al. (2010) Genome- wide analysis of allelic expression imbalance in human...K.W. (2002) Allelic variation in human gene expression. Science , 297, 1143. 6. Knight,J.C. (2004) Allele-specific gene expression uncovered. Trends

  18. Characterization and differential expression of cathepsin L3 alleles from Fasciola hepatica.

    Science.gov (United States)

    Zawistowska-Deniziak, A; Wasyl, K; Norbury, L J; Wesołowska, A; Bień, J; Grodzik, M; Wiśniewski, M; Bąska, P; Wędrychowicz, H

    2013-07-01

    Fasciola hepatica infections cause significant global problems in veterinary and human medicine, including causing huge losses in cattle and sheep production. F. hepatica host infection is a multistage process and flukes express papain-like cysteine proteases, termed cathepsins, which play pivotal roles in virulence through host entry, tissue migration and immune evasion. Expression of these proteases is developmentally regulated. Recent studies indicate that excystment of infective larvae is dependent on cysteine proteases and together FhCL3 and FhCB account for over 80% of total protease activity detectable in newly excysted juvenile (NEJ) fluke. This paper focuses on members of the cathepsin L gene family, specifically those belonging to the CL3 clade. The cDNA of two novel cathepsin L3 proteases--FhCL3-1 and FhCL3-2 were cloned. The mRNA transcript expression levels for these enzymes were significantly different at various time points in life development stages obtained in vitro, from dormant metacercariae to NEJ 24h after excystment. Maximum expression levels were observed in NEJ immediately after excystment. In all stages examined by Real Time PCR, FhCL3-2 was expressed at a higher level compared to FhCL3-1 which was expressed only at very low levels. Western blot and immunohistochemical analysis also indicated higher expression of the FhCL3-2 allele and its secretory nature. The ability of antibody responses from rats and sheep challenged with F. hepatica to recognize recombinant FhCL3-1 and FhCL3-2 was shown to differ. Differences were also confirmed through the use of anti-rFhCL3-1 and anti-rFhCL3-2 sera in Western blot analysis of juvenile excretory/secretory (ES) material separated by 2D electrophoresis. These results indicate analysis of relative expression of parasite virulence factors from different populations is required, as this will likely impact the effectiveness of vaccines based on these antigens.

  19. Variable allelic expression of imprinted genes in human pluripotent stem cells during differentiation into specialized cell types in vitro.

    Science.gov (United States)

    Park, Sang-Wook; Kim, Jihoon; Park, Jong-Lyul; Ko, Ji-Yun; Im, Ilkyun; Do, Hyo-Sang; Kim, Hyemin; Tran, Ngoc-Tung; Lee, Sang-Hun; Kim, Yong Sung; Cho, Yee Sook; Lee, Dong Ryul; Han, Yong-Mahn

    2014-04-01

    Genomic imprinting is an epigenetic phenomenon by which a subset of genes is asymmetrically expressed in a parent-of-origin manner. However, little is known regarding the epigenetic behaviors of imprinted genes during human development. Here, we show dynamic epigenetic changes in imprinted genes in hESCs during in vitro differentiation into specialized cell types. Out of 9 imprinted genes with single nucleotide polymorphisms, mono-allelic expression for three imprinted genes (H19, KCNQ1OT1, and IPW), and bi- or partial-allelic expression for three imprinted genes (OSBPL5, PPP1R9A, and RTL1) were stably retained in H9-hESCs throughout differentiation, representing imprinting stability. Three imprinted genes (KCNK9, ATP10A, and SLC22A3) showed a loss and a gain of imprinting in a lineage-specific manner during differentiation. Changes in allelic expression of imprinted genes were observed in another hESC line during in vitro differentiation. These findings indicate that the allelic expression of imprinted genes may be vulnerable in a lineage-specific manner in human pluripotent stem cells during differentiation.

  20. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression

    DEFF Research Database (Denmark)

    Hamdi, Yosr; Soucy, Penny; Kuchenbaeker, Karoline B

    2017-01-01

    1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast...

  1. ss-siRNAs allele selectively inhibit ataxin-3 expression: multiple mechanisms for an alternative gene silencing strategy.

    Science.gov (United States)

    Liu, Jing; Yu, Dongbo; Aiba, Yuichiro; Pendergraff, Hannah; Swayze, Eric E; Lima, Walt F; Hu, Jiaxin; Prakash, Thazha P; Corey, David R

    2013-11-01

    Single-stranded silencing RNAs (ss-siRNAs) provide an alternative approach to gene silencing. ss-siRNAs combine the simplicity and favorable biodistribution of antisense oligonucleotides with robust silencing through RNA interference (RNAi). Previous studies reported potent and allele-selective inhibition of human huntingtin expression by ss-siRNAs that target the expanded CAG repeats within the mutant allele. Mutant ataxin-3, the genetic cause of Machado-Joseph Disease, also contains an expanded CAG repeat. We demonstrate here that ss-siRNAs are allele-selective inhibitors of ataxin-3 expression and then redesign ss-siRNAs to optimize their selectivity. We find that both RNAi-related and non-RNAi-related mechanisms affect gene expression by either blocking translation or affecting alternative splicing. These results have four broad implications: (i) ss-siRNAs will not always behave similarly to analogous RNA duplexes; (ii) the sequences surrounding CAG repeats affect allele-selectivity of anti-CAG oligonucleotides; (iii) ss-siRNAs can function through multiple mechanisms and; and (iv) it is possible to use chemical modification to optimize ss-siRNA properties and improve their potential for drug discovery.

  2. Decreased humoral antibody episodes of acute renal allograft rejection in recipients expressing the HLA-DQβ1*0202 allele.

    Science.gov (United States)

    Mannam, Venkat K R; Santos, Mark; Lewis, Robert E; Cruse, Julius M

    2012-10-01

    The present investigation was designed to show the effect of human leukocyte antigen (HLA) class II molecular allelic specificities in the recipient on the induction of humoral antibody rejection, identified by C4d peritubular capillary staining, as well as specific antibody identified by Luminex technology. Major histocompatibility complex (MHC) class II molecules are expressed on dendritic cells, macrophages, and B lymphocytes and they present antigenic peptides to CD4 positive T lymphocytes. Human renal peritubular and glomerular capillaries express class II MHC molecules upon activation. Expression of class II molecules on renal microvascular endothelial cells exposes them to possible interaction with specific circulating antibodies. We hypothesize that HLA-DQβ1*0202 expression in recipients decreases the likelihood of antibody-mediated renal allograft rejection. We found that 80% (=25) of DQ2 positive haplotype recipients failed to induce humoral antibody renal allograft rejection and 20% (n=25) of DQ2 positive haplotype recipients induced humoral antibody renal allograft rejection (p=0.008). By contrast, 48% (n=46) of DQ2 negative haplotype recipients failed to induce a humoral antibody component of renal allograft rejection and 52% (n=46) of DQ2 negative haplotype recipients induced humoral antibody-mediated renal allograft rejection. Our results suggest that recipients who express the DQβ1*0202 allele are less likely to induce a humoral antibody component of acute renal allograft rejection than are those expressing DQ1, DQ3, or DQ4 alleles. DQβ1*0202 allele expression in recipients could possibly be protective against acute humoral allograft rejection and might serve as a future criterion in recipient selection and in appropriate therapy for acute renal rejection episodes.

  3. Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival.

    Directory of Open Access Journals (Sweden)

    Isabella Bray

    Full Text Available MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145 that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR and for DNA copy number alterations (array CGH to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96 and a validation set (n = 49 for data analysis. Thirty-seven miRNAs were significantly over- or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics.

  4. Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival.

    LENUS (Irish Health Repository)

    Bray, Isabella

    2009-01-01

    MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145) that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR) and for DNA copy number alterations (array CGH) to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96) and a validation set (n = 49) for data analysis. Thirty-seven miRNAs were significantly over- or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics.

  5. Infrequent detection of germline allele-specific expression of TGFBR1 in lymphoblasts and tissues of colon cancer patients.

    LENUS (Irish Health Repository)

    Guda, Kishore

    2009-06-15

    Recently, germline allele-specific expression (ASE) of the gene encoding for transforming growth factor-beta type I receptor (TGFBR1) has been proposed to be a major risk factor for cancer predisposition in the colon. Germline ASE results in a lowered expression of one of the TGFBR1 alleles (>1.5-fold), and was shown to occur in approximately 20% of informative familial and sporadic colorectal cancer (CRC) cases. In the present study, using the highly quantitative pyrosequencing technique, we estimated the frequency of ASE in TGFBR1 in a cohort of affected individuals from familial clusters of advanced colon neoplasias (cancers and adenomas with high-grade dysplasia), and also from a cohort of individuals with sporadic CRCs. Cases were considered positive for the presence of ASE if demonstrating an allelic expression ratio <0.67 or >1.5. Using RNA derived from lymphoblastoid cell lines, we find that of 46 informative Caucasian advanced colon neoplasia cases with a family history, only 2 individuals display a modest ASE, with allelic ratios of 1.65 and 1.73, respectively. Given that ASE of TGFBR1, if present, would likely be more pronounced in the colon compared with other tissues, we additionally determined the allele ratios of TGFBR1 in the RNA derived from normal-appearing colonic mucosa of sporadic CRC cases. We, however, found no evidence of ASE in any of 44 informative sporadic cases analyzed. Taken together, we find that germline ASE of TGFBR1, as assayed in lymphoblastoid and colon epithelial cells of colon cancer patients, is a relatively rare event.

  6. Transgene optimization, immunogenicity and in vitro efficacy of viral vectored vaccines expressing two alleles of Plasmodium falciparum AMA1.

    Directory of Open Access Journals (Sweden)

    Sumi Biswas

    Full Text Available BACKGROUND: Apical membrane antigen 1 (AMA1 is a leading candidate vaccine antigen against blood-stage malaria, although to date numerous clinical trials using mainly protein-in-adjuvant vaccines have shown limited success. Here we describe the pre-clinical development and optimization of recombinant human and simian adenoviral (AdHu5 and ChAd63 and orthopoxviral (MVA vectors encoding transgene inserts for Plasmodium falciparum AMA1 (PfAMA1. METHODOLOGY/PRINCIPAL FINDINGS: AdHu5-MVA prime-boost vaccination in mice and rabbits using these vectors encoding the 3D7 allele of PfAMA1 induced cellular immune responses as well as high-titer antibodies that showed growth inhibitory activity (GIA against the homologous but not heterologous parasite strains. In an effort to overcome the issues of PfAMA1 antigenic polymorphism and pre-existing immunity to AdHu5, a simian adenoviral (ChAd63 vector and MVA encoding two alleles of PfAMA1 were developed. This antigen, composed of the 3D7 and FVO alleles of PfAMA1 fused in tandem and with expression driven by a single promoter, was optimized for antigen secretion and transmembrane expression. These bi-allelic PfAMA1 vaccines, when administered to mice and rabbits, demonstrated comparable immunogenicity to the mono-allelic vaccines and purified serum IgG now showed GIA against the two divergent strains of P. falciparum encoded in the vaccine. CD8(+ and CD4(+ T cell responses against epitopes that were both common and unique to the two alleles of PfAMA1 were also measured in mice. CONCLUSIONS/SIGNIFICANCE: Optimized transgene inserts encoding two divergent alleles of the same antigen can be successfully inserted into adeno- and pox-viral vaccine vectors. Adenovirus-MVA immunization leads to the induction of T cell responses common to both alleles, as well as functional antibody responses that are effective against both of the encoded strains of P. falciparum in vitro. These data support the further clinical

  7. Effect of metallothionein 2A gene polymorphism on allele-specific gene expression and metal content in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Krześlak, Anna; Forma, Ewa [Department of Cytobiochemistry, University of Łódź, Pomorska 141/143, 90-236 Łódź (Poland); Chwatko, Grażyna [Department of Environmental Chemistry, University of Łódź, Pomorska 163, 90-236 Łódź (Poland); Jóźwiak, Paweł; Szymczyk, Agnieszka [Department of Cytobiochemistry, University of Łódź, Pomorska 141/143, 90-236 Łódź (Poland); Wilkosz, Jacek; Różański, Waldemar [2nd Department of Urology, Medical University of Łódź, Pabianicka 62, 93-513 Łódź (Poland); Bryś, Magdalena, E-mail: zreg@biol.uni.lodz.pl [Department of Cytobiochemistry, University of Łódź, Pomorska 141/143, 90-236 Łódź (Poland)

    2013-05-01

    Metallothioneins (MTs) are highly conserved, small molecular weight, cysteine rich proteins. The major physiological functions of metallothioneins include homeostasis of essential metals Zn and Cu and protection against cytotoxicity of heavy metals. The aim of this study was to determine whether there is an association between the − 5 A/G single nucleotide polymorphism (SNP; rs28366003) in core promoter region and expression of metallothionein 2A (MT2A) gene and metal concentration in prostate cancer tissues. MT2A polymorphism was determined by the polymerase chain reaction–restriction fragment length polymorphism technique (PCR–RFLP) using 412 prostate cancer tissue samples. MT2A gene expression analysis was performed by real-time RT-PCR method. A significant association between rs28366003 genotype and MT2A expression level was found. The average mRNA level was found to be lower among minor allele carriers (the risk allele) than average expression among homozygotes for the major allele. Metal levels were analyzed by flamed atomic absorption spectrometer system. Highly statistically significant associations were detected between the SNP and Cd, Zn, Cu and Pb levels. The results of Spearman's rank correlation showed that the expressions of MT2A and Cu, Pb and Ni concentrations were negatively correlated. On the basis of the results obtained in this study, we suggest that SNP polymorphism may affect the MT2A gene expression in prostate and this is associated with some metal accumulation. - Highlights: • MT2A gene expression and metal content in prostate cancer tissues • Association between SNP (rs28366003) and expression of MT2A • Significant associations between the SNP and Cd, Zn, Cu and Pb levels • Negative correlation between MT2A gene expression and Cu, Pb and Ni levels.

  8. Ribosomal protein genes are highly enriched among genes with allele-specific expression in the interspecific F1 hybrid catfish.

    Science.gov (United States)

    Chen, Ailu; Wang, Ruijia; Liu, Shikai; Peatman, Eric; Sun, Luyang; Bao, Lisui; Jiang, Chen; Li, Chao; Li, Yun; Zeng, Qifan; Liu, Zhanjiang

    2016-06-01

    Interspecific hybrids provide a rich source for the analysis of allele-specific expression (ASE). In this work, we analyzed ASE in F1 hybrid catfish using RNA-Seq datasets. While the vast majority of genes were expressed with both alleles, 7-8 % SNPs exhibited significant differences in allele ratios of expression. Of the 66,251 and 177,841 SNPs identified from the datasets of the liver and gill, 5420 (8.2 %) and 13,390 (7.5 %) SNPs were identified as significant ASE-SNPs, respectively. With these SNPs, a total of 1519 and 3075 ASE-genes were identified. Gene Ontology analysis revealed that genes encoding cytoplasmic ribosomal proteins (RP) were highly enriched among ASE genes. Parent-of-origin was determined for 27 and 30 ASE RP genes in the liver and gill, respectively. The results indicated that genes from both channel catfish and blue catfish were involved in ASE. However, each RP gene appeared to be almost exclusively expressed from only one parent, indicating that ribosomes in the hybrid catfish were in the "hybrid" form. Overall representation of RP transcripts among the transcriptome appeared lower in the F1 hybrid catfish than in channel catfish or blue catfish, suggesting that the "hybrid" ribosomes may work more efficiently for translation in the F1 hybrid catfish.

  9. Powerful identification of cis-regulatory SNPs in human primary monocytes using allele-specific gene expression.

    Directory of Open Access Journals (Sweden)

    Jonas Carlsson Almlöf

    Full Text Available A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs by genome-wide allele-specific gene expression (ASE analysis with that of traditional expression quantitative trait locus (eQTL mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.

  10. Effects on murine behavior and lifespan of selectively decreasing expression of mutant huntingtin allele by supt4h knockdown.

    Directory of Open Access Journals (Sweden)

    Hui-Min Cheng

    2015-03-01

    Full Text Available Production of protein containing lengthy stretches of polyglutamine encoded by multiple repeats of the trinucleotide CAG is a hallmark of Huntington's disease (HD and of a variety of other inherited degenerative neurological and neuromuscular disorders. Earlier work has shown that interference with production of the transcription elongation protein SUPT4H results in decreased cellular capacity to transcribe mutant huntingtin gene (Htt alleles containing long CAG expansions, but has little effect on expression of genes containing short CAG stretches. zQ175 and R6/2 are genetically engineered mouse strains whose genomes contain human HTT alleles that include greatly expanded CAG repeats and which are used as animal models for HD. Here we show that reduction of SUPT4H expression in brains of zQ175 mice by intracerebroventricular bolus injection of antisense 2'-O-methoxyethyl oligonucleotides (ASOs directed against Supt4h, or in R6/2 mice by deletion of one copy of the Supt4h gene, results in a decrease in mRNA and protein encoded specifically by mutant Htt alleles. We further show that reduction of SUPT4H in mouse brains is associated with decreased HTT protein aggregation, and in R6/2 mice, also with prolonged lifespan and delay of the motor impairment that normally develops in these animals. Our findings support the view that targeting of SUPT4H function may be useful as a therapeutic countermeasure against HD.

  11. Expression of tyrosine hydroxylase in CD4+ T cells contributes to alleviation of Th17/Treg imbalance in collagen-induced arthritis.

    Science.gov (United States)

    Wang, Xiao-Qin; Liu, Yan; Cai, Huan-Huan; Peng, Yu-Ping; Qiu, Yi-Hua

    2016-07-20

    Tyrosine hydroxylase (TH), a rate-limiting enzyme for the synthesis of catecholamines, is expressed in T lymphocytes. However, the role of T cell-expressed TH in rheumatoid arthritis (RA) is less clear. Herein, we aimed to show the contribution of TH expression by CD4(+) T cells to alleviation of helper T (Th)17/regulatory T (Treg) imbalance in collagen-induced arthritis (CIA), a mouse model of RA. CIA was prepared by intradermal injection of collagen type II (CII) at tail base of DBA1/J mice. Expression of TH in the spleen and the ankle joints was measured by real-time polymerase chain reaction and Western blot analysis. Percentages of TH-expressing Th17 and Treg cells in splenic CD4(+) T cells were determined by flow cytometry. Overexpression and knockdown of TH gene in CD4(+) T cells were taken to evaluate effects of TH on Th17 and Treg cells in CIA. TH expression was upregulated in both the inflamed tissues (spleen and ankle joints) and the CD4(+) T cells of CIA mice. In splenic CD4(+) T cells, the cells expressing TH were increased during CIA. These cells that expressed more TH in CIA were mainly Th17 cells rather than Treg cells. TH gene overexpression in CD4(+) T cells from CIA mice reduced Th17 cell percentage as well as Th17-related transcription factor and cytokine expression and secretion, whereas TH gene knockdown enhanced the Th17 cell activity. In contrast, TH gene overexpression increased Treg-related cytokine expression and secretion in CD4(+) T cells of CIA mice, while TH gene knockdown decreased the Treg cell changes. Collectively, these findings show that CIA induces TH expression in CD4(+) T cells, particularly in Th17 cells, and suggest that the increased TH expression during CIA represents an anti-inflammatory mechanism.

  12. Organ-specific gene expression in maize: The P-wr allele. Final report, August 15, 1993--August 14, 1996

    Energy Technology Data Exchange (ETDEWEB)

    Peterson, T.A.

    1997-06-01

    The ultimate aim of our work is to understand how a regulatory gene produces a specific pattern of gene expression during plant development. Our model is the P-wr gene of maize, which produces a distinctive pattern of pigmentation of maize floral organs. We are investigating this system using a combination of classical genetic and molecular approaches. Mechanisms of organ-specific gene expression are a subject of intense research interest, as it is the operation of these mechanisms during eukaryotic development which determine the characteristics of each organism Allele-specific expression has been characterized in only a few other plant genes. In maize, organ-specific pigmentation regulated by the R, B, and Pl genes is achieved by differential transcription of functionally conserved protein coding sequences. Our studies point to a strikingly different mechanism of organ-specific gene expression, involving post-transcriptional regulation of the regulatory P gene. The novel pigmentation pattern of the P-wr allele is associated with differences in the encoded protein. Furthermore, the P-wr gene itself is present as a unique tandemly amplified structure, which may affect its transcriptional regulation.

  13. FGFR4 Arg388 allele correlates with tumour thickness and FGFR4 protein expression with survival of melanoma patients.

    Science.gov (United States)

    Streit, S; Mestel, D S; Schmidt, M; Ullrich, A; Berking, C

    2006-06-19

    A single nucleotide polymorphism in the gene for FGFR4 (-Arg388) has been associated with progression in various types of human cancer. Although fibroblast growth factors (FGFs) belong to the most important growth factors in melanoma, expression of FGF receptor subtype 4 has not been investigated yet. In this study, the protein expression of this receptor was analysed in 137 melanoma tissues of different progression stages by immunohistochemistry. FGFR4 protein was expressed in 45% of the specimens and correlated with pTNM tumour stages (UICC, P = 0.023 and AJCC, P = 0.046), presence of microulceration (P = 0.009), tumour vascularity (P = 0.001), metastases (P = 0.025), number of primary tumours (P = 0.022), overall survival (P = 0.047) and disease-free survival (P = 0.024). Furthermore, FGFR4 Arg388 polymorphism was analysed in 185 melanoma patients by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Arg388 allele was detected in 45% of the melanoma patients and was significantly associated with tumour thickness (by Clark's level of invasion (P = 0.004) and by Breslow in mm (P = 0.02)) and the tumour subtype nodular melanoma (P = 0.002). However, there was no correlation of the FGFR4 Arg388 allele with overall and disease-free survival. In conclusion, the Arg388 genotype and the protein expression of FGFR4 may be potential markers for progression of melanoma.

  14. Concerns on Monotonic Imbalance Bounding Matching Methods

    OpenAIRE

    Yatracos, Yannis G.

    2013-01-01

    Concerns are expressed for the Monotonic Imbalance Bounding (MIB) property (Iacus et al. 2011) and for MIB matching because i) the definition of the MIB property leads to inconsistencies and the nature of the imbalance measure is not clearly defined, ii) MIB property does not generalize Equal Percent Bias Reducing (EPBR) property, iii) MIB matching does not provide statistical information available with EPBR matching.

  15. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

    NARCIS (Netherlands)

    Y. Hamdi (Yosr); Soucy, P. (Penny); Adoue, V. (Véronique); K. Michailidou (Kyriaki); S. Canisius (Sander); Lemaçon, A. (Audrey); A. Droit (Arnaud); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); Arndt, V. (Volker); Baynes, C. (Caroline); C. Blomqvist (Carl); N.V. Bogdanova (Natalia); S.E. Bojesen (Stig); M.K. Bolla (Manjeet K.); B. Bonnani (Bernardo); A.-L. Borresen-Dale (Anne-Lise); J.S. Brand (Judith S.); H. Brauch (Hiltrud); Brenner, H. (Hermann); A. Broeks (Annegien); B. Burwinkel (Barbara); J. Chang-Claude (Jenny); Couch, F.J. (Fergus J.); A. Cox (Angela); S.S. Cross (Simon); K. Czene (Kamila); H. Darabi (Hatef); J. Dennis (Joe); P. Devilee (Peter); T. Dörk (Thilo); I. dos Santos Silva (Isabel); M. Eriksson (Mats); P.A. Fasching (Peter); J.D. Figueroa (Jonine); H. Flyger (Henrik); M. García-Closas (Montserrat); Giles, G.G. (Graham G.); M.S. Goldberg (Mark); A. González-Neira (Anna); G. Grenaker Alnæs (Grethe); P. Guénel (Pascal); L. Haeberle (Lothar); C.A. Haiman (Christopher); U. Hamann (Ute); Hallberg, E. (Emily); M.J. Hooning (Maartje); J.L. Hopper (John); A. Jakubowska (Anna); M. Jones (Michael); M. Kabisch (Maria); V. Kataja (Vesa); Lambrechts, D. (Diether); L. Le Marchand (Loic); A. Lindblom (Annika); J. Lubinski (Jan); A. Mannermaa (Arto); M. Maranian (Melanie); S. Margolin (Sara); Marme, F. (Frederik); R.L. Milne (Roger); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); P. Neven (Patrick); C. Olswold (Curtis); J. Peto (Julian); Plaseska-Karanfilska, D. (Dijana); K. Pykäs (Katri); P. Radice (Paolo); A. Rudolph (Anja); E.J. Sawyer (Elinor); M.K. Schmidt (Marjanka); X.-O. Shu (Xiao-Ou); M.C. Southey (Melissa); A.J. Swerdlow (Anthony ); R.A.E.M. Tollenaar (Rob); I.P. Tomlinson (Ian); D. Torres (Diana); T. Truong (Thérèse); C. Vachon (Celine); A.M.W. van den Ouweland (Ans); Q. Wang (Qin); R. Winqvist (Robert); W. Zheng (Wei); J. Benítez (Javier); G. Chenevix-Trench (Georgia); A.M. Dunning (Alison); P.D.P. Pharoah (Paul); Kristensen, V. (Vessela); P. Hall (Per); D.F. Easton (Douglas); T. Pastinen (Tomi); S. Nord (Silje); J. Simard (Jacques)

    2016-01-01

    textabstractThere are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are fun

  16. Identifying breast cancer risk loci by global differential allele-specific expression (DASE analysis in mammary epithelial transcriptome

    Directory of Open Access Journals (Sweden)

    Gao Chuan

    2012-10-01

    Full Text Available Abstract Background The significant mortality associated with breast cancer (BCa suggests a need to improve current research strategies to identify new genes that predispose women to breast cancer. Differential allele-specific expression (DASE has been shown to contribute to phenotypic variables in humans and recently to the pathogenesis of cancer. We previously reported that nonsense-mediated mRNA decay (NMD could lead to DASE of BRCA1/2, which is associated with elevated susceptibility to breast cancer. In addition to truncation mutations, multiple genetic and epigenetic factors can contribute to DASE, and we propose that DASE is a functional index for cis-acting regulatory variants and pathogenic mutations, and that global analysis of DASE in breast cancer precursor tissues can be used to identify novel causative alleles for breast cancer susceptibility. Results To test our hypothesis, we employed the Illumina® Omni1-Quad BeadChip in paired genomic DNA (gDNA and double-stranded cDNA (ds-cDNA samples prepared from eight BCa patient-derived normal mammary epithelial lines (HMEC. We filtered original array data according to heterozygous genotype calls and calculated DASE values using the Log ratio of cDNA allele intensity, which was normalized to the corresponding gDNA. We developed two statistical methods, SNP- and gene-based approaches, which allowed us to identify a list of 60 candidate DASE loci (DASE ≥ 2.00, P ≤ 0.01, FDR ≤ 0.05 by both methods. Ingenuity Pathway Analysis of DASE loci revealed one major breast cancer-relevant interaction network, which includes two known cancer causative genes, ZNF331 (DASE = 2.31, P = 0.0018, FDR = 0.040 and USP6 (DASE = 4.80, P = 0.0013, FDR = 0.013, and a breast cancer causative gene, DMBT1 (DASE=2.03, P = 0.0017, FDR = 0.014. Sequence analysis of a 5′ RACE product of DMBT1 demonstrated that rs2981745, a putative breast cancer risk locus, appears to be one of the causal variants leading to DASE

  17. N-glycosylation of asparagine 8 regulates surface expression of major histocompatibility complex class I chain-related protein A (MICA) alleles dependent on threonine 24

    DEFF Research Database (Denmark)

    Pedersen, Maiken Mellergaard; Skovbakke, Sarah Line; Schneider, Christine L.

    2014-01-01

    -glycosylation and the retention was rescued by T24A substitution. Our study reveals N-glycosylation as an allele-specific regulatory mechanism important for regulation of surface expression of MICA018 and we pinpoint the residues essential for this N-glycosylation dependency. In addition we show that this regulatory mechanism...... for cell-surface expression and sought to identify the essential residues. We found that a single N-glycosylation site (N8) was important for MICA018 surface expression. The frequently expressed MICA allele 008, with an altered transmembrane and intracellular domain, was not affected by mutation of this N...

  18. Expression of BCR/ABL p210 from a Knockin Allele Enhances Bone Marrow Engraftment without Inducing Neoplasia

    Directory of Open Access Journals (Sweden)

    Samantha B. Foley

    2013-10-01

    Full Text Available Chronic myeloid leukemia (CML and some acute lymphoblastic leukemias are characterized by the t(9;22 chromosome, which encodes the BCR/ABL oncogene. Multiple mouse models of CML express BCR/ABL at high levels from non-Bcr promoters, resulting in the development of leukemias. In contrast, a significant fraction of healthy humans have been found to have BCR/ABL-positive hematopoietic cells. To bridge the gap between the information derived from current mouse models and nonleukemic humans with the BCR/ABL oncogene, we generated a knockin model with BCR/ABL p210 expressed from the Bcr locus. Unlike previous models, expression of BCR/ABL from the knockin allele did not induce leukemia. BCR/ABL mutant cells did exhibit favorable bone marrow engraftment compared to control cells. These data suggest that BCR/ABL expression alone is insufficient to induce disease. This model allows for inducible spatial and temporal control of BCR/ABL expression for analysis of early steps in the pathogenesis of BCR/ABL-expressing leukemias.

  19. Insulin Like Growth Factor 2 Expression in the Rat Brain Both in Basal Condition and following Learning Predominantly Derives from the Maternal Allele.

    Directory of Open Access Journals (Sweden)

    Xiaojing Ye

    Full Text Available Insulin like growth factor 2 (Igf2 is known as a maternally imprinted gene involved in growth and development. Recently, Igf2 was found to also be regulated and required in the adult rat hippocampus for long-term memory formation, raising the question of its allelic regulation in adult brain regions following experience and in cognitive processes. We show that, in adult rats, Igf2 is abundantly expressed in brain regions involved in cognitive functions, like hippocampus and prefrontal cortex, compared to the peripheral tissues. In contrast to its maternal imprinting in peripheral tissues, Igf2 is mainly expressed from the maternal allele in these brain regions. The training-dependent increase in Igf2 expression derives proportionally from both parental alleles, and, hence, is mostly maternal. Thus, Igf2 parental expression in the adult rat brain does not follow the imprinting rules found in peripheral tissues, suggesting differential expression regulation and functions of imprinted genes in the brain.

  20. Swine Leukocyte Antigen (SLA) class I allele typing of Danish swine herds and the identification of commonly expressed haplotypes using sequence specific low- and high resolution primers

    DEFF Research Database (Denmark)

    Pedersen, Lasse Eggers; Fink, Dorte Rosenbek; Jungersen, Gregers

    The genomic region (SLA) of the swine major histocompatibility complex (MHC), which bind and present endogenous peptides to circulating T cells of the immune system, is extremely polymorphic comprising high numbers of different alleles, many of which encode a distinct MHC class I molecule. Each SLA...... individual. Therefore analyses of the prevalence of SLA alleles in a population are fundamental to employ pathogen-specific subunits or peptides in novel vaccines or immune diagnostics. In this study we present the use of low- and high-resolution PCR-based typing methods to identify individual and commonly...... expressed SLA class I alleles in Danish outbred swine. A total of 108 animals from eight different production herds were tested, and with low resolution sequence specific primer (SSP)-PCR typing the top five most commonly expressed SLA class I allele groups were found to be SLA-3*04XX, SLA-1*08XX, SLA-1...

  1. ANALYSIS OF SEQUENCE POLYMORPHISM OF SCR CLASS I AND II ALLELES AND STUDY REGULATION OF THEIR EXPRESSION

    Directory of Open Access Journals (Sweden)

    Jana ŽALUDOVÁ

    2012-06-01

    Full Text Available Self-incompatibility (AI is a widespread mechanism used by flowering plants to prevent inbreeding depression and helps create and maintain genetic diversity within a species. Oilseed rape (Brassica napus L. and especially its modern varieties are characterized by high level of self-fertility. In an effort to increase the production current breeding is focused on the production of inbred lines for making the F1 hybrids and the self-incompatibility can be an interesting tool for production self- sterile lines. In Brassica napus, we found two recessive alleles of a gene SCR II. Different expression of both alleles does not correspond to phenotypic manifestation of self-incompatibility and we can assume that it is prevailed by repressor gene that does not lie on the S-locus. This is also reason, why the SCR gene cannot serve as a molecular marker of self-incompatibility in Brassica napus, although many authors believe that this gene is essential in AI reaction. Brassica napus belong to plants with complex genetic constitution, is composed by two genomes, A and C, which give the possibility of different interactions and makes it difficult to study compared with diploid B. rapa and B. oleracea. In further study it is therefore important to focus on the interactions between genes SCR, SRK and SLG, and their influence on others, such as supressor gene systems.

  2. Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression.

    Directory of Open Access Journals (Sweden)

    Daisuke Sakurai

    Full Text Available Immunoregulatory cytokine interleukin-10 (IL-10 is elevated in sera from patients with systemic lupus erythematosus (SLE correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA (P = 2.7×10⁻⁸, OR = 1.30, but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively, and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1 detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele

  3. Analysis of allelic expression patterns of IL-2, IL-3, IL-4, and IL-13 in human CD4+ T cell clones.

    NARCIS (Netherlands)

    Bayley, J.P.; Bakker, AM; Kaijzel, EL; Wierenga, EA; Pouw Kraan, van der C.T.M.; Huizinga, T.W.; Verweij, C.L.

    2003-01-01

    The occurrence of monoallelic expression of cytokine genes in single cells has been convincingly demonstrated, but there have been few reports of this phenomenon in T cell clones. Here we describe studies on the expression of alleles of the human genes encoding IL-2, IL-3, IL-4, and IL-13 in human C

  4. Common chromosomal imbalances and stemness-related protein expression markers in endometriotic lesions from different anatomical sites

    DEFF Research Database (Denmark)

    Silveira, Cássia G T; Abrão, Mauricio S; Dias, João A

    2012-01-01

    BACKGROUND: Endometriosis is a multifactorial gynecological disease characterized by the presence of functional endometrium-like tissue in ectopic sites. Several studies have focused on elucidating the immunological, endocrine, environmental and genetic factors involved in endometriosis. However...... genomic alterations in stromal and epithelial cells from different anatomical sites of the same patient and the expression of stemness-related markers suggested that endometriosis arises as a clonal proliferation with the putative involvement of stem cells....

  5. Imbalance between expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in invasiveness and metastasis of human gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Sheng Zhang; Li Li; Jian-Yin Lin; Hua Lin

    2003-01-01

    AIM: The expressive balance between matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a critical role in maintaining the degradation and synthesis of extracellular matrix. Loss of such balance is associated with invasion and metastasis of tumors. This study aimed to determine the expression of MMP-9 and TIMP-1 in gastric carcinoma, and the association of the expressive imbalance between MMP9 and TIMP-1 with the invasion and metastasis and prognosis of gastric carcinoma.METHODS: We used immunohistochemistry to determine the expressions of MMP-9, TTMP-1 and proliferating cell nuclear antigen Ki-67 in the gastric specimens taken from 256 patients with primary gastric carcinoma. The patients were followed-up for up to 96 months.RESULTS: No association between the expression of MMP9 and TIMP-1 and patients' sex and age, tumor size and location of gastric carcinoma was observed. The incidence of the positive expression of MMP-9 in cases with tumors invasion to muscularis propria and visceral peritoneum (70.13% and 69.09%, respectively) was significantly higher than that in cases with tumor invasion only to lamina propria or submucosa (42.50 %, P=0.0162). The positive correlation between MMP-9 expression and the depth of tumor invasion was observed (Pearson correlation coefficient=0.2129,P=0.016). Along with the increase of the metastatic station of lymph nodes, the incidence of the MMP-9 expression was increased by degrees; a positive correlation between them was observed (Pearson correlation coefficient=0.2910,P=0.0001). There was also a significant correlation between MMP-9 expression and the TNM stage in gastric carcinoma (Pearson correlation coefficient=0.3027, P<0.0001). The incidence of MMP-9 expression in stage Ⅱ and Ⅲ/Ⅳ (75.00%and 76.15%, respectively) was significantly higher than those in stage Ⅰ (46.15 %, P<0.0001). A negative correlation between TIMP-1 immunoreactivity and the depth of invasion

  6. Paramutation: a heritable change in gene expression by allelic interactions in trans

    NARCIS (Netherlands)

    Stam, M.

    2009-01-01

    Epigenetic gene regulation involves the stable propagation of gene activity states through mitotic, and sometimes even meiotic, cell divisions without changes in DNA sequence. Paramutation is an epigenetic phenomenon involving changes in gene expression that are stably transmitted through mitosis as

  7. Risk alleles of genes with monoallelic expression are enriched in gain-of-function variants and depleted in loss-of-function variants for neurodevelopmental disorders.

    Science.gov (United States)

    Savova, V; Vinogradova, S; Pruss, D; Gimelbrant, A A; Weiss, L A

    2017-03-07

    Over 3000 human genes can be expressed from a single allele in one cell, and from the other allele-or both-in neighboring cells. Little is known about the consequences of this epigenetic phenomenon, monoallelic expression (MAE). We hypothesized that MAE increases expression variability, with a potential impact on human disease. Here, we use a chromatin signature to infer MAE for genes in lymphoblastoid cell lines and human fetal brain tissue. We confirm that across clones MAE status correlates with expression level, and that in human tissue data sets, MAE genes show increased expression variability. We then compare mono- and biallelic genes at three distinct scales. In the human population, we observe that genes with polymorphisms influencing expression variance are more likely to be MAE (PMolecular Psychiatry advance online publication, 7 March 2017; doi:10.1038/mp.2017.13.

  8. The imbalance in expression of angiogenic and anti-angiogenic factors as candidate predictive biomarker in preeclampsia

    Directory of Open Access Journals (Sweden)

    Pooneh Nikuei

    2015-07-01

    Full Text Available Preeclampsia is an important pregnancy disorder with serious maternal and fetal complications which its etiology has not been completely understood yet. Early diagnosis and management of disease could reduce its potential side effects. The vascular endothelial growth factor (VEGF family including VEGF-A is the most potent endothelial growth factor which induces angiogenesis and endothelial cell proliferation and has basic role in vasculogenesis. VEGF and its tyrosine kinase receptors (Flt1 and KDR are major factors for fetal and placental angiogenic development. Finding mechanisms involved in expression of angiogenic factors may lead to new prognostic and therapeutic points in management of preeclampsia. Recent researches, has shown capability of some anti-angiogenic factors as potential candidate to be used as early predictors for preeclampsia. Soluble fms-like tyrosin kinase-1 (sFlt1 is a truncated splice variant of the membrane-bound VEGF receptor Flt1, that is produced by the placenta and it can bind to angiogenic growth factors and neutraliz, their effects. It is also observed that the ratio of sFlt1 to placental growth factor is valuable as prognostic marker. In this review, VEGF family member’s role in angiogenesis is evaluated as biomarkers to be used for prediction of preeclampsia.

  9. A common polymorphism in the promoter region of the TNFSF4 gene is associated with lower allele-specific expression and risk of myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Massimiliano Ria

    Full Text Available BACKGROUND: The TNFSF4/TNFRSF4 system, along with several other receptor-ligand pairs, is involved in the recruitment and activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previously shown that genetic variants in TNFSF4 are associated with myocardial infarction (MI in women. This prompted functional studies of TNFSF4 expression. METHODS AND RESULTS: Based on a screening of the TNFSF4 genomic region, a promoter polymorphism (rs45454293 and a haplotype were identified, conceivably involved in gene regulation. The rs45454293T-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rs45454293 and rs3850641 polymorphisms is functionally important, the rs45454293T- and rs3850641G-alleles being associated with lower transcriptional activity in cells heterozygous for both polymorphisms. The functional role of rs45454293 on transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the rs45454293T-allele decreased gene expression when compared with the rs45454293C-allele, while the rs3850641 SNP did not have any effect on TNFSF4 promoter activity. Electromobility shift assay showed that the rs45454293 polymorphism, but not rs3850641, affects the binding of nuclear factors, thus suggesting that the lower transcriptional activity is attributed to binding of one or more transcriptional repressor(s to the T-allele. CONCLUSIONS: Our data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of MI.

  10. Generation and Characterization of Mice Expressing a Conditional Allele of the Interleukin-1 Receptor Type 1

    Science.gov (United States)

    Robson, Matthew J.; Zhu, Chong-Bin; Quinlan, Meagan A.; Botschner, David A.; Baganz, Nicole L.; Lindler, Kathryn M.; Thome, Jason G.; Hewlett, William A.; Blakely, Randy D.

    2016-01-01

    The cytokines IL-1α and IL-1β exert powerful pro-inflammatory actions throughout the body, mediated primarily by the intracellular signaling capacity of the interleukin-1 receptor (IL-1R1). Although Il1r1 knockout mice have been informative with respect to a requirement for IL-1R1 signaling in inflammatory events, the constitutive nature of gene elimination has limited their utility in the assessment of temporal and spatial patterns of cytokine action. To pursue such questions, we have generated C57Bl/6J mice containing a floxed Il1r1 gene (Il1r1loxP/loxP), with loxP sites positioned to flank exons 3 and 4 and thereby the ability to spatially and temporally eliminate Il1r1 expression and signaling. We found that Il1r1loxP/loxP mice breed normally and exhibit no gross physical or behavioral phenotypes. Moreover, Il1r1loxP/loxP mice exhibit normal IL-1R1 receptor expression in brain and spleen, as well as normal IL-1R1-dependent increases in serum IL-6 following IL-1α injections. Breeding of Il1r1loxP/loxP mice to animals expressing a cytomegalovirus (CMV)-driven Cre recombinase afforded efficient excision at the Il1r1 locus. The Il1r1loxP/loxP line should be a valuable tool for the assessment of contributions made by IL-1R1 signaling in diverse cell types across development. PMID:26930558

  11. Generation and Characterization of Mice Expressing a Conditional Allele of the Interleukin-1 Receptor Type 1.

    Directory of Open Access Journals (Sweden)

    Matthew J Robson

    Full Text Available The cytokines IL-1α and IL-1β exert powerful pro-inflammatory actions throughout the body, mediated primarily by the intracellular signaling capacity of the interleukin-1 receptor (IL-1R1. Although Il1r1 knockout mice have been informative with respect to a requirement for IL-1R1 signaling in inflammatory events, the constitutive nature of gene elimination has limited their utility in the assessment of temporal and spatial patterns of cytokine action. To pursue such questions, we have generated C57Bl/6J mice containing a floxed Il1r1 gene (Il1r1loxP/loxP, with loxP sites positioned to flank exons 3 and 4 and thereby the ability to spatially and temporally eliminate Il1r1 expression and signaling. We found that Il1r1loxP/loxP mice breed normally and exhibit no gross physical or behavioral phenotypes. Moreover, Il1r1loxP/loxP mice exhibit normal IL-1R1 receptor expression in brain and spleen, as well as normal IL-1R1-dependent increases in serum IL-6 following IL-1α injections. Breeding of Il1r1loxP/loxP mice to animals expressing a cytomegalovirus (CMV-driven Cre recombinase afforded efficient excision at the Il1r1 locus. The Il1r1loxP/loxP line should be a valuable tool for the assessment of contributions made by IL-1R1 signaling in diverse cell types across development.

  12. Expression of murine APOBEC3 alleles in different mouse strains and their effect on mouse mammary tumor virus infection.

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    Okeoma, Chioma M; Petersen, Josiah; Ross, Susan R

    2009-04-01

    Recent work has shown that mouse APOBEC3 restricts infection by mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) and that there are polymorphic APOBEC3 alleles found in different inbred mouse strains. For example, C57BL/6 mice, which are resistant to Friend MLV (F-MLV), encode a APOBEC3 gene different from that encoded by F-MLV-susceptible BALB/c mice; the predominant RNA produced in C57BL/6 mice lacks exon 5 (mA3(-5)) and encodes a protein with 15 polymorphic amino acids. It has also been reported that BALB/c mice produce only a variant RNA that lacks exon 2 (mA3(-2)). In this study, we examined the effect of these polymorphic APOBEC3 proteins on MMTV infection. We found that the major RNA made in C57BL/6 and B10.BR mice lacks exon 5 but that BALB/c and C3H/HeN mice predominantly express an RNA that contains all nine exons. In addition to producing the splice variant, C57BL/6 and B10.BR cells and tissues had levels of mA3 RNA fivefold higher than those from BALB/c and C3H/HeN mice. A cloned C57BL/6-derived mA3 protein lacking exon 5 inhibited MMTV infection better than a cloned full-length protein derived from 129/Ola RNA when packaged into MMTV virions. We also tested dendritic cells derived from different inbred mouse strains for their abilities to be infected by MMTV and showed that susceptibility to infection correlated with the presence of the exon 5-encoding allele. In vivo susceptibility to infection cosegregated with the inherited mA3 allele in a C57BL/6 x BALB/c backcross analysis. Moreover, virus produced in vivo in the mammary tissue of mA3 knockout and BALB/c mice was more infectious than that produced in the tissue of C57BL/6 mice. These data indicate that mA3 plays a role in the genetics of susceptibility and resistance to MMTV infection.

  13. Fixed Sagittal Plane Imbalance

    OpenAIRE

    Savage, Jason W.; Patel, Alpesh A.

    2014-01-01

    Study Design Literature review. Objective To discuss the evaluation and management of fixed sagittal plane imbalance. Methods A comprehensive literature review was performed on the preoperative evaluation of patients with sagittal plane malalignment, as well as the surgical strategies to address sagittal plane deformity. Results Sagittal plane imbalance is often caused by de novo scoliosis or iatrogenic flat back deformity. Understanding the etiology and magnitude of sagittal malalignment is ...

  14. Characterization and comparative analysis of HMW glutenin 1Ay alleles with differential expressions

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    Wang Feng

    2009-02-01

    Full Text Available Abstract Background High-molecular-weight glutenin subunits (HMW-GSs have been considered as most important seed storage proteins for wheat flour quality. 1Ay subunits are of great interest because they are always silent in common wheat. The presence of expressed 1Ay subunits in diploid and tetraploid wheat genotypes makes it possible to investigate molecular information of active 1Ay genes. Results We identified 1Ay subunits with different electrophoretic mobility from 141 accessions of diploid and tetraploid wheats, and obtained the complete ORFs and 5' flanking sequences of 1Ay genes including 6 active and 3 inactive ones. Furthermore, the 5' flanking sequences were characterized from 23 wild diploid species of Triticeae. All 6 active 1Ay possess a typical HMW-GS primary structure and some novel characteristics. The conserved cysteine residue within the repetitive domain of y-type subunits was replaced by phenylalanine residue in subunits of 1Ay (Tu-e1, 1Ay (Tu-e2, 1Ay (Ta-e2 and 1Ay (Td-e. Particularly, 1Ay (Ta-e3 has an unusual large molecular weight of 2202 bp and was one of the known largest y-type HMW-GSs. The translations of 1Ay (Tu-s, 1Ay (Ta-s and 1Ay (Td-s were disrupted by premature stop codons in their coding regions. The 5' flanking sequences of active and inactive 1Ay genes differ in a few base substitutions and insertions or deletions. The 85 bp deletions have been found in promoter regions of all 1Ay genes and the corresponding positions of 6 species from Aegilops and Hordeum. Conclusion The possession of larger molecular weight and fewer conserved cysteine residues are unique structural features of 1Ay genes; it would be interested to express them in bread wheat and further to examine their impact to processing quality of wheat. The 1Ay genes from T. urartu are closer to the genes from T. turgidum dicoccon and T. aestivum, than those from T. monococcum aegilopoides. The 85 bp deletion and some variations in the 5'flanking

  15. Interrogation of allelic chromatin states in human cells by high-density ChIP-genotyping.

    Science.gov (United States)

    Light, Nicholas; Adoue, Véronique; Ge, Bing; Chen, Shu-Huang; Kwan, Tony; Pastinen, Tomi

    2014-09-01

    Allele-specific (AS) assessment of chromatin has the potential to elucidate specific cis-regulatory mechanisms, which are predicted to underlie the majority of the known genetic associations to complex disease. However, development of chromatin landscapes at allelic resolution has been challenging since sites of variable signal strength require substantial read depths not commonly applied in sequencing based approaches. In this study, we addressed this by performing parallel analyses of input DNA and chromatin immunoprecipitates (ChIP) on high-density Illumina genotyping arrays. Allele-specificity for the histone modifications H3K4me1, H3K4me3, H3K27ac, H3K27me3, and H3K36me3 was assessed using ChIP samples generated from 14 lymphoblast and 6 fibroblast cell lines. AS-ChIP SNPs were combined into domains and validated using high-confidence ChIP-seq sites. We observed characteristic patterns of allelic-imbalance for each histone-modification around allele-specifically expressed transcripts. Notably, we found H3K4me1 to be significantly anti-correlated with allelic expression (AE) at transcription start sites, indicating H3K4me1 allelic imbalance as a marker of AE. We also found that allelic chromatin domains exhibit population and cell-type specificity as well as heritability within trios. Finally, we observed that a subset of allelic chromatin domains is regulated by DNase I-sensitive quantitative trait loci and that these domains are significantly enriched for genome-wide association studies hits, with autoimmune disease associated SNPs specifically enriched in lymphoblasts. This study provides the first genome-wide maps of allelic-imbalance for five histone marks. Our results provide new insights into the role of chromatin in cis-regulation and highlight the need for high-depth sequencing in ChIP-seq studies along with the need to improve allele-specificity of ChIP-enrichment.

  16. Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms.

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    Laura De Lellis

    Full Text Available The identification of germline variants predisposing to hereditary nonpolyposis colorectal cancer (HNPCC is crucial for clinical management of carriers, but several probands remain negative for such variants or bear variants of uncertain significance (VUS. Here we describe the results of integrative molecular analyses in 132 HNPCC patients providing evidences for improved genetic testing of HNPCC with traditional or next generation methods. Patients were screened for: germline allele-specific expression (ASE, nucleotide variants, rearrangements and promoter methylation of mismatch repair (MMR genes; germline EPCAM rearrangements; tumor microsatellite instability (MSI and immunohistochemical (IHC MMR protein expression. Probands negative for pathogenic variants of MMR genes were screened for germline APC and MUTYH sequence variants. Most germline defects identified were sequence variants and rearrangements of MMR genes. Remarkably, altered germline ASE of MMR genes was detected in 8/22 (36.5% probands analyzed, including 3 cases negative at other screenings. Moreover, ASE provided evidence for the pathogenic role and guided the characterization of a VUS shared by 2 additional probands. No germline MMR gene promoter methylation was observed and only one EPCAM rearrangement was detected. In several cases, tumor IHC and MSI diverged from germline screening results. Notably, APC or biallelic MUTYH germline defects were identified in 2/19 probands negative for pathogenic variants of MMR genes. Our results show that ASE complements gDNA-based analyses in the identification of MMR defects and in the characterization of VUS affecting gene expression, increasing the number of germline alterations detected. An appreciable fraction of probands negative for MMR gene variants harbors APC or MUTYH variants. These results indicate that germline ASE analysis and screening for APC and MUTYH defects should be included in HNPCC diagnostic algorithms.

  17. Identification of transcriptome SNPs between Xiphophorus lines and species for assessing allele specific gene expression within F1 interspecies hybrids☆

    Science.gov (United States)

    Shen, Yingjia; Catchen, Julian; Garcia, Tzintzuni; Amores, Angel; Beldroth, Ion; Wagner, Jonathon R; Zhang, Ziping; Postlethwait, John; Warren, Wes; Schartl, Manfred; Walter, Ronald B.

    2011-01-01

    Variations in gene expression are essential for the evolution of novel phenotypes and for speciation. Studying allelic specific gene expression (ASGE) within interspecies hybrids provides a unique opportunity to reveal underlying mechanisms of genetic variation. Using Xiphophorus interspecies hybrid fishes and high-throughput next generation sequencing technology, we were able to assess variations between two closely related vertebrate species, X. maculatus and X. couchianus, and their F1 interspecies hybrids. We constructed transcriptome-wide SNP polymorphism sets between two highly inbred X. maculatus lines (JP 163 A and B), and between X. maculatus and a second species, X. couchianus. The X. maculatus JP 163 A and B parental lines have been separated in the laboratory for ≈ 70 years and we were able to identify SNPs at a resolution of 1 SNP per 49 kb of transcriptome. In contrast, SNP polymorphisms between X. couchianus and X. maculatus species, which diverged ≈ 5–10 million years ago, were identified about every 700 bp. Using 6,524 transcripts with identified SNPs between the two parental species (X. maculatus and X. couchianus), we mapped RNA-seq reads to determine ASGE within F1 interspecies hybrids. We developed an in silico X. couchianus transcriptome by replacing 90,788 SNP bases for X. maculatus transcriptome with the consensus X. couchianus SNP bases and provide evidence that this procedure overcomes read mapping biases. Employment of the insilico reference transcriptome and tolerating 5 mismatches during read mapping allow direct assessment of ASGE in the F1 interspecies hybrids. Overall, these results show that Xiphophorus is a tractable vertebrate experimental model to investigate how genetic variations that occur during speciation may affect gene interactions and the regulation of gene expression. PMID:21466860

  18. Identification of transcriptome SNPs between Xiphophorus lines and species for assessing allele specific gene expression within F₁ interspecies hybrids.

    Science.gov (United States)

    Shen, Yingjia; Catchen, Julian; Garcia, Tzintzuni; Amores, Angel; Beldorth, Ion; Wagner, Jonathan; Zhang, Ziping; Postlethwait, John; Warren, Wes; Schartl, Manfred; Walter, Ronald B

    2012-01-01

    Variations in gene expression are essential for the evolution of novel phenotypes and for speciation. Studying allelic specific gene expression (ASGE) within interspecies hybrids provides a unique opportunity to reveal underlying mechanisms of genetic variation. Using Xiphophorus interspecies hybrid fishes and high-throughput next generation sequencing technology, we were able to assess variations between two closely related vertebrate species, Xiphophorus maculatus and Xiphophorus couchianus, and their F(1) interspecies hybrids. We constructed transcriptome-wide SNP polymorphism sets between two highly inbred X. maculatus lines (JP 163 A and B), and between X. maculatus and a second species, X. couchianus. The X. maculatus JP 163 A and B parental lines have been separated in the laboratory for ≈70 years and we were able to identify SNPs at a resolution of 1 SNP per 49 kb of transcriptome. In contrast, SNP polymorphisms between X. couchianus and X. maculatus species, which diverged ≈5-10 million years ago, were identified about every 700 bp. Using 6524 transcripts with identified SNPs between the two parental species (X. maculatus and X. couchianus), we mapped RNA-seq reads to determine ASGE within F(1) interspecies hybrids. We developed an in silico X. couchianus transcriptome by replacing 90,788 SNP bases for X. maculatus transcriptome with the consensus X. couchianus SNP bases and provide evidence that this procedure overcomes read mapping biases. Employment of the in silico reference transcriptome and tolerating 5 mismatches during read mapping allow direct assessment of ASGE in the F(1) interspecies hybrids. Overall, these results show that Xiphophorus is a tractable vertebrate experimental model to investigate how genetic variations that occur during speciation may affect gene interactions and the regulation of gene expression.

  19. Cardiac-Restricted Expression of VCP/TER94 RNAi or Disease Alleles Perturbs Drosophila Heart Structure and Impairs Function

    Science.gov (United States)

    Viswanathan, Meera C.; Blice-Baum, Anna C.; Sang, Tzu-Kang; Cammarato, Anthony

    2016-01-01

    Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP's role(s) in the heart. Its functional diversity is determined by differential binding of distinct cofactors/adapters, which is likely disrupted during disease. VCP mutations cause multisystem proteinopathy (MSP), a pleiotropic degenerative disorder that involves inclusion body myopathy. MSP patients display progressive muscle weakness. They also exhibit cardiomyopathy and die from cardiac and respiratory failure, which are consistent with critical myocardial roles for the enzyme. Nonetheless, efficient models to interrogate VCP in cardiac muscle remain underdeveloped and poorly studied. Here, we investigated the significance of VCP and mutant VCP in the Drosophila heart. Cardiac-restricted RNAi-mediated knockdown of TER94, the Drosophila VCP homolog, severely perturbed myofibrillar organization and heart function in adult flies. Furthermore, expression of MSP disease-causing alleles engendered cardiomyopathy in adults and structural defects in embryonic hearts. Drosophila may therefore serve as a valuable model for examining role(s) of VCP in cardiogenesis and for identifying novel heart-specific VCP interactions, which when disrupted via mutation, contribute to or elicit cardiac pathology. PMID:27500162

  20. Earth's Energy Imbalance

    Science.gov (United States)

    Trenberth, K. E.; Fasullo, J.

    2013-12-01

    'Global warming' from increased greenhouse gases really refers to a global energy imbalance at the top-of-atmosphere (TOA). TOA measurements of radiation from space can track changes over time but lack absolute accuracy. An inventory of energy shows that over 90% of the imbalance is manifested as ocean heat content (OHC). Here we use ORAS4 ocean reanalysis data and other OHC estimates to compare the OHC rates of change with model-based estimates of TOA energy imbalance (from CCSM4), and with TOA satellite measurements for the year 2000 onwards. Most of the ocean-only OHC analyses extend to only 700 m depth, have large discrepancies among the rates of change of OHC, and do not resolve interannual variability adequately to capture ENSO and volcanic eruption effects. For the first time we show that ORAS4 OHC quantitatively agrees with the radiative forcing estimates of impacts of the 3 major volcanic eruptions since 1960 (Mt. Agung 1963, El Chichón 1982, and Mt. Pinatubo 1991). The natural variability of the energy imbalance is substantial from month-to-month associated with cloud and weather variations, and interannually mainly associated with ENSO, while the sun affects 15% of the climate change signal on decadal timescales. All estimates (OHC and TOA) show that over the past decade the energy imbalance ranges between about 0.5 and 1 W m-2. By using the full-depth ocean, there is a better overall accounting for energy, but discrepancies remain at interannual timescales between OHC and TOA radiation measurements, notably in 2008-09.

  1. Vip3A resistance alleles exist at high levels in Australian targets before release of cotton expressing this toxin.

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    Rod J Mahon

    Full Text Available Crops engineered to produce insecticidal crystal (Cry proteins from the soil bacterium Bacillus thuringiensis (Bt have revolutionised pest control in agriculture. However field-level resistance to Bt has developed in some targets. Utilising novel vegetative insecticidal proteins (Vips, also derived from Bt but genetically distinct from Cry toxins, is a possible solution that biotechnical companies intend to employ. Using data collected over two seasons we determined that, before deployment of Vip-expressing plants in Australia, resistance alleles exist in key targets as polymorphisms at frequencies of 0.027 (n = 273 lines, 95% CI = 0.019-0.038 in H. armigera and 0.008 (n = 248 lines, 0.004-0.015 in H. punctigera. These frequencies are above mutation rates normally encountered. Homozygous resistant neonates survived doses of Vip3A higher than those estimated in field-grown plants. Fortunately the resistance is largely, if not completely, recessive and does not confer resistance to the Bt toxins Cry1Ac or Cry2Ab already deployed in cotton crops. These later characteristics are favourable for resistance management; however the robustness of Vip3A inclusive varieties will depend on resistance frequencies to the Cry toxins when it is released (anticipated 2016 and the efficacy of Vip3A throughout the season. It is appropriate to pre-emptively screen key targets of Bt crops elsewhere, especially those such as H. zea in the USA, which is not only closely related to H. armigera but also will be exposed to Vip in several varieties of cotton and corn.

  2. Vip3A resistance alleles exist at high levels in Australian targets before release of cotton expressing this toxin.

    Science.gov (United States)

    Mahon, Rod J; Downes, Sharon J; James, Bill

    2012-01-01

    Crops engineered to produce insecticidal crystal (Cry) proteins from the soil bacterium Bacillus thuringiensis (Bt) have revolutionised pest control in agriculture. However field-level resistance to Bt has developed in some targets. Utilising novel vegetative insecticidal proteins (Vips), also derived from Bt but genetically distinct from Cry toxins, is a possible solution that biotechnical companies intend to employ. Using data collected over two seasons we determined that, before deployment of Vip-expressing plants in Australia, resistance alleles exist in key targets as polymorphisms at frequencies of 0.027 (n = 273 lines, 95% CI = 0.019-0.038) in H. armigera and 0.008 (n = 248 lines, 0.004-0.015) in H. punctigera. These frequencies are above mutation rates normally encountered. Homozygous resistant neonates survived doses of Vip3A higher than those estimated in field-grown plants. Fortunately the resistance is largely, if not completely, recessive and does not confer resistance to the Bt toxins Cry1Ac or Cry2Ab already deployed in cotton crops. These later characteristics are favourable for resistance management; however the robustness of Vip3A inclusive varieties will depend on resistance frequencies to the Cry toxins when it is released (anticipated 2016) and the efficacy of Vip3A throughout the season. It is appropriate to pre-emptively screen key targets of Bt crops elsewhere, especially those such as H. zea in the USA, which is not only closely related to H. armigera but also will be exposed to Vip in several varieties of cotton and corn.

  3. Expression levels of barley Cbf genes at the Frost resistance-H2 locus are dependent upon alleles at Fr-H1 and Fr-H2.

    Science.gov (United States)

    Stockinger, Eric J; Skinner, Jeffrey S; Gardner, Kip G; Francia, Enrico; Pecchioni, Nicola

    2007-07-01

    Genetic analyses have identified two loci in wheat and barley that mediate the capacity to overwinter in temperate climates. One locus co-segregates with VRN-1, which affects the vernalization requirement. This locus is known as Frost resistance-1 (Fr-1). The second locus, Fr-2, is coincident with a cluster of more than 12 Cbf genes. Cbf homologs in Arabidopsis thaliana play a key regulatory role in cold acclimatization and the acquisition of freezing tolerance. Here we report that the Hordeum vulgare (barley) locus VRN-H1/Fr-H1 affects expression of multiple barley Cbf genes at Fr-H2. RNA blot analyses, conducted on a 'Nure'x'Tremois' barley mapping population segregating for VRN-H1/Fr-H1 and Fr-H2, revealed that transcript levels of all cold-induced Cbf genes at Fr-H2 were significantly higher in recombinants harboring the vrn-H1 winter allele than in recombinants harboring the Vrn-H1 spring allele. Steady-state Cbf2 and Cbf4 levels were also significantly higher in recombinants harboring the Nure allele at Fr-H2. Additional experiments indicated that, in vrn-H1 genotypes requiring vernalization, Cbf expression levels were dampened after plants were vernalized, and dampened Cbf expression was accompanied by robust expression of Vrn-1. Cbf levels were also significantly higher in plants grown under short days than under long days. Experiments in wheat and rye indicated that similar regulatory mechanisms occurred in these plants. These results suggest that VRN-H1/Fr-H1 acts in part to repress or attenuate expression of the Cbf at Fr-H2; and that the greater level of low temperature tolerance attributable to the Nure Fr-H2 allele may be due to the greater accumulation of Cbf2 and Cbf4 transcripts during normal growth and development.

  4. Allelic asymmetry of the Lethal hybrid rescue (Lhr) gene expression in the hybrid between Drosophila melanogaster and D. simulans: confirmation by using genetic variations of D. melanogaster.

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    Shirata, Mika; Araye, Quenta; Maehara, Kazunori; Enya, Sora; Takano-Shimizu, Toshiyuki; Sawamura, Kyoichi

    2014-02-01

    In the cross between Drosophila melanogaster females and D. simulans males, hybrid males die at the late larval stage, and the sibling females also die at later stages at high temperatures. Removing the D. simulans allele of the Lethal hybrid rescue gene (Lhr (sim) ) improves the hybrid incompatibility phenotypes. However, the loss-of-function mutation of Lhr (sim) (Lhr (sim0) ) does not rescue the hybrid males in crosses with several D. melanogaster strains. We first describe the genetic factor possessed by the D. melanogaster strains. It has been suggested that removing the D. melanogaster allele of Lhr (Lhr (mel) ), that is Lhr (mel0) , does not have the hybrid male rescue effect, contrasting to Lhr (sim0) . Because the expression level of the Lhr gene is known to be Lhr (sim) > Lhr (mel) in the hybrid, Lhr (mel0) may not lead to enough of a reduction in total Lhr expression. Then, there is a possibility that the D. melanogaster factor changes the expression level to Lhr (sim) Lhr (mel) in the hybrid irrespectively of the presence of the factor. At last, we showed that Lhr (mel0) slightly improves the viability of hybrid females, which was not realized previously. All of the present results are consistent with the allelic asymmetry model of the Lhr gene expression in the hybrid.

  5. The Minor Allele of rs7574865 in the STAT4 Gene Is Associated with Increased mRNA and Protein Expression

    Science.gov (United States)

    Lamana, Amalia; López-Santalla, Mercedes; Castillo-González, Raquel; Ortiz, Ana María; Martín, Javier; García-Vicuña, Rosario; González-Álvaro, Isidoro

    2015-01-01

    Objective The T allele of rs7574865 in STAT4 confers risk of developing autoimmune disorders. However, its functional significance remains unclear. Here we analyze how rs7574865 affects the transcription of STAT4 and its protein expression. Methods We studied 201 patients (80% female; median age, 54 years; median disease duration, 5.4 months) from PEARL study. Demographic, clinical, laboratory and therapeutic data were collected at each visit. IL-6 serum levels were measured by enzyme immune assay. The rs7574865 was genotyped using TaqMan probes. The expression levels of STAT4 mRNA were determined at 182 visits from 69 patients using quantitative real-time polymerase chain reaction. STAT4 protein was assessed by western blot in 62 samples from 34 patients. To determine the effect of different variables on the expression of STAT4 mRNA and protein, we performed multivariate longitudinal analyses using generalized linear models. Results After adjustment for age, disease activity and glucocorticoid dose as confounders, the presence of at least one copy of the T allele of rs7574865 was significantly associated with higher levels of STAT4 mRNA. Similarly, TT patients showed significantly higher levels of STAT4 protein than GG patients. IL-6 induced STAT4 and STAT5 phosphorylation in peripheral blood lymphocytes. Patients carrying at least one T allele of rs7574865 displayed lower levels of serum IL-6 compared to GG homozygous; by contrast the production of C-reactive protein was similar in both populations. Conclusion Our data suggest that the presence of the rs7574865 T allele enhances STAT4 mRNA transcription and protein expression. It may enhance the signaling of molecules depending on the STAT4 pathway. PMID:26569609

  6. Fixed sagittal plane imbalance.

    Science.gov (United States)

    Savage, Jason W; Patel, Alpesh A

    2014-12-01

    Study Design Literature review. Objective To discuss the evaluation and management of fixed sagittal plane imbalance. Methods A comprehensive literature review was performed on the preoperative evaluation of patients with sagittal plane malalignment, as well as the surgical strategies to address sagittal plane deformity. Results Sagittal plane imbalance is often caused by de novo scoliosis or iatrogenic flat back deformity. Understanding the etiology and magnitude of sagittal malalignment is crucial in realignment planning. Objective parameters have been developed to guide surgeons in determining how much correction is needed to achieve favorable outcomes. Currently, the goals of surgery are to restore a sagittal vertical axis Sagittal plane malalignment is an increasingly recognized cause of pain and disability. Treatment of sagittal plane imbalance varies according to the etiology, location, and severity of the deformity. Fixed sagittal malalignment often requires complex reconstructive procedures that include osteotomy correction. Reestablishing harmonious spinopelvic alignment is associated with significant improvement in health-related quality-of-life outcome measures and patient satisfaction.

  7. The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.

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    Hayley C Whitaker

    Full Text Available BACKGROUND: Microseminoprotein-beta (MSMB regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. CONCLUSIONS: These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

  8. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

    Science.gov (United States)

    Hamdi, Yosr; Soucy, Penny; Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G; Goldberg, Mark S; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J; Hopper, John L; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Le Marchand, Loic; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J; Schmidt, Marjanka K; Shu, Xiao-Ou; Southey, Melissa C; Swerdlow, Anthony; Tollenaar, Rob A E M; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M W; Wang, Qin; Winqvist, Robert; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M; Pharoah, Paul D P; Kristensen, Vessela; Hall, Per; Easton, Douglas F; Pastinen, Tomi; Nord, Silje; Simard, Jacques

    2016-12-06

    There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

  9. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

    Science.gov (United States)

    Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Goldberg, Mark S.; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Marchand, Loic Le; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J.; Schmidt, Marjanka K.; Shu, Xiao-Ou; Southey, Melissa C.; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M. W.; Wang, Qin; Winqvist, Robert; Investigators, kConFab/AOCS; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M.; Pharoah, Paul D. P.; Kristensen, Vessela; Hall, Per; Easton, Douglas F.; Pastinen, Tomi; Nord, Silje; Simard, Jacques

    2016-01-01

    There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas. PMID:27792995

  10. Hybrid weakness in a rice interspecific hybrid is nitrogen-dependent, and accompanied by changes in gene expression at both total transcript level and parental allele partitioning

    Science.gov (United States)

    Lin, Xiuyun; Wang, Jie; Yu, Jiamiao; Sun, Yue; Miao, Yiling; Li, Qiuping; Sanguinet, Karen A.; Liu, Bao

    2017-01-01

    Background Hybrid weakness, a phenomenon opposite to heterosis, refers to inferior growth and development in a hybrid relative to its pure-line parents. Little attention has been paid to the phenomenological or mechanistic aspect of hybrid weakness, probably due to its rare occurrence. Methodology/Principal findings Here, using a set of interspecific triploid F1 hybrids between Oryza sativa, ssp. japonica (genome AA) and a tetraploid wild rice species, O. alta (genome, CCDD), we investigated the phenotypic and physiological differences between the F1 hybrids and their parents under normal and nitrogen-limiting conditions. We quantified the expression levels of 21 key genes involved in three important pathways pertinent to the assayed phenotypic and physiological traits by real-time qRT-PCR. Further, we assayed expression partitioning of parental alleles for eight genes in the F1 hybrids relative to the in silico “hybrids” (parental cDNA mixture) under both normal and N-limiting conditions by using locus-specific cDNA pyrosequencing. Conclusions/Significance We report that the F1 hybrids showed weakness in several phenotypic traits at the final seedling-stage compared with their corresponding mid-parent values (MPVs). Nine of the 21 studied genes showed contrasted expression levels between hybrids and parents (MPVs) under normal vs. N-limiting conditions. Interestingly, under N-limiting conditions, the overtly enhanced partitioning of maternal allele expression in the hybrids for eight assayed genes echo their attenuated hybrid weakness in phenotypes, an observation further bolstered by more resemblance of hybrids to the maternal parent under N-limiting conditions compared to normal conditions in a suite of measured physiological traits. Our observations suggest that both overall expression level and differential partitioning of parental alleles of critical genes contribute to condition-specific hybrid weakness. PMID:28248994

  11. Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients.

    Science.gov (United States)

    Dabora, Sandra L; Roberts, Penelope; Nieto, Andres; Perez, Ron; Jozwiak, Sergiusz; Franz, David; Bissler, John; Thiele, Elizabeth A; Sims, Katherine; Kwiatkowski, David J

    2002-10-01

    Tuberous sclerosis complex (TSC) is a familial hamartoma syndrome in which renal involvement is common and, at times, life threatening. We have investigated the potential effect of a non-TSC gene on renal disease in a cohort of 172 TSC patients with TSC2 mutations. Patients were genotyped for an interferon-gamma (IFN-gamma) microsatellite polymorphism, within intron 1, for which one common allele (allele 2, with 12 CA repeats) has been shown to have a higher expression of IFN-gamma. A chi(2) analysis was used to examine the association between IFN-gamma allele 2 and the development of kidney angiomyolipomas (KAMLs) in this TSC2 cohort. Because of the age-dependent development of KAMLs in TSC, we initially focused on the 127 patients who were >5 years old. Additional subgroup analyses were done to investigate the influence of age and gender. The transmission/disequilibrium test (TDT) was also performed in a subset of this cohort (46 probands) for whom parent and/or sibling samples were available for analysis. Both chi(2) analysis and TDT suggested an association between IFN-gamma allele 2 and the absence of KAMLs in patients who have known TSC2 mutations. Among the 127 patients who were >5 years old, KAMLs were present in 95 (75%) and were absent in 32 (25%). In the group with KAML present, the frequency of IFN-gamma allele 2 was 56%; in the group with KAML absent, the frequency of IFN-gamma allele 2 was significantly higher, at 78% (P=.02, by chi(2) analysis). The family-based TDT analysis gave similar results, with a TDT statistic (TDT chi2=5.45) corresponding to a P value of.02. Subgroup analyses show that both age and gender may influence the impact of this association. Although these results should be replicated in other populations with TSC, the present study suggests that modifier genes play a role in the variable expression of TSC and also suggests a potential therapy for KAMLs in patients with TSC.

  12. MRP1/GS-X pump ATPase expression: is this the explanation for the cytoprotection of the heart against oxidative stress-induced redox imbalance in comparison to skeletal muscle cells?

    Science.gov (United States)

    Krause, Maurício S; Oliveira, Lino P; Silveira, Elza M S; Vianna, Damiana R; Rossato, Juliane S; Almeida, Bibiana S; Rodrigues, Mariana F; Fernandes, Augustus J M; Costa, João A Bonatto; Curi, Rui; de Bittencourt, Paulo I Homem

    2007-01-01

    Striated muscle activity is always accompanied by oxidative stress (OxStress): the more intense muscle work and/or its duration, the more a redox imbalance may be attained. In spite of cardiac muscle functioning continuously, it is well known that the heart does not suffer from OxStress-induced damage over a broad physiological range. Although the expression of antioxidant enzymes may be of importance in defending heart muscle against OxStress, a series of combined antioxidant therapeutic approaches have proved to be mostly ineffective in avoiding cellular injury. Hence, additional mechanisms may be involved in heart cytoprotection other than antioxidant enzyme activities. The strong cardiotoxic effect of doxorubicin-induced cancer chemotherapy shed light on the possible role for multidrug resistance-associated proteins (MRP) in this context. Muscle activity-induced 'physiological' OxStress enhances the production of glutathione disulfide (GSSG) thus increasing the ratio of GSSG to glutathione (GSH) content inside the cells, which, in turn, leads to redox imbalance. Since MRP1 gene product (a GS-X pump ATPase) is a physiological GSSG transporter, adult Wistar rats were tested for MRP1 expression and activity in the heart and skeletal muscle (gastrocnemius), in as much as the latter is known to be extremely sensitive to muscle activity-induced OxS. MRP1 expression was completely absent in skeletal muscle. In contrast, the heart showed an exercise training-dependent induction of MRP1 protein expression which was further augmented (2.4-fold) as trained rats were challenged with a session of acute exercise. On the other hand, inducible expression of the 70-kDa heat shock protein (HSP70), a universal marker of cellular stress, was completely absent in the heart of sedentary and acutely exercised rats, whereas skeletal muscle showed a conspicuous exercise-dependent HSP70 expression, which decreased by 45% with exercise training. This effect was paralleled by a 58

  13. Functional characterization of a full length pregnane X receptor, expression in vivo, and identification of PXR alleles, in Zebrafish (Danio rerio)

    Energy Technology Data Exchange (ETDEWEB)

    Bainy, Afonso C.D. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Departamento de Bioquímica, CCB, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900 (Brazil); Kubota, Akira; Goldstone, Jared V. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Lille-Langøy, Roger [Department of Biology, University of Bergen, N-5020 Bergen (Norway); Karchner, Sibel I. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Celander, Malin C. [Department of Biological and Environmental Sciences, University of Gothenburg, SE 405 30 Göteborg (Sweden); Hahn, Mark E. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Goksøyr, Anders [Department of Biology, University of Bergen, N-5020 Bergen (Norway); Stegeman, John J., E-mail: jstegeman@whoi.edu [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States)

    2013-10-15

    Highlights: •Full-length pxr has been cloned from zebrafish. •Alleles of pxr were identified in zebrafish. •Full length Pxr was activated less strongly than ligand binding domain in cell-based reporter assays. •High levels of pxr expression were found in eye and brain as well as in liver. •TCPOBOP and PB did not significantly alter expression of pxr in liver. -- Abstract: The pregnane X receptor (PXR) (nuclear receptor NR1I2) is a ligand activated transcription factor, mediating responses to diverse xenobiotic and endogenous chemicals. The properties of PXR in fish are not fully understood. Here we report on cloning and characterization of full-length PXR of zebrafish, Danio rerio, and pxr expression in vivo. Initial efforts gave a cDNA encoding a 430 amino acid protein identified as zebrafish pxr by phylogenetic and synteny analysis. The sequence of the cloned Pxr DNA binding domain (DBD) was highly conserved, with 74% identity to human PXR-DBD, while the ligand-binding domain (LBD) of the cloned sequence was only 44% identical to human PXR-LBD. Sequence variation among clones in the initial effort prompted sequencing of multiple clones from a single fish. There were two prominent variants, one sequence with S183, Y218 and H383 and the other with I183, C218 and N383, which we designate as alleles pxr*1 (nr1i2*1) and pxr*2 (nr1i2*2), respectively. In COS-7 cells co-transfected with a PXR-responsive reporter gene, the full-length Pxr*1 (the more common variant) was activated by known PXR agonists clotrimazole and pregnenolone 16α-carbonitrile but to a lesser extent than the full-length human PXR. Activation of full-length Pxr*1 was only 10% of that with the Pxr*1 LBD. Quantitative real time PCR analysis showed prominent expression of pxr in liver and eye, as well as brain and intestine of adult zebrafish. The pxr was expressed in heart and kidney at levels similar to that in intestine. The expression of pxr in liver was weakly induced by ligands for

  14. Dijet imbalance in hadronic collisions

    NARCIS (Netherlands)

    Boer, Daniel; Mulders, Piet J.; Pisano, Cristian

    2009-01-01

    The imbalance of dijets produced in hadronic collisions has been used to extract the average transverse momentum of partons inside the hadrons. In this paper we discuss new contributions to the dijet imbalance that could complicate or even hamper this extraction. They are due to polarization of init

  15. A functional polymorphism in the Eta-1 promoter is associated with allele specific binding to the transcription factor Sp1 and elevated gene expression

    DEFF Research Database (Denmark)

    Hummelshoj, Tina; Ryder, Lars P; Madsen, Hans O

    2005-01-01

    Early T lymphocyte activator 1 (Eta-1), also known as Osteopontin, is a cytokine produced by macrophages and T lymphocytes. It is involved in the regulation of IL-12 and IL-10 expression in macrophages and stimulates the polarization of T cells to the Th1 subset. Three promoter polymorphisms...... of the human Eta-1 gene, -443T/C, -156delG/G, -66T/G, were investigated for possible influence on gene expression. Electrophoretic mobility shift assays (EMSA) with nuclear extract from the human myeloid leukaemia premonocyte cell line, THP-1, revealed sequence specific binding of the transcription factor Sp1...... to the -66T allele but not the -66G allele, and haplotype -443C/-156G/-66T showed a marked increase in promoter activity of a luciferase reporter gene. Thus, a substitution of the T-base with G at position -66 in the Eta-1 promoter modulates the promoter activity of the Eta-1 gene, which might influence...

  16. Matrix metalloproteinase imbalance in muscle disuse atrophy.

    Science.gov (United States)

    Giannelli, G; De Marzo, A; Marinosci, F; Antonaci, S

    2005-01-01

    Muscle atrophy commonly occurs as a consequence of prolonged muscle inactivity, as observed after cast immobilization, bed rest or space flights. The molecular mechanisms responsible for muscle atrophy are still unknown, but a role has been proposed for altered permeability of the sarcolemma and of the surrounding connective tissue. Matrix metallo-proteinases (MMPs) are a family of enzymes with proteolytic activity toward a number of extracellular matrix (ECM) components; they are inhibited by tissue inhibitors of MMPs (TIMPs). In a rat tail-suspension experimental model, we show that after fourteen days of non-weight bearing there is increased expression of MMP-2 in the atrophic soleus and gastrocnemius and decreased expression of TIMP-2. In the same experimental model the expression of Collagen I and Collagen IV, two main ECM components present in the muscles, was reduced and unevenly distributed in unloaded animals. The difference was more evident in the soleus than in the gastrocnemius muscle. This suggests that muscle disuse induces a proteolytic imbalance, which could be responsible for the breakdown of basal lamina structures such as Collagen I and Collagen IV, and that this leads to an altered permeability with consequent atrophy. In conclusion, an MMP-2/TIMP-2 imbalance could have a role in the mechanism underlying muscle disuse atrophy; more studies are needed to expand our molecular knowledge on this issue and to explore the possibility of targeting the proteolytic imbalance with MMP inhibitors.

  17. Chiral imbalance in QCD

    Directory of Open Access Journals (Sweden)

    Andrianov Alexander

    2017-01-01

    Full Text Available The chiral imbalance (ChI is given by a difference between the numbers of RH and LH quarks which may occur in the fireball after heavy ion collision. To characterize it adiabatically a quark chiral (axial chemical potential must be introduced taking into account emergence of a ChI in such a phase. In this report the phenomenology of formation of Local spatial Parity Breaking (LPB in the hot and dense baryon matter is discussed and its simulation within a number of QCD-inspired models is outlined. The appearance of new states in the spectra of scalar, pseudoscalar and vector particles in such a matter is elucidated. In particular, from the effective vector meson theory in the presence of Chern-Simons interaction it is demonstrated that the spectrum of massive vector mesons splits into three polarization components with different effective masses. The asymmetry in production of longitudinally and transversely polarized states of ρ and ω mesons for various values of the dilepton invariant mass can serve as a characteristic indication of the LPB in PHENIX, STAR and ALICE experiments.

  18. Illegitimate translation causes unexpected gene expression from on-target out-of-frame alleles created by CRISPR-Cas9

    Science.gov (United States)

    Makino, Shigeru; Fukumura, Ryutaro; Gondo, Yoichi

    2016-01-01

    CRISPR-Cas9 is efficient enough to knock out both alleles directly by introducing out-of-frame mutations. We succeeded in making biallelic on-target frameshift mutations of the endogenous Gli3 gene; however, the GLI3 protein was expressed in all six of the established cell lines carrying homozygous out-of-frame mutations. We developed a dual-tagged expression vector and proved that illegitimate translation (ITL) was the cause of the unexpected Gli3 expression. Thus, gene expression must be examined even if designed on-target out-of-frame sequences are introduced by genome editing. In addition, it is highly recommended to pre-examine the occurrence of ITL in vitro prior to the design and construction of any genome-editing vectors. In vitro assay systems such as the dual-tagged ITL assay system developed in this study should aid the identification and elucidation of ITL-based human diseases and gene expression. PMID:28000783

  19. Resistance to chronic wasting disease in transgenic mice expressing a naturally occurring allelic variant of deer prion protein

    NARCIS (Netherlands)

    Meade-White, K.; Race, B.; Trifilo, M.; Bossers, A.; Favara, C.; Lacasse, R.; Miller, M.; Williams, E.; Oldstone, M.; Race, R.; Chesebro, B.

    2007-01-01

    Prion protein (PrP) is a required factor for susceptibility to transmissible spongiform encephalopathy or prion diseases. In transgenic mice, expression of prion protein (PrP) from another species often confers susceptibility to prion disease from that donor species. For example, expression of deer

  20. Differences in the expressed HLA class I alleles effect the differential clustering of HIV type 1-specific T cell responses in infected Chinese and Caucasians

    Institute of Scientific and Technical Information of China (English)

    Yu,XG; Addo,MM; Perkins,BA; Wej,FL; Rathod,A; Geer,SC; Parta,M; Cohen,D; Stone,DR; Russell,CJ; Tanzi,G; Mei,S; Wureel,AG; Frahm,N; Lichterfeld,M; Heath,L; Mullins,JI; Marincola,F; Goulder,PJR; Brander,C; Allen,T; Cao,YZ; Walker,BD; Altfeld,M

    2005-01-01

    China is a region of the world with a rapidly spreading HIV-1 epidemic. Studies providing insights into HIV-1 pathogenesis in infected Chinese are urgently needed to support the design and testing of an effective HIV-1 vaccine for this population. HIV-1-specific T cell responses were characterized in 32 HIV-1-infected individuals of Chinese origin and compared to 34 infected caucasians using 410 overlapping peptides spanning the entire HIV-1 clade B consensus sequence in an IFN-gamma ELISpot assay. All HIV-1 proteins were targeted with similar frequency in both populations and all study subjects recognized at least one overlapping peptide. HIV-1-specific T cell responses clustered in seven different regions of the HIV-1 genome in the Chinese cohort and in nine different regions in the caucasian cohort. The dominant HLA class I alleles expressed in the two populations differed significantly, and differences in epitope clustering pattern were shown to be influenced by differences in class I alleles that restrict immunodominant epitopes. These studies demonstrate that the clustering of HIV-1-specific T cell responses is influenced by the genetic HLA class I background in the study populations. The design and testing of candidate vaccines to fight the rapidly growing HIV-1 epidemic must therefore take the HLA genetics of the population into account as specific regions of the virus can be expected to be differentially targeted in ethnically diverse populations.

  1. Frequent lambda light chain gene rearrangement and expression in a Ly-1 B lymphoma with a productive kappa chain allele.

    OpenAIRE

    Hardy, R R; Dangl, J L; Hayakawa, K.; Jager, G.; Herzenberg, L.A.

    1986-01-01

    We describe here a murine Ly-1-bearing pre-B-cell tumor that, when induced for kappa light chain expression with bacterial lipopolysaccharide, also gives rise spontaneously to a few percent of cells expressing surface lambda light chains. These lambda-positive cells have undergone DNA rearrangements involving either V lambda 1 or V lambda 2 genes. Nearly all clones of lambda-bearing cells express mu and lambda on their surface (but not kappa). However, all these lambda-positive clones continu...

  2. Differential expression of a BMP4 reporter allele in anterior fungiform versus posterior circumvallate taste buds of mice

    Directory of Open Access Journals (Sweden)

    Barlow Linda A

    2010-10-01

    Full Text Available Abstract Background Bone Morphogenetic Protein 4 (BMP4 is a diffusible factor which regulates embryonic taste organ development. However, the role of BMP4 in taste buds of adult mice is unknown. We utilized transgenic mice with LacZ under the control of the BMP4 promoter to reveal the expression of BMP4 in the tongues of adult mice. Further we evaluate the pattern of BMP4 expression with that of markers of specific taste bud cell types and cell proliferation to define and compare the cell populations expressing BMP4 in anterior (fungiform papillae and posterior (circumvallate papilla tongue. Results BMP4 is expressed in adult fungiform and circumvallate papillae, i.e., lingual structures composed of non-taste epithelium and taste buds. Unexpectedly, we find both differences and similarities with respect to expression of BMP4-driven ß-galactosidase. In circumvallate papillae, many fusiform cells within taste buds are BMP4-ß-gal positive. Further, a low percentage of BMP4-expressing cells within circumvallate taste buds is immunopositive for markers of each of the three differentiated taste cell types (I, II and III. BMP4-positive intragemmal cells also expressed a putative marker of immature taste cells, Sox2, and consistent with this finding, intragemmal cells expressed BMP4-ß-gal within 24 hours after their final mitosis, as determined by BrdU birthdating. By contrast, in fungiform papillae, BMP4-ß-gal positive cells are never encountered within taste buds. However, in both circumvallate and fungiform papillae, BMP4-ß-gal expressing cells are located in the perigemmal region, comprising basal and edge epithelial cells adjacent to taste buds proper. This region houses the proliferative cell population that gives rise to adult taste cells. However, perigemmal BMP4-ß-gal cells appear mitotically silent in both fungiform and circumvallate taste papillae, as we do not find evidence of their active proliferation using cell cycle immunomarkers

  3. Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele.

    Directory of Open Access Journals (Sweden)

    Cheryl A Hawkes

    Full Text Available Failure of elimination of amyloid-β (Aβ from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD and cerebral amyloid angiopathy (CAA. In addition to age, possession of an apolipoprotein E (APOE ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR mice expressing the human APOE3 (TRE3 or APOE4 (TRE4 genes and wildtype mice received intracerebral injections of human Aβ(40. Aβ(40 aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.

  4. Human bronchial epithelial cells exposed in vitro to diesel exhaust particles exhibit alterations in cell rheology and cytotoxicity associated with decrease in antioxidant defenses and imbalance in pro- and anti-apoptotic gene expression.

    Science.gov (United States)

    Seriani, Robson; de Souza, Claudia Emanuele Carvalho; Krempel, Paloma Gava; Frias, Daniela Perroni; Matsuda, Monique; Correia, Aristides Tadeu; Ferreira, Márcia Zotti Justo; Alencar, Adriano Mesquita; Negri, Elnara Marcia; Saldiva, Paulo Hilário Nascimento; Mauad, Thais; Macchione, Mariangela

    2016-05-01

    Diesel exhaust particles (DEPs) from diesel engines produce adverse alterations in cells of the airways by activating intracellular signaling pathways and apoptotic gene overexpression, and also by influencing metabolism and cytoskeleton changes. This study used human bronchial epithelium cells (BEAS-2B) in culture and evaluates their exposure to DEPs (15ug/mL for 1 and 2 h) in order to determine changes to cell rheology (viscoelasticity) and gene expression of the enzymes involved in oxidative stress, apoptosis, and cytotoxicity. BEAS-2B cells exposed to DEPs were found to have a significant loss in stiffness, membrane stability, and mitochondrial activity. The genes involved in apoptosis [B cell lymphoma 2 (BCL-2 and caspase-3)] presented inversely proportional expressions (p = 0.05, p = 0.01, respectively), low expression of the genes involved in antioxidant responses [SOD1 (superoxide dismutase 1); SOD2 (superoxide dismutase 2), and GPx (glutathione peroxidase) (p = 0.01)], along with an increase in cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) (p = 0.01). These results suggest that alterations in cell rheology and cytotoxicity could be associated with oxidative stress and imbalance between pro- and anti-apoptotic genes.

  5. Reduced stability and bi-allelic, coequal expression of profilaggrin mRNA in keratinocytes cultured from subjects with ichthyosis vulgaris.

    Science.gov (United States)

    Nirunsuksiri, W; Zhang, S H; Fleckman, P

    1998-06-01

    Ichthyosis vulgaris (IV) is an inherited scaling skin disorder in which expression of profilaggrin is reduced. Previous studies have indicated that the reduction is caused by defective post-transcriptional control of gene expression. Here we present evidence that profilaggrin mRNA in keratinocytes cultured from subjects with IV is intrinsically unstable and has a shorter half-life compared with that in normal cells. When IV-affected keratinocytes were treated with the protein synthesis inhibitor cycloheximide, the steady-state level of profilaggrin mRNA was increased due to stabilization of the transcript. In addition, the number of filaggrin repeats within the profilaggrin gene was studied. The number of filaggrin repeats (10-12) in individuals with IV did not differ from that of unaffected subjects. Expression of the gene was bi-allelic and coequal in both control and affected individuals. Our results suggest a model in which a labile ribonuclease and a stabilizing factor may modulate the profilaggrin mRNA steady-state level in normal cells, whereas the stabilizing factor may be absent or functionally inactive in IV-affected keratinocytes.

  6. Horizontal fiscal imbalance in Germany

    Directory of Open Access Journals (Sweden)

    Paweł Kowalik

    2015-04-01

    Full Text Available Regional inequalities are currently a challenge for the majority of the countries, in particular the large ones. The problem of public income redistribution emerges due to possible differentiation of the economic development level of territorial units. The most often considered problem is the vertical distribution. The horizontal division of income is far less frequently considered. Horizontal fiscal imbalance or regional tax inequalities seem to be graver than the vertical imbalance, particularly in developing countries. The public finance system, in particular in federations, is often very complex. Public finance of federations and federated states are not often based on the same assumptions. This leads to differences among regions, both vertical and horizontal. The use of the presented measures helps identify those differences and permits developing mechanisms equalising those inequalities. It should be remembered that those measures may have certain drawbacks, and they mainly focus on certain specific values of income redistribution. Thereby several measures should be applied in measurements and the obtained results should be compared. There are no up-to-date measurements and comparisons of horizontal fiscal imbalance among countries.. The aim of this paper is to measure horizontal fiscal imbalance in Germany, especially after reunification, which represents one of two models of federalism. At the beginning it shows the static and dynamic measurements presented in the literature that can be used to measure the horizontal fiscal imbalance. And then it is followed by the results of calculations for Germany in the period 1970-2013. As expected, horizontal imbalance was much lower before than after the reunification of Germany. After the reunification there were large disparities between "old" and "new" länder. This imbalance is gradually reduced. In comparison with the results obtained for the USA [Kowalik 2014, pp. 144-148] it can be said

  7. Chronic vitamin C deficiency promotes redox imbalance in the brain but does not alter sodium-dependent vitamin C transporter 2 expression

    DEFF Research Database (Denmark)

    Paidi, Maya Devi; Schjoldager, Janne Gram; Lykkesfeldt, Jens

    2014-01-01

    achieved by the sodium dependent VitC transporter (SVCT2). This study investigated the effects of chronic pre-and postnatal VitC deficiency as well as the effects of postnatal VitC repletion, on brain SVCT2 expression and markers of oxidative stress in young guinea pigs. Biochemical analyses demonstrated...

  8. Inverse imbalance reconstruction in rotordynamics

    Energy Technology Data Exchange (ETDEWEB)

    Ramlau, R. [Austrian Academy of Sciences, Linz (Austria). Johann Radon Inst. for Computational and Applied Mathematics; Dicken, V. [MeVis GmbH, Bremen (Germany); Maass, P. [Bremen Univ. (Germany). Zentrum fuer Technomathematik; Streller, C. [Rolls-Royce Germany GmbH, Dahlewitz (Germany); Rienaecker, A. [MTU Aero Engines GmbH, Muenchen (Germany)

    2006-05-15

    The goal of this work is to establish and compare algorithms for inverse imbalance reconstruction in aircraft turbines. Such algorithms are based on a validated whole engine model of a turbo engine under consideration. Base on the model, the impact of an imbalance distribution on the vibration behaviour of the turbine can be described as a matrix-vector multiplication Af = g, where f is the imbalance distribution and g the vibration response. It turns out that the matrix A is very ill-conditioned. As the measured data is highly affected with noise, we have to use regularization methods in order to stabilize the inversion. Our main interest was in the use of nonlinear regularization methods, in particular nonlinear filtered singular value decomposition and conjugate gradient regularization. (orig.)

  9. HMG CoA Lyase (HL): Mutation detection and development of a bacterial expression system for screening the activity of mutant alleles from HL-deficient patients

    Energy Technology Data Exchange (ETDEWEB)

    Robert, M.F.; Ashmarina, L.; Poitier, E. [Hospital Ste-Justine, Montreal (Canada)] [and others

    1994-09-01

    HL catalyzes the last step of ketogenesis, and autosomal recessive HL deficiency in humans can cause episodes of hypoglycemia and coma. Structurally, HL is a dimer of identical 325-residue peptides which requires a reducing environment to maintain activity. We cloned the human and mouse HL cDNAs and genes and have performed mutation analysis on cells from 30 HL-deficient probands. Using SSCP and also genomic Southern analysis we have identified putative mutations on 53/60 alleles of these patients (88%). To date, we have found 20 mutations: 3 large deletions, 4 termination mutations, 5 frameshift mutations, and 8 missense mutations which we suspect to be pathogenic based on evolutionary conservation and/or our previous studies on purified HL protein. We have also identified 3 polymorphic variants. In order to directly test the activity of the missense mutations, we established a pGEX-based system, using a glutathione S transferase (GST)-HL fusion protein. Expressed wild-type GST-HL was insoluble. We previously located a reactive Cys at the C-terminus of chicken HL which is conserved in human HL. We produced a mutant HL peptide, C323S, which replaced Cys323 with Ser. Purified C323S is soluble and has similar kinetics to wild-type HL. C323S-containing GST-HL is soluble and enzymatically active. We are cloning and expressing the 8 missense mutations.

  10. The expression of one ankyrin pk2 allele of the WO prophage is correlated with the Wolbachia feminizing effect in isopods

    Directory of Open Access Journals (Sweden)

    Pichon Samuel

    2012-04-01

    Full Text Available Abstract Background The maternally inherited α-Proteobacteria Wolbachia pipientis is an obligate endosymbiont of nematodes and arthropods, in which they induce a variety of reproductive alterations, including Cytoplasmic Incompatibility (CI and feminization. The genome of the feminizing wVulC Wolbachia strain harboured by the isopod Armadillidium vulgare has been sequenced and is now at the final assembly step. It contains an unusually high number of ankyrin motif-containing genes, two of which are homologous to the phage-related pk1 and pk2 genes thought to contribute to the CI phenotype in Culex pipiens. These genes encode putative bacterial effectors mediating Wolbachia-host protein-protein interactions via their ankyrin motifs. Results To test whether these Wolbachia homologs are potentially involved in altering terrestrial isopod reproduction, we determined the distribution and expression of both pk1 and pk2 genes in the 3 Wolbachia strains that induce CI and in 5 inducing feminization of their isopod hosts. Aside from the genes being highly conserved, we found a substantial copy number variation among strains, and that is linked to prophage diversity. Transcriptional analyses revealed expression of one pk2 allele (pk2b2 only in the feminizing Wolbachia strains of isopods. Conclusions These results reveal the need to investigate the functions of Wolbachia ankyrin gene products, in particular those of Pk2, and their host targets with respect to host sex manipulation.

  11. Choreography of Ig allelic exclusion.

    Science.gov (United States)

    Cedar, Howard; Bergman, Yehudit

    2008-06-01

    Allelic exclusion guarantees that each B or T cell only produces a single antigen receptor, and in this way contributes to immune diversity. This process is actually initiated in the early embryo when the immune receptor loci become asynchronously replicating in a stochastic manner with one early and one late allele in each cell. This distinct differential replication timing feature then serves an instructive mark that directs a series of allele-specific epigenetic events in the immune system, including programmed histone modification, nuclear localization and DNA demethylation that ultimately bring about preferred rearrangement on a single allele, and this decision is temporally stabilized by feedback mechanisms that inhibit recombination on the second allele. In principle, these same molecular components are also used for controlling monoallelic expression at other genomic loci, such as those carrying interleukins and olfactory receptor genes that require the choice of one gene out of a large array. Thus, allelic exclusion appears to represent a general epigenetic phenomenon that is modeled on the same basis as X chromosome inactivation.

  12. Impaired learning and memory in rats induced by a high-fat diet: involvement with the imbalance of nesfatin-1 abundance and copine 6 expression.

    Science.gov (United States)

    Chen, Zheng; Xu, Ya-Yun; Wu, Rui; Han, Yin-Xiu; Yu, Yue; Ge, Jin-Fang; Chen, Fei-Hu

    2017-02-17

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, resulting not only in liver dysfunction, glucose and lipid metabolism disorder, but also in neuropsychiatric damage. In the present study, a NAFLD rat model was established via feeding of a high-fat diet, and the behavior was observed via the open field test (OFT), the sucrose preference test (SPT), the elevated plus maze (EPM), the forced swimming test (FST), and the Morris water maze (MWM). The plasma concentrations of alanine aminotransferase (ALT), glucose, free fatty acid (FFA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were detected using chemiluminescence technique. The plasma levels of nesfatin-1, leptin, and insulin were measured via enzyme-linked immunosorbent assay (ELISA), and the protein expressions of p-GSK-3β, GSK-3β, p-β-catenin, β-catenin, cyclinD, and copine 6 in the hippocampus and prefrontal cortex (PFC) were detected using western blotting. After 4 consecutive weeks of feeding with a high-fat diet, the rats showed obesity; increased plasma concentrations of ALT, glucose, FFA, TC, TG, HDL-C, and LDL-C; decreased plasma levels of leptin and insulin; and inflammation and mild hepatocyte steatosis in the liver. Although there was no significant difference between groups with regard to performance in the OFT, EPM, or FST, the NAFLD rats showed a decreased sucrose preference index in the SPT and impaired learning and memory in the MWM task. Moreover, the present study provides the first evidence of an increased plasma nesfatin-1 concentration in the NAFLD rats, which was significantly correlated with the plasma lipid concentrations and the behavioral performance. Furthermore, copine 6 and p-β-catenin protein expression decreased and p-GSK-3β increased in the hippocampus and PFC of NAFLD rats. These results suggested that consuming of a high-fat diet for 4

  13. Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences.

    Directory of Open Access Journals (Sweden)

    Melinda Butsch Kovacic

    Full Text Available BACKGROUND: Asthma is a chronic inflammatory disease with a strong genetic predisposition. A major challenge for candidate gene association studies in asthma is the selection of biologically relevant genes. METHODOLOGY/PRINCIPAL FINDINGS: Using epithelial RNA expression arrays, HapMap allele frequency variation, and the literature, we identified six possible candidate susceptibility genes for childhood asthma including ADCY2, DNAH5, KIF3A, PDE4B, PLAU, SPRR2B. To evaluate these genes, we compared the genotypes of 194 predominantly tagging SNPs in 790 asthmatic, allergic and non-allergic children. We found that SNPs in all six genes were nominally associated with asthma (p<0.05 in our discovery cohort and in three independent cohorts at either the SNP or gene level (p<0.05. Further, we determined that our selection approach was superior to random selection of genes either differentially expressed in asthmatics compared to controls (p = 0.0049 or selected based on the literature alone (p = 0.0049, substantiating the validity of our gene selection approach. Importantly, we observed that 7 of 9 SNPs in the KIF3A gene more than doubled the odds of asthma (OR = 2.3, p<0.0001 and increased the odds of allergic disease (OR = 1.8, p<0.008. Our data indicate that KIF3A rs7737031 (T-allele has an asthma population attributable risk of 18.5%. The association between KIF3A rs7737031 and asthma was validated in 3 independent populations, further substantiating the validity of our gene selection approach. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that KIF3A, a member of the kinesin superfamily of microtubule associated motors that are important in the transport of protein complexes within cilia, is a novel candidate gene for childhood asthma. Polymorphisms in KIF3A may in part be responsible for poor mucus and/or allergen clearance from the airways. Furthermore, our study provides a promising framework for the identification and

  14. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

    NARCIS (Netherlands)

    Y. Hamdi (Yosr); Soucy, P. (Penny); Kuchenbaeker, K.B. (Karoline B.); Pastinen, T. (Tomi); A. Droit (Arnaud); Lemaçon, A. (Audrey); J.W. Adlard (Julian); K. Aittomäki (Kristiina); I.L. Andrulis (Irene); A. Arason (Adalgeir); N. Arnold (Norbert); B.K. Arun (Banu); J. Azzollini; A.L. Bane (Anita L.); Barjhoux, L. (Laure); D. Barrowdale (Daniel); J. Benítez (Javier); P. Berthet (Pascaline); M.J. Blok (Marinus); K.A. Bobolis (Kristie A.); V. Bonadona (Valérie); B. Bonnani (Bernardo); Bradbury, A.R. (Angela R.); C. Brewer (Carole); B. Buecher (Bruno); Buys, S.S. (Saundra S.); M.A. Caligo (Maria); Chiquette, J. (Jocelyne); W. Chung (Wendy); K.B.M. Claes (Kathleen B.M.); Daly, M.B. (Mary B.); F. Damiola (Francesca); R. Davidson (Rosemarie); M. de La Hoya (Miguel); K. De Leeneer (Kim); O. Díez (Orland); Y.C. Ding (Yuan); R. Dolcetti (Riccardo); S.M. Domchek (Susan); C.M. Dorfling (Cecilia); D. Eccles (Diana); R. Eeles (Ros); Z. Einbeigi (Zakaria); B. Ejlertsen (Bent); EMBRACE; C. Engel (Christoph); Gareth Evans, D.; L. Feliubadaló (L.); L. Foretova (Lenka); F. Fostira (Florentia); Foulkes, W.D. (William D.); G. Fountzilas (George); E. Friedman (Eitan); D. Frost (Debra); P. Ganschow (Pamela); P.A. Ganz (Patricia A.); J. Garber (Judy); S.A. Gayther (Simon); GEMO Study Collaborators; A-M. Gerdes (Anne-Marie); G. Glendon (Gord); A.K. Godwin (Andrew K.); D. Goldgar (David); M.H. Greene (Mark H.); J. Gronwald (Jacek); E. Hahnen (Eric); U. Hamann (Ute); T.V.O. Hansen (Thomas); S. Hart (Stewart); J. Hays (John); HEBON; F.B.L. Hogervorst (Frans); P.J. Hulick (Peter); E.N. Imyanitov (Evgeny); C. Isaacs (Claudine); L. Izatt (Louise); A. Jakubowska (Anna); M. James (Margaret); R. Janavicius (Ramunas); U.B. Jensen; E.M. John (Esther); V. Joseph (Vijai); Just, W. (Walter); Kaczmarek, K. (Katarzyna); Karlan, B.Y. (Beth Y.); KConFab Investigators; C.M. Kets; J. Kirk (Judy); Kriege, M. (Mieke); Y. Laitman (Yael); Laurent, M. (Maïté); C. Lazaro (Conxi); Leslie, G. (Goska); K.J. Lester (Kathryn); F. Lesueur (Fabienne); A. Liljegren (Annelie); N. Loman (Niklas); J.T. Loud (Jennifer); S. Manoukian (Siranoush); Mariani, M. (Milena); S. Mazoyer (Sylvie); L. McGuffog (Lesley); E.J. Meijers-Heijboer (Hanne); A. Meindl (Alfons); A. Miller (Austin); M. Montagna (Marco); A.-M. Mulligan (Anna-Marie); K.L. Nathanson (Katherine); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); R.L. Nussbaum (Robert L.); Olah, E. (Edith); O.I. Olopade (Olufunmilayo I.); K.-R. Ong (Kai-Ren); J.C. Oosterwijk (Jan); A. Osorio (Ana); L. Papi (Laura); S.K. Park (Sue K.); Pedersen, I.S. (Inge Sokilde); B. Peissel (Bernard); P.P. Segura (Pedro Perez); P. Peterlongo (Paolo); C. Phelan (Catherine); P. Radice (Paolo); J. Rantala (Johanna); Rappaport-Fuerhauser, C. (Christine); G. Rennert (Gad); A.L. Richardson (Andrea); M. Robson (Mark); G.C. Rodriguez (Gustavo); M.A. Rookus (Matti); R.K. Schmutzler (Rita); N. Sevenet (Nicolas); Shah, P.D. (Payal D.); C.F. Singer (Christian); Slavin, T.P. (Thomas P.); Snape, K. (Katie); J. Sokolowska (Johanna); Sønderstrup, I.M.H. (Ida Marie Heeholm); M.C. Southey (Melissa); A.B. Spurdle (Amanda); Stadler, Z. (Zsofia); D. Stoppa-Lyonnet (Dominique); G. Sukiennicki (Grzegorz); C. Sutter (Christian); Tan, Y. (Yen); M.-K. Tea; P.J. Teixeira; A. Teulé (A.); S.-H. Teo; M.B. Terry (Mary Beth); M. Thomassen (Mads); L. Tihomirova (Laima); M. Tischkowitz (Marc); S. Tognazzo (Silvia); A.E. Toland (Amanda); N. Tung (Nadine); A.M.W. van den Ouweland (Ans); R.B. van der Luijt (Rob); K. van Engelen (Klaartje); E.J. van Rensburg (Elizabeth); R. Varon-Mateeva (Raymonda); B. Wapenschmidt (Barbara); J.T. Wijnen (Juul); R. Rebbeck (Timothy); G. Chenevix-Trench (Georgia); K. Offit (Kenneth); Couch, F.J. (Fergus J.); S. Nord (Silje); D.F. Easton (Douglas F.); A.C. Antoniou (Antonis C.); Simard, J. (Jacques)

    2016-01-01

    textabstractPurpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility

  15. Alteration in Oxidative/nitrosative imbalance, histochemical expression of osteopontin and antiurolithiatic efficacy of Xanthium strumarium (L.) in ethylene glycol induced urolithiasis.

    Science.gov (United States)

    Panigrahi, Padma Nibash; Dey, Sahadeb; Sahoo, Monalisa; Choudhary, Shyam Sundar; Mahajan, Sumit

    2016-12-01

    Xanthium strumarium has traditionally been used in the treatment of urolitiasis especially by the rural people in India, but its antiurolithiatic efficacy was not explored scientifically till now. Therefore, the present study was designed to validate the ethnic practice scientifically, and explore the possible antiurolithiatic effect to rationalize its medicinal use. Urolitiasis was induced in hyperoxaluric rat model by giving 0.75% ethylene glycol (EG) for 28days along with 1% ammonium chloride (AC) for first 14days. Antiurolithiatic effect of aqueous-ethanol extract of Xanthium strumarium bur (xanthium) was evaluated based on urine and serum biochemistry, oxidative/nitrosative stress indices, histopathology, kidney calcium and calcium oxalate content and immunohistochemical expression of matrix glycoprotein, osteopontin (OPN). Administration of EG and AC resulted in hyperoxaluria, crystalluria, hypocalciuria, polyurea, raised serum urea, creatinine, erythrocytic lipid peroxidise and nitric oxide, kidney calcium content as well as crystal deposition in kidney section in lithiatic group rats. However, xanthium treatment significantly restored the impairment in above kidney function test as that of standard treatment, cystone. The up-regulation of OPN was also significantly decreased after xanthium treatment. The present findings demonstrate the curative efficacy of xanthium in ethylene glycol induced urolithiasis, possibly mediated through inhibition of various pathways involved in renal calcium oxalate formation, antioxidant property and down regulation of matrix glycoprotein, OPN. Therefore, future studies may be established to evaluate its efficacy and safety for clinical use.

  16. Imbalance of Excitatory/Inhibitory Synaptic Protein Expression in iPSC-derived Neurons from FOXG1+/− Patients and in Foxg1+/− Mice

    Science.gov (United States)

    Patriarchi, Tommaso; Amabile, Sonia; Frullanti, Elisa; Landucci, Elisa; Lo Rizzo, Caterina; Ariani, Francesca; Costa, Mario; Olimpico, Francesco; Hell, Johannes W.; Vaccarino, Flora M.; Renieri, Alessandra; Meloni, Ilaria

    2015-01-01

    Rett Syndrome (RTT) is a severe neurodevelopmental disorder associated with mutations in either MECP2, CDKL5 or FOXG1. The precise molecular mechanisms that lead to the pathogenesis of RTT have yet to be elucidated. We recently reported that expression of GluD1 (orphan Glutamate receptor Delta-1 subunit) is increased in iPSC-derived neurons obtained from patients with mutations in either MECP2 or CDKL5. GluD1 controls synaptic differentiation and shifts the balance between excitatory and inhibitory synapses towards the latter. Thus, an increase in GluD1 might be a critical factor in the etiology of RTT by affecting the excitatory/inhibitory balance in the developing brain. To test this hypothesis, we generated iPSC-derived neurons from FOXG1+/− patients. We analyzed mRNA and protein levels of GluD1 together with key markers of excitatory and inhibitory synapses in these iPSC-derived neurons and in Foxg1+/− mouse fetal (E11.5) and adult (P70) brains. We found strong correlation between iPSC-derived neurons and fetal mouse brains, where GluD1 and inhibitory synaptic markers (GAD67 and GABA AR-α1) were increased, while the levels of a number of excitatory synaptic markers (VGLUT1, GluA1, GluN1, PSD-95) were decreased. In adult mice, GluD1 was decreased along with all GABAergic and glutamatergic markers. Our findings further the understanding of the etiology of RTT by introducing a new pathological event occurring in the brain of FOXG1+/− patients during embryonic development and its time-dependent shift toward a general decrease in brain synapses. PMID:26443267

  17. DMD transcript imbalance determines dystrophin levels.

    Science.gov (United States)

    Spitali, Pietro; van den Bergen, Janneke C; Verhaart, Ingrid E C; Wokke, Beatrijs; Janson, Anneke A M; van den Eijnde, Rani; den Dunnen, Johan T; Laros, Jeroen F J; Verschuuren, Jan J G M; 't Hoen, Peter A C; Aartsma-Rus, Annemieke

    2013-12-01

    Duchenne and Becker muscular dystrophies are caused by out-of-frame and in-frame mutations, respectively, in the dystrophin encoding DMD gene. Molecular therapies targeting the precursor-mRNA are in clinical trials and show promising results. These approaches will depend on the stability and expression levels of dystrophin mRNA in skeletal muscles and heart. We report that the DMD gene is more highly expressed in heart than in skeletal muscles, in mice and humans. The transcript mutated in the mdx mouse model shows a 5' to 3' imbalance compared with that of its wild-type counterpart and reading frame restoration via antisense-mediated exon skipping does not correct this event. We also report significant transcript instability in 22 patients with Becker dystrophy, clarifying the fact that transcript imbalance is not caused by premature nonsense mutations. Finally, we demonstrate that transcript stability, rather than transcriptional rate, is an important determinant of dystrophin protein levels in patients with Becker dystrophy. We suggest that the availability of the complete transcript is a key factor to determine protein abundance and thus will influence the outcome of mRNA-targeting therapies.

  18. A novel allelic variant of the human TSG-6 gene encoding an amino acid difference in the CUB module. Chromosomal localization, frequency analysis, modeling, and expression.

    Science.gov (United States)

    Nentwich, Hilke A; Mustafa, Zehra; Rugg, Marilyn S; Marsden, Brian D; Cordell, Martin R; Mahoney, David J; Jenkins, Suzanne C; Dowling, Barbara; Fries, Erik; Milner, Caroline M; Loughlin, John; Day, Anthony J

    2002-05-03

    Tumor necrosis factor-stimulated gene-6 (TSG-6) encodes a 35-kDa protein, which is comprised of contiguous Link and CUB modules. TSG-6 protein has been detected in the articular joints of osteoarthritis (OA) patients, with little or no constitutive expression in normal adult tissues. It interacts with components of cartilage matrix (e.g. hyaluronan and aggrecan) and thus may be involved in extracellular remodeling during joint disease. In addition, TSG-6 has been found to have anti-inflammatory properties in models of acute and chronic inflammation. Here we have mapped the human TSG-6 gene to 2q23.3, a region of chromosome 2 linked with OA. A single nucleotide polymorphism was identified that involves a non-synonymous G --> A transition at nucleotide 431 of the TSG-6 coding sequence, resulting in an Arg to Gln alteration in the CUB module (at residue 144 in the preprotein). Molecular modeling of the CUB domain indicated that this amino acid change might lead to functional differences. Typing of 400 OA cases and 400 controls revealed that the A(431) variant identified here is the major TSG-6 allele in Caucasians (with over 75% being A(431) homozygotes) but that this polymorphism is not a marker for OA susceptibility in the patients we have studied. Expression of the Arg(144) and Gln(144) allotypes in Drosophila Schneider 2 cells, and functional characterization, showed that there were no significant differences in the ability of these full-length proteins to bind hyaluronan or form a stable complex with inter-alpha-inhibitor.

  19. A humanized UGT1 mouse model expressing the UGT1A1*28 allele for assessing drug clearance by UGT1A1-dependent glucuronidation.

    Science.gov (United States)

    Cai, Hongliang; Nguyen, Nghia; Peterkin, Vincent; Yang, Young-Sun; Hotz, Kathy; La Placa, Deirdre Beaton; Chen, Shujuan; Tukey, Robert H; Stevens, Jeffrey C

    2010-05-01

    Humanized mice that express the human UDP-glucuronosyltransferase (UGT) 1 locus have been developed in a Ugt1-null background as a model to improve predictions of human UGT1A-dependent drug clearance. Enzyme kinetic parameters (K(m) and V(max)) and pharmacokinetic properties of three probe drugs were compared using wild-type and humanized UGT1 mice that express the Gilbert's UGT1A1*28 allele [Tg(UGT1(A1*28)) Ugt1(-/-) mice]. The well characterized substrate for UGT1A1, 7-ethyl-10-hydroxy-camptothecin (SN-38), showed the greatest difference in parent drug exposure ( approximately 3-fold increase) and clearance ( approximately 3-fold decrease) in Tg(UGT1(A1*28)) Ugt1(-/-) mice after intravenous administration compared with wild-type and phenobarbital-treated animals. In contrast, the clearance of the UGT2B7 substrate (-)-17-allyl-4, 5alpha-epoxy-3, 14-dihydroxymorphinan-6-one (naloxone) was not altered in Tg(UGT1(A1*28)) Ugt1(-/-) mice. In addition, pharmacokinetic parameters with 1-(4-fluorophenyl)3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (ezetimibe, Zetia; Merck & Co., Whitehouse Station, NJ), considered to be a major substrate for UGT1A1, showed small to no dependence on UGT1A1-directed glucuronidation. Enzyme kinetic parameters assessed for SN-38, ezetimibe, and naloxone using liver microsomes prepared from wild-type and Tg(UGT1(A1*28)) Ugt1(-/-) mice showed patterns consistent with the in vivo pharmacokinetic data. For SN-38 glucuronidation, V(max) decreased 5-fold in Tg(UGT1(A1*28)) Ugt1(-/-) mouse liver microsomes compared with microsomes prepared from wild-type mice, and decreased 10-fold compared with phenobarbital-treated Tg(UGT1(A1*28)) Ugt1(-/-) mice. These differences are consistent with SN-38 glucuronidation activities using HLMs isolated from individuals genotyped as UGT1A1*1 or UGT1A1*28. For ezetimibe and naloxone the differences in V(max) were minimal. Thus, Tg(UGT1(A1*28)) Ugt1(-/-) mice can serve as a

  20. Isolation of an Escherichia coli K-12 mutant strain able to form biofilms on inert surfaces: involvement of a new ompR allele that increases curli expression.

    Science.gov (United States)

    Vidal, O; Longin, R; Prigent-Combaret, C; Dorel, C; Hooreman, M; Lejeune, P

    1998-05-01

    Classical laboratory strains of Escherichia coli do not spontaneously colonize inert surfaces. However, when maintained in continuous culture for evolution studies or industrial processes, these strains usually generate adherent mutants which form a thick biofilm, visible with the naked eye, on the wall of the culture apparatus. Such a mutant was isolated to identify the genes and morphological structures involved in biofilm formation in the very well characterized E. coli K-12 context. This mutant acquired the ability to colonize hydrophilic (glass) and hydrophobic (polystyrene) surfaces and to form aggregation clumps. A single point mutation, resulting in the replacement of a leucine by an arginine residue at position 43 in the regulatory protein OmpR, was responsible for this phenotype. Observations by electron microscopy revealed the presence at the surfaces of the mutant bacteria of fibrillar structures looking like the particular fimbriae described by the Olsén group and designated curli (A. Olsén, A. Jonsson, and S. Normark, Nature 338:652-655, 1989). The production of curli (visualized by Congo red binding) and the expression of the csgA gene encoding curlin synthesis (monitored by coupling a reporter gene to its promoter) were significantly increased in the presence of the ompR allele described in this work. Transduction of knockout mutations in either csgA or ompR caused the loss of the adherence properties of several biofilm-forming E. coli strains, including all those which were isolated in this work from the wall of a continuous culture apparatus and two clinical strains isolated from patients with catheter-related infections. These results indicate that curli are morphological structures of major importance for inert surface colonization and biofilm formation and demonstrate that their synthesis is under the control of the EnvZ-OmpR two-component regulatory system.

  1. Nutrient imbalance in Norway spruce

    Energy Technology Data Exchange (ETDEWEB)

    Thelin, Gunnar

    2000-11-01

    The studies presented in my thesis indicate that growing Norway spruce in monoculture does not constitute sustainable forest management in a high N and S deposition environment, such as in southern Sweden. The combination of N-induced high growth rates and leaching due to soil acidification causes soil reserves of nutrients to decrease. This will increase the risk of nutrient imbalance within the trees when nutrient demands are not met. The development of nutrient imbalance in Scania, southern Sweden, was shown as negative trends in needle and soil nutrient status from the mid-80s to the present in Norway spruce and Scots pine stands. This imbalance appears to be connected to high levels of N and S deposition. Clear negative effects on tree vitality were found when using a new branch development method. Today, growth and vitality seems to be limited by K, rather than N, in spruce stands older than 40 years. However, younger stands appear to be able to absorb the deposited N without negative effects on growth and vitality. When investigating effects of nutrient stress on tree vitality, indicators such as branch length and shoot multiplication rate, which include effects accumulated over several years, are suitable. Countermeasures are needed in order to maintain the forest production at a high level. Positive effects on tree nutrient status after vitality fertilization (N-free fertilization) was shown in two micronutrient deficient stands in south-central Sweden. In addition, tree vitality was positively affected after the application of a site-adapted fertilizer to the canopy. Site-adaption of fertilizers will most likely improve the possibilities of a positive response on tree growth and vitality in declining stands. In a survey of Norway spruce in mixtures with beech, birch, or oak compared to monocultures it was shown that spruce nutrient status was higher in mixtures with deciduous species than in monocultures. By using mixed-species stands the need for

  2. The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.

    NARCIS (Netherlands)

    Whitaker, H.C.; Kote-Jarai, Z.; Ross-Adams, H.; Warren, A.Y.; Burge, J.; George, A.; Bancroft, E.; Jhavar, S.; Leongamornlert, D.; Tymrakiewicz, M.; Saunders, E.; Page, E.; Mitra, A.; Mitchell, G.; Lindeman, G.J.; Evans, D.G.; Blanco, I.; Mercer, C.; Rubinstein, W.S.; Clowes, V.; Douglas, F.; Hodgson, S.; Walker, L.; Donaldson, A.; Izatt, L.; Dorkins, H.; Male, A.; Tucker, K.; Stapleton, A.; Lam, J.; Kirk, J.; Lilja, H.; Easton, D.; Cooper, C.; Eeles, R.; Neal, D.E.

    2010-01-01

    BACKGROUND: Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to

  3. Nucleotide variation and identification of novel blast resistance alleles of Pib by allele mining strategy.

    Science.gov (United States)

    Ramkumar, G; Madhav, M S; Devi, S J S Rama; Prasad, M S; Babu, V Ravindra

    2015-04-01

    Pib is one of significant rice blast resistant genes, which provides resistance to wide range of isolates of rice blast pathogen, Magnaporthe oryzae. Identification and isolation of novel and beneficial alleles help in crop enhancement. Allele mining is one of the best strategies for dissecting the allelic variations at candidate gene and identification of novel alleles. Hence, in the present study, Pib was analyzed by allele mining strategy, and coding and non-coding (upstream and intron) regions were examined to identify novel Pib alleles. Allelic sequences comparison revealed that nucleotide polymorphisms at coding regions affected the amino acid sequences, while the polymorphism at upstream (non-coding) region affected the motifs arrangements. Pib alleles from resistant landraces, Sercher and Krengosa showed better resistance than Pib donor variety, might be due to acquired mutations, especially at LRR region. The evolutionary distance, Ka/Ks and phylogenetic analyzes also supported these results. Transcription factor binding motif analysis revealed that Pib (Sr) had a unique motif (DPBFCOREDCDC3), while five different motifs differentiated the resistance and susceptible Pib alleles. As the Pib is an inducible gene, the identified differential motifs helps to understand the Pib expression mechanism. The identified novel Pib resistant alleles, which showed high resistance to the rice blast, can be used directly in blast resistance breeding program as alternative Pib resistant sources.

  4. Expression of progesterone- induced blocking factor in severe preeclampsia and its association with immune tolerance imbalance%重度子痫前期PIBF的表达及其与免疫耐受失衡的关系

    Institute of Scientific and Technical Information of China (English)

    林靓; 黄云鹏; 余艳红; 杨茵

    2015-01-01

    目的:探讨重度子痫前期胎盘及外周血孕酮诱导封闭因子(PIBF)表达情况及其与免疫耐受失衡的关系。方法选取2012年1月~12月期间早发型重度子痫前期(EOPE)25例,晚发型重度子痫前期(LOPE)22例,对照组25例,收集产前外周血与产后胎盘。用免疫组织化学(SABC法)检测胎盘PIBF的表达及定位,ELISA试剂盒检测血清PIBF水平,流式细胞仪检测外周血中Th1和Th2细胞百分率,计算Th1/Th2比值。结果胎盘PIBF表达于蜕膜组织、合体滋养层细胞和部分绒毛滋养层细胞。血清PIBF水平在EOPE组为213.58±44.93 ng/ml,LOPE组为243.00±61.19 ng/ml,对照组为273.91±48.57 ng/ml。三组间血清PIBF含量、Th1/Th2比值和胎盘PIBF-IOD值差异均有统计学意义(P<0.05)。EOPE组和对照组相比,血清PIBF降低、胎盘PIBF表达量(PIBF-IOD)减少、外周血Th1/Th2比值增高(P<0.05)。重度子痫前期孕妇血清PIBF与胎盘PIBF-IOD呈正相关关系,与外周血Th1/Th2呈负相关关系(P<0.05)。但只有EOPE组血清PIBF与24h尿蛋白定量呈负相关关系(P<0.05)。结论 PIBF介导的免疫耐受失衡可能参与重度子痫前期发病机制。PIBF是妊娠诱发淋巴细胞分泌的免疫调节抑制因子及重度子痫前期的保护因素,有望成为新的治疗靶点。%Objective To explore progesterone-induced blocking factor (PIBF) expression in the placenta and blood of patients with severe preeclampsia and its relationship with immune tolerance imbalance. Methods Forty-seven patients admitted between January and December, 2012 were enrolled in this study, including 25 patients with early-onset severe preeclampsia (EOPE) and 22 with late-onset severe preeclampsia (LOPE), with 25 women with normal pregnancy serving as control group. The antenatal blood and postpartum placenta were collected for immunohistochemical staining to detect PIBF expression in the placenta and for

  5. What is Imbalance of Nature?

    Science.gov (United States)

    Kontar, V. A.

    2012-12-01

    The Mother Nature is imbalanced at all. The Mother Nature is every moment new, never returns to previous condition. The gravity and magnetosphere are changeable and imbalanced. The Sun is changeable and imbalanced. The climate is changeable and imbalanced. The atmosphere is changeable and imbalanced. The ocean is changeable and imbalanced. The crust and deep interior are changeable and imbalanced. The cryosphere is changeable and imbalanced. The life is simultaneously as the creator and the result of the imbalance of Nature. The people society is changeable and imbalanced. All chemical, physical, social, and other phenomenons are changeable and imbalanced. It's just that each phenomenon of the Mother Nature has some personal time-scale: one change in a nanosecond, and looks like for us as instable, i.e. imbalanced; while others change over millions years and, therefore, to us looks like not changeable, i.e. balanced. The scientists who are studying the Nature have convinced that the real balance never exist in Nature. Sometimes we can see something that is stable, i.e. balanced. But on closer study it appears that we are witnessing is not eternal rest and balance, it is not eternal STOP, but it is the perpetual motion, changing, there are a lot of imbalances. The balance it can be some result of the temporary mutual compensation the imbalanced processes in opposite directions. The balance it can be also some result of the inaccurate measurement, misunderstanding of conception or even request from bosses. But if we start use more accurate measurements, improve the models and not fear the bosses, than usually we got some new details. These new details show thet under the balanced visibility in really is hiding the interaction of many imbalanced processes of different directions. The balanced logic usually answers to question: What is it? The balanced answers are approximate and it will be updated many times during the development of science and practice. The

  6. The HLA-G*0105N null allele induces cell surface expression of HLA-E molecule and promotes CD94/NKG2A-mediated recognition in JAR choriocarcinoma cell line.

    Science.gov (United States)

    Sala, Frédéric G; Del Moral, Pierre-Marie; Pizzato, Nathalie; Legrand-Abravanel, Florence; Le Bouteiller, Philippe; Lenfant, Françoise

    2004-12-01

    HLA-G is a non-classical HLA class Ib molecule primarily expressed in trophoblast cells, and is thought to play a key role in the induction of materno-fetal tolerance during pregnancy. In addition, the HLA-G gene provides a suitable leader sequence peptide capable of binding to HLA-E. However, the existence of placentas homozygous for the HLA-G*0105N null allele suggests that HLA-G1 might not be essential for fetal survival. To investigate whether expression of the HLA-G*0105N allele supports HLA-E cell surface expression, we transfected the HLA-G*0105N gene into JAR trophoblast cells. Flow cytometry analysis showed that HLA-G*0105N-transfected cells express surface HLA-E to a similar extent as the unmutated HLA-G gene, whereas HLA-G1 cell surface expression was undetectable. Using the NKL cell line in a standard (51)Cr release assay, the HLA-E molecules were found to inhibit natural killer lysis, through a mechanism partially dependent on CD94/NKG2A-mediated recognition.

  7. The − 5 A/G single-nucleotide polymorphism in the core promoter region of MT2A and its effect on allele-specific gene expression and Cd, Zn and Cu levels in laryngeal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Starska, Katarzyna, E-mail: katarzyna.starska@umed.lodz.pl [I Department of Otolaryngology and Laryngological Oncology, Medical University of Łódź, Kopcinskiego 22, 90-153 Łódź (Poland); Krześlak, Anna; Forma, Ewa [Department of Cytobiochemistry, University of Łódź, Pomorska 142/143, 90-236 Łódź (Poland); Olszewski, Jurek [II Department of Otolaryngology and Laryngological Oncology, Medical University of Łódź, Żeromskiego 113, 90-549 Łódź (Poland); Morawiec-Sztandera, Alina [Department of Head and Neck Surgery, Medical University of Łódź, Paderewskiego 4, 93-509 Łódź (Poland); Aleksandrowicz, Paweł [Department of Otolaryngology and Laryngological Oncology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin (Poland); Lewy-Trenda, Iwona [Department of Pathology, Medical University of Łódź, Pomorska 251, 92-213 Łódź (Poland); and others

    2014-10-15

    Metallothioneins (MTs) are low molecular weight, cysteine-rich heavy metal-binding proteins which participate in the mechanisms of Zn homeostasis, and protect against toxic metals. MTs contain metal-thiolate cluster groups and suppress metal toxicity by binding to them. The aim of this study was to determine the − 5 A/G (rs28366003) single-nucleotide polymorphism (SNP) in the core promoter region of the MT2A gene and to investigate its effect on allele-specific gene expression and Cd, Zn and Cu content in squamous cell laryngeal cancer (SCC) and non-cancerous laryngeal mucosa (NCM) as a control. The MT2A promoter region − 5 A/G SNP was determined by restriction fragment length polymorphism using 323 SCC and 116 NCM. MT2A gene analysis was performed by quantitative real-time PCR. The frequency of A allele carriage was 94.2% and 91.8% in SCC and NCM, respectively, while G allele carriage was detected in 5.8% and 8.2% of SCC and NCM samples, respectively. As a result, a significant association was identified between the − 5 A/G SNP in the MT2A gene with mRNA expression in both groups. Metal levels were analyzed by flame atomic absorption spectrometry. The significant differences were identified between A/A and both the A/G and G/G genotypes, with regard to the concentration of the contaminating metal. The Spearman rank correlation results showed that the MT2A expression and Cd, Zn, Cu levels were negatively correlated. Results obtained in this study suggest that − 5 A/G SNP in MT2A gene may have an effect on allele-specific gene expression and accumulation of metal levels in laryngeal cancer. - Highlights: • MT2A gene expression and metal content in laryngeal cancer tissues • Association between SNP (rs28366003) and expression of MT2A • Significant associations between the SNP and Cd, Zn and Cu levels • Negative correlation between MT2A gene expression and Cd, Zn and Cu levels.

  8. Initial invasion of gametophytic self-incompatibility alleles in the absence of tight linkage between pollen and pistil S alleles.

    Science.gov (United States)

    Sakai, Satoki; Wakoh, Haluka

    2014-08-01

    In homomorphic self-incompatibility (SI) systems of plants, the loci controlling the pollen and pistil types are tightly linked, and this prevents the generation of compatible combinations of alleles expressing pollen and pistil types, which would result in self-fertilization. We modeled the initial invasion of the first pollen and pistil alleles in gametophytic SI to determine whether these alleles can stably coexist in a population without tight linkage. We assume pollen and pistil loci each carry an incompatibility allele S and an allele without an incompatibility function N. We assume that pollen with an S allele are incompatible with pistils carrying S alleles, whereas other crosses are compatible. Ovules in pistils carrying an S allele suffer viability costs because recognition consumes resources. We found that the cost of carrying a pistil S allele allows pollen and pistil S alleles to coexist in a stable equilibrium if linkage is partial. This occurs because parents that carry pistil S alleles but are homozygous for pollen N alleles cannot avoid self-fertilization; however, they suffer viability costs. Hence, pollen N alleles are selected again. When pollen and pistil S alleles can coexist in a polymorphic equilibrium, selection will favor tighter linkage.

  9. REGIONAL IMBALANCES IN DISTRIBUTION OF BULGARIAN HEALTH PROFESSIONALS

    Directory of Open Access Journals (Sweden)

    Maria Rohova

    2017-01-01

    Full Text Available Introduction: There are many factors influencing health inequities; health workforce availability and skill mix are among them. Regional distribution of health workers determines access to health services. The aim of this study is to analyse and to assess the distribution of health professionals among the statistical regions and districts in Bulgaria. Methods and materials: The current study uses health professionals to population ratio, Gini index and Lorenz curve to measure and assess the proportionality of health workers distribution. Data are provided from the National Statistical Institute and European Health for All databases. Results and discussion: In Bulgaria, health professionals per population ratio are comparable with the EU average except for the nurses. Beside the shortage of nursing professionals, geographically uneven distribution of health workers is among the main challenges in human resource management.Regional imbalances are significant among the districts in the country. More than half of the physicians are concentrated in 6 districts. The analysis shows an upward trend in imbalances, expressed as absolute or relative differences.The distribution of dentists is much more variant and diverse than this of physicians. The values of Gini index for specialised medical care also reveal considerable imbalances. Conclusions: Differet coefficients have proved the unequal distribution of health workers among the districts.Regional imbalances are not the only reason for health inequities in Bulgaria but they have significant influence in rural and remote areas and in regions with high unemployment, low incomes and ageing population.

  10. Drivers of imbalance cost of wind power

    DEFF Research Database (Denmark)

    Obersteiner, C.; Siewierski, T.; Andersen, Anders

    2010-01-01

    In Europe an increasing share of wind power is sold on the power market. Therefore more and more wind power generators become balancing responsible and face imbalance cost that reduce revenues from selling wind power. A comparison of literature illustrates that the imbalance cost of wind power...

  11. How does Chinese medicine target cytokine imbalance in rheumatoid arthritis?

    Science.gov (United States)

    Liu, Jian; Sun, Yue

    2013-11-01

    Rheumatoid arthritis (RA) manifests as an imbalance between pro- and anti-inflammatory cytokines. Cytokine imbalance is suggested to play critical roles in the development of RA. Currently, various treatments for RA, including biological agents such as antibodies against inflammation mediators, or Chinese herbal medicines, intervene the disease by restoring the balance of cytokines. Chinese medicine (CM) can not only suppress the expression of pro-inflammatory cytokines, but also induce the expression of cytokines with anti-inflammatory and immunomodulatory effects. Thus, Chinese medicine can effectively reduce inflammatory cell infiltration into synovial tissue, pannus formation, and degradation of the extracellular matrix surrounding cartilage cells, thereby reducing subchondral bone damage. This paper reviews the changes of cytokine profiling during development of RA and discuss the mechanisms by which Chinese medicine restores the cytokine balance.

  12. Are chromosomal imbalances important in cancer?

    Science.gov (United States)

    Stallings, Raymond L

    2007-06-01

    Tumor-specific patterns of large-scale chromosomal imbalances characterize most forms of cancer. Based on evidence primarily from neuroblastomas, it can be argued that large-scale chromosomal imbalances are crucial for tumor pathogenesis and have an impact on the global transcriptional profile of cancer cells, and that some imbalances even initiate cancer. The genes and genetic pathways that have been dysregulated by such imbalances remain surprisingly elusive. Many genes are affected by the regions of gain and loss, and there are complex interactions and relationships that occur between these genes, hindering their identification. The study of untranslated RNA sequences, such as microRNAs, is in its infancy, and it is likely that such sequences are also dysregulated by chromosomal imbalance, contributing to pathogenesis.

  13. Gender Imbalance and Terrorism in Developing Countries.

    Science.gov (United States)

    Younas, Javed; Sandler, Todd

    2017-03-01

    This article investigates whether gender imbalance may be conducive to domestic terrorism in developing countries. A female-dominated society may not provide sufficient administration, law, or order to limit domestic terrorism, especially since societies in developing countries primarily turn to males for administration, policing, and paramilitary forces. Other economic considerations support female imbalance resulting in grievance-generated terrorism. Because male dominance may also be linked to terrorism, empirical tests are ultimately needed to support our prediction. Based on panel data for 128 developing countries for 1975 to 2011, we find that female gender imbalance results in more total and domestic terrorist attacks. This female gender imbalance does not affect transnational terrorism in developing countries or domestic and transnational terrorism in developed countries. Further tests show that gender imbalance affects terrorism only when bureaucratic institutions are weak. Many robustness tests support our results.

  14. Earth's energy imbalance and implications

    Directory of Open Access Journals (Sweden)

    J. Hansen

    2011-12-01

    Full Text Available Improving observations of ocean heat content show that Earth is absorbing more energy from the Sun than it is radiating to space as heat, even during the recent solar minimum. The inferred planetary energy imbalance, 0.58 ± 0.15 W m−2 during the 6-yr period 2005–2010, confirms the dominant role of the human-made greenhouse effect in driving global climate change. Observed surface temperature change and ocean heat gain together constrain the net climate forcing and ocean mixing rates. We conclude that most climate models mix heat too efficiently into the deep ocean and as a result underestimate the negative forcing by human-made aerosols. Aerosol climate forcing today is inferred to be −1.6 ± 0.3 W m−2, implying substantial aerosol indirect climate forcing via cloud changes. Continued failure to quantify the specific origins of this large forcing is untenable, as knowledge of changing aerosol effects is needed to understand future climate change. We conclude that recent slowdown of ocean heat uptake was caused by a delayed rebound effect from Mount Pinatubo aerosols and a deep prolonged solar minimum. Observed sea level rise during the Argo float era is readily accounted for by ice melt and ocean thermal expansion, but the ascendency of ice melt leads us to anticipate acceleration of the rate of sea level rise this decade.

  15. Earth's Energy Imbalance and Implications

    CERN Document Server

    Hansen, James; Kharecha, Pushker; von Schuckmann, Karina

    2011-01-01

    Improving observations of ocean temperature confirm that Earth is absorbing more energy from the sun than it is radiating to space as heat, even during the recent solar minimum. The inferred planetary energy imbalance, 0.59 \\pm 0.15 W/m2 during the 6-year period 2005-2010, provides fundamental verification of the dominant role of the human-made greenhouse effect in driving global climate change. Observed surface temperature change and ocean heat gain constrain the net climate forcing and ocean mixing rates. We conclude that most climate models mix heat too efficiently into the deep ocean and as a result underestimate the negative forcing by human-made aerosols. Aerosol climate forcing today is inferred to be -1.6 \\pm 0.3 W/m2, implying substantial aerosol indirect climate forcing via cloud changes. Continued failure to quantify the specific origins of this large forcing is untenable, as knowledge of changing aerosol effects is needed to understand future climate change. A recent decrease in ocean heat uptake ...

  16. Interaction of ACTN3 gene polymorphism and muscle imbalance effects on kinematic efficiency in combat sports athletes

    Science.gov (United States)

    Lee, Namju; Park, Sok

    2016-01-01

    [Purpose] The purpose of this study was to determine the interaction of ACTN3 gene polymorphism and muscle imbalance effects on kinematic efficiency changes in combat sports athletes. [Methods] Six types of combat sports athletes (Judo, Taekwondo, boxing, kendo, wrestling, and Korean Ssi-reum) participated in the study. ATCN3 gene polymorphism and muscle imbalance in lower extremity were evaluated followed by analysis of differences of moment in hip, knee, and ankle joint during V-cut jumping and stop. To examine the moment difference due to an interaction of ATCN3 polymorphism and muscle imbalance, all participants were divided into 4 groups (R+MB, R+MIB, X+MB, and X+MIB). [Results] There was no significant difference of hip, knee, and ankle joint moment in R allele and X allele during V-cut jumping and stop based on ACTN3 gene polymorphism. Otherwise, muscle imbalance of knee moment in X-axis and ground reaction force of knee in Z-axis showed a higher significance in muscle imbalance during V-cut jumping and stop compared to muscle balance (p<0.05). In addition, joint analysis showed that muscle imbalance in X allele group had significantly higher knee moment of V-cut ground reaction force in X-axis and higher ankle moment of jumping ground reaction force in X and Z-axis compared to muscle balance with R and/or X group (p <0.05). [Conclusion] This study confirmed that muscle imbalance in lower extremity of combat athletes might induce higher risk factors of sports injury incidence than genetic factor and training might reduce the ratio of sports injury risk incidence. PMID:27508148

  17. Diversity of Lactase Persistence Alleles in Ethiopia

    DEFF Research Database (Denmark)

    Jones, BL; Raga, TO; Liebert, Anke

    2013-01-01

    The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (−13910∗T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene...... LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other...... alleles (−13907∗G, rs41525747; −13915∗G, rs41380347; −14010∗C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP...

  18. Expression of sterol regulatory element-binding transcription factor (SREBF 2 and SREBF cleavage-activating protein (SCAP in human atheroma and the association of their allelic variants with sudden cardiac death

    Directory of Open Access Journals (Sweden)

    Kytömäki Leena

    2008-12-01

    Full Text Available Abstract Background Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2 and the SREBF cleavage-activating protein (SCAP. We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, SREBF-2 1784G>C (rs2228314 and SCAP 2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD. Methods Whole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33–69 years Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the SREBF-2 and SCAP genotypes. Results Whole genome expression profiling showed a significant (p = 0.02 down-regulation of SREBF-2 in atherosclerotic carotid plaques (types IV-V, but not in the aorta or femoral arteries (p = NS for both, as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the SREBF-2 1784G>C and the SCAP 2386A>G genotype was observed on the risk of SCD (p = 0.046. Men with the SREBF-2 C allele and the SCAP G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07–6.71, compared to SCAP AA homologous subjects carrying the SREBF-2 C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the

  19. Earth's energy imbalance and implications

    Directory of Open Access Journals (Sweden)

    J. Hansen

    2011-09-01

    Full Text Available Improving observations of ocean heat content show that Earth is absorbing more energy from the sun than it is radiating to space as heat, even during the recent solar minimum. The inferred planetary energy imbalance, 0.59 ± 0.15 W m−2 during the 6-year period 2005–2010, confirms the dominant role of the human-made greenhouse effect in driving global climate change. Observed surface temperature change and ocean heat gain together constrain the net climate forcing and ocean mixing rates. We conclude that most climate models mix heat too efficiently into the deep ocean and as a result underestimate the negative forcing by human-made aerosols. Aerosol climate forcing today is inferred to be −1.6 ± 0.3 W m−2, implying substantial aerosol indirect climate forcing via cloud changes. Continued failure to quantify the specific origins of this large forcing is untenable, as knowledge of changing aerosol effects is needed to understand future climate change. We conclude that recent slowdown of ocean heat uptake was caused by a delayed rebound effect from Mount Pinatubo aerosols and a deep prolonged solar minimum. Observed sea level rise during the Argo float era is readily accounted for by ice melt and ocean thermal expansion, but the ascendency of ice melt leads us to anticipate acceleration of the rate of sea level rise this decade.

    Humanity is potentially vulnerable to global temperature change, as discussed in the Intergovernmental Panel on Climate Change (IPCC, 2001, 2007 reports and by innumerable authors. Although climate change is driven by many climate forcing agents and the climate system also exhibits unforced (chaotic variability, it is now widely agreed that the strong global warming trend of recent decades is caused predominantly by human-made changes of atmospheric composition (IPCC, 2007.

    The basic physics underlying this global warming, the greenhouse effect, is simple. An increase of gases

  20. Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry

    Science.gov (United States)

    Nikolic, Ana; Ricci, Giulia; Sera, Francesco; Bucci, Elisabetta; Govi, Monica; Mele, Fabiano; Rossi, Marta; Ruggiero, Lucia; Vercelli, Liliana; Ravaglia, Sabrina; Brisca, Giacomo; Fiorillo, Chiara; Villa, Luisa; Maggi, Lorenzo; Cao, Michelangelo; D'Amico, Maria Chiara; Siciliano, Gabriele; Antonini, Giovanni; Santoro, Lucio; Mongini, Tiziana; Moggio, Maurizio; Morandi, Lucia; Pegoraro, Elena; Angelini, Corrado; Di Muzio, Antonio; Rodolico, Carmelo; Tomelleri, Giuliano; Grazia D'Angelo, Maria; Bruno, Claudio; Berardinelli, Angela; Tupler, Rossella

    2016-01-01

    Objectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1–3 repeats (1–3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1–3 DRA. Setting Italy. Participants 66 index cases and 33 relatives carrying 1–3 DRA. Outcomes The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk. Results No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1–3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment. Conclusions The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high

  1. Hepatic Interferon-λ3 (IFNL3 Gene Expression Reveals Not to Be Attenuated in Non-Favorable IFNL3 rs4803217 or IFNL4 rs368234815 Minor Allele Carriers in Chronic Hepatitis C.

    Directory of Open Access Journals (Sweden)

    Ahmad Amanzada

    Full Text Available Genetic polymorphisms in the region of the interferon-λ genes (IFNL associate with clearance of hepatitis C virus (HCV infection. One of these polymorphisms, IFNL4 rs368234815, determines loss or gain of function of the IFNL4 gene by frameshift variation. The very same and a second one, IFNL3 rs4803217, are supposed to impact the expression of IFNL3: while IFNL4 rs368234815 is suggested to modulate IFNL3 transcription, IFNL3 rs4803217 is thought to alter IFNL3 mRNA stability. The latter process is believed to be partially driven by an HCV-induced ectopic expression of myosin heavy chain genes 7B and 7 and their co-expressed microRNAs mir499 and mir208B. These ideas are evidenced by functional investigations on peripheral blood mononuclear and hepatoma cells in culture. Our study aimed at exploring IFNL3 gene expression in clinical samples, i.e., in ex vivo derived liver tissue from patients with chronic hepatitis C (n = 57 and various other diseases (n = 56. By applying an assay designed to specifically quantify IFNL3 and discriminating paralogous IFNL2 transcripts, IFNL3 mRNA expression was not found to differ significantly between chronic hepatitis C and control samples. Among patients with chronic HCV infection, moreover, IFNL3 rs4803217 or IFNL4 rs368234815 minor alleles did not associate with reduced IFNL3 gene expression. Finally, myosin heavy chain genes 7B and 7 and corresponding microRNAs mir499 and mir208B were not found activated in liver in chronic HCV infection. Of note, detectability of MYH7 mRNA related to the procedure of liver biopsy sampling, as tissue obtained by direct punctation of the liver during laparoscopic inspection was less likely to contain MYH7 transcripts than samples acquired by percutaneous punctation. In conclusion, data on ex vivo derived liver tissue samples argue against an attenuating impact of IFNL3 rs4803217 or IFNL4 rs368234815 minor alleles on hepatic IFNL3 gene expression in vivo.

  2. Allelic imbalance in oral lichen planus and assessment of its classification as a premalignant condition

    Science.gov (United States)

    Accurso, Brent T.; Warner, Blake M.; Knobloch, Thomas J.; Weghorst, Christopher M.; Shumway, Brian S.; Allen, Carl M.; Kalmar, John R.

    2012-01-01

    OLP is a relatively common immune-mediated mucosal condition with a predilection for middle-aged women. Although classified as a premalignant condition, this classification remains controversial. Using stringent diagnostic criteria, some authors have found that OLP patients are not at increased risk for oral SCC. Credible but limited genetic evidence also indicates that epithelial tissues from OLP patients diagnosed using stringent criteria differs from premalignant or malignant oral lesions but is similar to epithelium from benign oral lesions. To further investigate this genetic line of evidence, biopsy specimens diagnosed as fibroma, OLP, low-grade dysplasia, high-grade dysplasia, and SCC were retrieved from the archives of the Oral Pathology Consultants at the Ohio State University. Using laser capture microdissection, tissue of interest was captured from each case and DNA subsequently extracted. Fluorescently labeled PCR primers were used to amplify DNA at 3 tumor suppressor gene loci (3p14.2, 9p21, and 17p13) and evaluated for LOH or microsatellite instability (MSI). OLP was found to be significantly different from low-grade dysplasia, high-grade dysplasia, and SCC when LOH/MSI was found at more than 1 loci (P = .011, P = .032, P = .003), but not different from benign fibromas (P = .395). In agreement with previous studies, well-documented cases of OLP diagnosed using stringent criteria exhibit a genetic profile more similar to a benign or reactive process than a premalignant/malignant one. These findings do not support the classification of OLP as a premalignant condition. PMID:21764610

  3. BaalChIP: Bayesian analysis of allele-specific transcription factor binding in cancer genomes.

    Science.gov (United States)

    de Santiago, Ines; Liu, Wei; Yuan, Ke; O'Reilly, Martin; Chilamakuri, Chandra Sekhar Reddy; Ponder, Bruce A J; Meyer, Kerstin B; Markowetz, Florian

    2017-02-24

    Allele-specific measurements of transcription factor binding from ChIP-seq data are key to dissecting the allelic effects of non-coding variants and their contribution to phenotypic diversity. However, most methods of detecting an allelic imbalance assume diploid genomes. This assumption severely limits their applicability to cancer samples with frequent DNA copy-number changes. Here we present a Bayesian statistical approach called BaalChIP to correct for the effect of background allele frequency on the observed ChIP-seq read counts. BaalChIP allows the joint analysis of multiple ChIP-seq samples across a single variant and outperforms competing approaches in simulations. Using 548 ENCODE ChIP-seq and six targeted FAIRE-seq samples, we show that BaalChIP effectively corrects allele-specific analysis for copy-number variation and increases the power to detect putative cis-acting regulatory variants in cancer genomes.

  4. ABO blood group A antigen expression in A201 allele analysis of activity%ABO血型A201等位基因表达A抗原活性的分析

    Institute of Scientific and Technical Information of China (English)

    曾学平; 王恭; 陆理; 李涛; 冯学冠

    2014-01-01

    目的:研究ABO血型A201等位基因表达A抗原活性。方法运用血型血清学方法对1家2代3人的唾液及血液标本的ABO血型进行检测;运用Identifiler法医基因分析试剂盒作为亲缘关系鉴定;PCR扩增ABO基因后,对所有外显子做DNA测序分析,运用PCR-RFLP法进行同步检测A201等位基因中的序列变异。结果亲缘关系鉴定在Identifiler的15个遗传标记系统中显示,父母可以将所有的等位基因提供给子女,确定具有亲缘关系;然而运用不同来源的3份抗体对ABO血型进行检验时,却出现了正定型否定了母子关系,反定型无法排除母子关系的现象。3个标本ABO基因的测序:父、母、子的基因型分别为O01/O01、A201/B101及A201/O01,符合反定型结果,这就说明A201等位基因在A表型及AB表型中表达的A抗原活性差异显著。运用PCR-RFLP法可将A201等位基因中的2个主要变异点1059-1061delC和467C/T。结论 ABO血型A201基因在AB及A表型中表达A抗原活性,可由于检测抗体不同出现一定的差异;基因测序与PCR-RFLP法进行同步分析能够快速简便的鉴定A201等位基因中的1059-1061delC和467C/T。%Objective To study the ABO blood group A antigen expression in A201 allele activity. Methods Using serological methods, a two-generation three human saliva and blood samples were used to detect ABO blood. Forensic genetic analysis using Identifiler kit was used as kinship identification including PCR amplification ABO gene,exons do for all DNA sequencing,PCR-RFLP method using synchronous detection of sequence variation A201 allele. Results Identification of the genetic relationship of 15 genetic markers was performed using Identifiler system, which shows that parents can have all the alleles,be available to children determined to have kinship. However,after the use of three different sources of ABO blood group antibodies,they appeared the mother-child relationship was

  5. On the chiral imbalance and Weibel instabilities

    Science.gov (United States)

    Kumar, Avdhesh; Bhatt, Jitesh R.; Kaw, P. K.

    2016-06-01

    We study the chiral-imbalance and the Weibel instabilities in presence of the quantum anomaly using the Berry-curvature modified kinetic equation. We argue that in many realistic situations, e.g. relativistic heavy-ion collisions, both the instabilities can occur simultaneously. The Weibel instability depends on the momentum anisotropy parameter ξ and the angle (θn) between the propagation vector and the anisotropy direction. It has maximum growth rate at θn = 0 while θn = π / 2 corresponds to a damping. On the other hand the pure chiral-imbalance instability occurs in an isotropic plasma and depends on difference between the chiral chemical potentials of right and left-handed particles. It is shown that when θn = 0, only for a very small values of the anisotropic parameter ξ ∼ξc, growth rates of the both instabilities are comparable. For the cases ξc Weibel modes dominate over the chiral-imbalance instability if μ5 / T ≤ 1. However, when μ5 / T ≥ 1, it is possible to have dominance of the chiral-imbalance modes at certain values of θn for an arbitrary ξ.

  6. The Hegelian dialectics of global imbalances

    Directory of Open Access Journals (Sweden)

    Célestin Monga

    2012-11-01

    Full Text Available Traditional narratives of external imbalances have focused on the analysis of national accounts, trade flows, and financial flows. They have generated two opposing views of the current situation of the world economy: on one side, a prudent, if not pessimistic view considers large imbalances as evidence of problems with the international monetary and financial system, and symptoms of domestic distortions (mainly in the United States and China. On the other side, a relaxed, if not optimistic view suggests that global imbalances are not anomalies but simply the predictable outcome of a world with increasingly globalized financial flows in search of the right mix of risks and returns. This paper offers a critical analysis of these competing explanations of the United States-China imbalances and suggests a way of reconciling them. The paper uses Hegel’s parable of the development of self-consciousness to explain the dynamics between the two countries. Hegel may not have been a great philosopher of history but his study of lordship and bondage provides a good framework for analyzing the dialectics of recognition and acknowledgement that currently characterizes the macroeconomic relationships between the United States and China.

  7. Paralogous gene conversion, allelic divergence of attacin genes and its expression profile in response to BmNPV infection in silkworm Bombyx mori

    Directory of Open Access Journals (Sweden)

    G Lekha

    2015-08-01

    Full Text Available The genomic organization, structure and polymorphism of attacin gene within the mulberry silkworm Bombyx mori strains have been analyzed. Genomic contig (AADK01007556 of B. mori attacin gene contains locus with two transcribed basic attacin genes, which were designated as attacin I and attacin II. Survey of the naturally occurring genetic variation in different strains of silkworm B. mori at the promoter and coding regions of two attacin genes revealed high levels of silent nucleotide variations (1- 4 % per nucleotide heterozygosity without polymorphism at the amino acid level (nonSynonymous substitution. We also investigated variations in gene expression of attacin I and attacin II in silkworm B. mori infected with nucleopolyhedrovirus (BmNPV. Two B. mori strains, Sarupat, CSR-2 which were resistant and susceptible to BmNPV infection respectively were used in this study. Expression profiles of B. mori genes were analyzed using microarray technique and results revealed that the immune response genes including attacin were selectively up regulated in virus invaded midguts of both races. Microarray data and real-time qPCR results revealed that attacin I gene was significantly up-regulated in the midgut of Sarupat following BmNPV infection, indicating its specific role in the anti-viral response. Our results imply that these up-regulated attacin genes were not only involved in anti-bacterial mechanism, but are also involved in B. mori immune response against BmNPV infection.

  8. A new analysis tool for individual-level allele frequency for genomic studies

    Directory of Open Access Journals (Sweden)

    Pan Wen-Harn

    2010-07-01

    Full Text Available Abstract Background Allele frequency is one of the most important population indices and has been broadly applied to genetic/genomic studies. Estimation of allele frequency using genotypes is convenient but may lose data information and be sensitive to genotyping errors. Results This study utilizes a unified intensity-measuring approach to estimating individual-level allele frequencies for 1,104 and 1,270 samples genotyped with the single-nucleotide-polymorphism arrays of the Affymetrix Human Mapping 100K and 500K Sets, respectively. Allele frequencies of all samples are estimated and adjusted by coefficients of preferential amplification/hybridization (CPA, and large ethnicity-specific and cross-ethnicity databases of CPA and allele frequency are established. The results show that using the CPA significantly improves the accuracy of allele frequency estimates; moreover, this paramount factor is insensitive to the time of data acquisition, effect of laboratory site, type of gene chip, and phenotypic status. Based on accurate allele frequency estimates, analytic methods based on individual-level allele frequencies are developed and successfully applied to discover genomic patterns of allele frequencies, detect chromosomal abnormalities, classify sample groups, identify outlier samples, and estimate the purity of tumor samples. The methods are packaged into a new analysis tool, ALOHA (Allele-frequency/Loss-of-heterozygosity/Allele-imbalance. Conclusions This is the first time that these important genetic/genomic applications have been simultaneously conducted by the analyses of individual-level allele frequencies estimated by a unified intensity-measuring approach. We expect that additional practical applications for allele frequency analysis will be found. The developed databases and tools provide useful resources for human genome analysis via high-throughput single-nucleotide-polymorphism arrays. The ALOHA software was written in R and R GUI and

  9. Education in the imbalance of Nature

    Science.gov (United States)

    Shlafman, L. M.; Kontar, V. A.

    2013-12-01

    There are two concepts understanding of the real Nature: balanced and imbalanced. The traditional balanced concept understanding of Nature was originated in prehistoric times to calm the frightened souls of prehistoric man and manage groups of people. The balanced concept presupposes that Nature is isotropic, balanced, etc. The balanced concept of understanding of Nature gradually has moved to science and technology. The balanced concept of understanding of Nature is dominating from the prehistoric time up to today. But always parallel and opposite was exists the concept imbalanced understanding of Nature, which presupposes that Nature is anisotropy, imbalanced, etc. The balanced concept is much simpler than Imbalanced. The balanced concept has given mankind a lot of rough description of Nature which helped to solve a lot of practical problems but with sufficient accuracy, i.e. approximately, but not with an absolute precision. While people were few, and a lot of resources, person could take from Nature only what Nature gave willingly. During this period, people feared and respected Nature and Nature was able easily compensate the activity of people. The high accuracy of the description of Nature was not needed when resources were plentiful and people were few. But now the situation is completely different. The population has become a very large and growing. Traditional resources are almost run out and the lack of resources escalates. People are not afraid of Nature and bravely try to take by force what Nature does not give voluntarily. People invaded into imbalance Nature, and Nature can no longer compensate activity of people. The era of global change is started, including those that man provokes. In the conditions of global changes is insufficiently of the approximate solutions of the traditional balanced concept. The balanced concept is exhausted, and increasingly misleads people. The balanced concept cannot solve the problems that arise in the global change

  10. Muscular Imbalance Correction in the Power Fitness Training

    OpenAIRE

    Olga E. Aftimichuk; Alexander V. Varvarich

    2013-01-01

    Muscular imbalance is one of the manifestations of pathological-biomechanical changes in muscular-skeletal system. It is the result of tonus-power imbalance of short and relaxed muscles. Muscle shortening is the most striking sign of muscular imbalance. Hypodynamia and passive lifestyle can cause such results. The paper justifies the experimental technique of women muscular imbalances correction by means of power training. Selection of exercises, weights and machines was made, taking into acc...

  11. Allele coding in genomic evaluation

    Directory of Open Access Journals (Sweden)

    Christensen Ole F

    2011-06-01

    Full Text Available Abstract Background Genomic data are used in animal breeding to assist genetic evaluation. Several models to estimate genomic breeding values have been studied. In general, two approaches have been used. One approach estimates the marker effects first and then, genomic breeding values are obtained by summing marker effects. In the second approach, genomic breeding values are estimated directly using an equivalent model with a genomic relationship matrix. Allele coding is the method chosen to assign values to the regression coefficients in the statistical model. A common allele coding is zero for the homozygous genotype of the first allele, one for the heterozygote, and two for the homozygous genotype for the other allele. Another common allele coding changes these regression coefficients by subtracting a value from each marker such that the mean of regression coefficients is zero within each marker. We call this centered allele coding. This study considered effects of different allele coding methods on inference. Both marker-based and equivalent models were considered, and restricted maximum likelihood and Bayesian methods were used in inference. Results Theoretical derivations showed that parameter estimates and estimated marker effects in marker-based models are the same irrespective of the allele coding, provided that the model has a fixed general mean. For the equivalent models, the same results hold, even though different allele coding methods lead to different genomic relationship matrices. Calculated genomic breeding values are independent of allele coding when the estimate of the general mean is included into the values. Reliabilities of estimated genomic breeding values calculated using elements of the inverse of the coefficient matrix depend on the allele coding because different allele coding methods imply different models. Finally, allele coding affects the mixing of Markov chain Monte Carlo algorithms, with the centered coding being

  12. Global imbalances, saving glut and investment strike.

    OpenAIRE

    Moëc, G.; Frey, L

    2006-01-01

    The present state of the global economy is characterised by persistent and increasingly polarised current account imbalances, in a context of historically low long-term interest rates, which stand below the equilibrium levels proxied by potential growth and trend inflation. A comprehensive analysis by Ben Bernanke1 attributes those two phenomena to one common cause: a global saving glut outside the United States. The approach below is more pessimistic than the global saving glut theory as far...

  13. A genome-wide screen in human embryonic stem cells reveals novel sites of allele-specific histone modification associated with known disease loci

    LENUS (Irish Health Repository)

    Prendergast, James G D

    2012-05-19

    AbstractBackgroundChromatin structure at a given site can differ between chromosome copies in a cell, and such imbalances in chromatin structure have been shown to be important in understanding the molecular mechanisms controlling several disease loci. Human genetic variation, DNA methylation, and disease have been intensely studied, uncovering many sites of allele-specific DNA methylation (ASM). However, little is known about the genome-wide occurrence of sites of allele-specific histone modification (ASHM) and their relationship to human disease. The aim of this study was to investigate the extent and characteristics of sites of ASHM in human embryonic stem cells (hESCs).ResultsUsing a statistically rigorous protocol, we investigated the genomic distribution of ASHM in hESCs, and their relationship to sites of allele-specific expression (ASE) and DNA methylation. We found that, although they were rare, sites of ASHM were substantially enriched at loci displaying ASE. Many were also found at known imprinted regions, hence sites of ASHM are likely to be better markers of imprinted regions than sites of ASM. We also found that sites of ASHM and ASE in hESCs colocalize at risk loci for developmental syndromes mediated by deletions, providing insights into the etiology of these disorders.ConclusionThese results demonstrate the potential importance of ASHM patterns in the interpretation of disease loci, and the protocol described provides a basis for similar studies of ASHM in other cell types to further our understanding of human disease susceptibility.

  14. Down-regulation of the cytoglobin gene, located on 17q25, in tylosis with oesophageal cancer (TOC): evidence for trans-allele repression.

    Science.gov (United States)

    McRonald, Fiona E; Liloglou, Triantafillos; Xinarianos, George; Hill, Laura; Rowbottom, Lynn; Langan, Joanne E; Ellis, Anthony; Shaw, Joan M; Field, John K; Risk, Janet M

    2006-04-15

    Tylosis (focal non-epidermolytic palmoplantar keratoderma) is an autosomal dominant skin disorder that is associated with the early onset of squamous cell oesophageal cancer (SCOC) in three families. Our previous linkage and haplotype analyses have mapped the tylosis with oesophageal cancer (TOC) locus to a 42.5 kb region on chromosome 17q25 that has also been implicated in the aetiology of sporadically occurring SCOC from a number of different geographical populations. Oesophageal cancer is one of the 10 leading causes of cancer mortality worldwide. No inherited disease-causing mutations have been identified in the genes located in the 42.5 kb minimal region. We now show that cytoglobin gene expression in oesophageal biopsies from tylotic patients is dramatically reduced by approximately 70% compared with normal oesophagus. Furthermore, both alleles are equally repressed. Given the autosomal dominant nature of the disease, these results exclude haploinsufficiency as a mechanism of the disease and instead suggest a novel trans-allele interaction. We also show that the promoter is hypermethylated in sporadic oesophageal cancer samples: this may constitute the 'second hit' of a gene previously implicated in this disease by allelic imbalance studies.

  15. On the Chiral imbalance and Weibel Instabilities

    CERN Document Server

    Kumar, Avdhesh; Kaw, Predhiman K

    2016-01-01

    We study the chiral-imbalance and the Weibel instabilities in presence of the quantum anomaly using the Berry-curvature modified kinetic equation. We argue that in many realistic situations, e.g. relativistic heavy-ion collisions, both the instabilities can occur simultaneously. The Weibel instability depends on the momentum anisotropy parameter $\\xi$ and the angle ($\\theta_n$) between the propagation vector and the anisotropy direction. It has maximum growth rate at $\\theta_n=0$ while $\\theta_n=\\pi/2$ corresponds to a damping. On the other hand the pure chiral-imbalance instability occurs in an isotropic plasma and depends on difference between the chiral chemical potentials of right and left-handed particles. It is shown that when $\\theta_n=0$, only for a very small values of the anisotropic parameter $\\xi\\sim \\xi_c$, growth rates of the both instabilities are comparable. For the cases $\\xi_c<\\xi\\ll1$, $\\xi\\approx 1$ or $\\xi \\geq 1$ at $\\theta_n=0$, the Weibel modes dominate over the chiral-imbalance ins...

  16. The FOXO3A rs2802292 G-Allele Associates with Improved Peripheral and Hepatic Insulin Sensitivity and Increased Skeletal Muscle-FOXO3A mRNA Expression in Twins

    DEFF Research Database (Denmark)

    Banasik, Karina; Ribel-Madsen, Rasmus; Gjesing, Anette P;

    2011-01-01

    Objective: The minor G-allele of FOXO3A rs2802292 has been associated with longevity. We aimed to investigate whether a phenotype related to healthy metabolic aging could be identified in individuals carrying the longevity-associated FOXO3A rs2802292 G-allele. Research Design and Methods: rs2802292...

  17. Hypobaric Hypoxia Imbalances Mitochondrial Dynamics in Rat Brain Hippocampus

    Directory of Open Access Journals (Sweden)

    Khushbu Jain

    2015-01-01

    Full Text Available Brain is predominantly susceptible to oxidative stress and mitochondrial dysfunction during hypobaric hypoxia, and therefore undergoes neurodegeneration due to energy crisis. Evidences illustrate a high degree of association for mitochondrial fusion/fission imbalance and mitochondrial dysfunction. Mitochondrial fusion/fission is a recently reported dynamic mechanism which frequently occurs among cellular mitochondrial network. Hence, the study investigated the temporal alteration and involvement of abnormal mitochondrial dynamics (fusion/fission along with disturbed mitochondrial functionality during chronic exposure to hypobaric hypoxia (HH. The Sprague-Dawley rats were exposed to simulated high altitude equivalent to 25000 ft for 3, 7, 14, 21, and 28 days. Mitochondrial morphology, distribution within neurons, enzyme activity of respiratory complexes, Δψm, ADP: ATP, and expression of fission/fusion key proteins were determined. Results demonstrated HH induced alteration in mitochondrial morphology by damaged, small mitochondria observed in neurons with disturbance of mitochondrial functionality and reduced mitochondrial density in neuronal processes manifested by excessive mitochondrial fragmentation (fission and decreased mitochondrial fusion as compared to unexposed rat brain hippocampus. The study suggested that imbalance in mitochondrial dynamics is one of the noteworthy mechanisms occurring in hippocampal neurons during HH insult.

  18. Financial Imbalances and Macro-prudential Policies

    Directory of Open Access Journals (Sweden)

    Polikarpova Olga S.

    2015-11-01

    Full Text Available The credit crisis and its transformation into a sovereign debt crisis have illustrated the limited character of the traditional macro financial politics. The financial crisis has shown that the priority of price stability does not guarantee macroeconomic stability. Revision of the goals and objectives of the monetary and credit policy is being carried out in many countries. In order to ensure macroeconomic stability, central banks have to use new instruments considering financial stability as an additional object. Since 2009 the IMF recommends central banks to use macro-prudential instruments for reducing macro-financial risks and imbalances in the financial system structure. The effectiveness of macro-prudential policy depends on its calibration with the monetary and credit policy. The growth of financial imbalances in the first decade after the adoption of the euro, presence of contradictory fiscal policies, deployment of a spiral of rapid crediting and price inflation have led to apraxia in the monetary and credit policy, and fiscal policy was limited by institutional arrangements. Accumulating funds during the budget surplus the countries-members of the European Monetary System (EMS attempted to reduce asymmetric shocks. The priority of price stability in the EMS had been achieved but the economies of these countries suffered from financial imbalances. Macro-prudential policy is aimed at prevention and mitigation of systemic risk, plays a significant role in reforming the new policy of central banks. That is why European countries are developing new methods and an institutional framework for the implementation of a new macro-prudential policy. Problems of structural arbitration and the possibility of emergence of new financial imbalances in the EMS are becoming increasingly real. The flow of financial capitals and financial institutions to more lenient jurisdictions is connected with the establishment of macro-prudential policy. The macro

  19. Momentum Imbalance Observables as a Probe of Gluon TMDs

    CERN Document Server

    Pisano, Cristian

    2015-01-01

    The unpolarized and linearly polarized gluon TMDs can be directly probed in heavy quark and jet pair production in unpolarized electron-proton collisions by looking at observables, like transverse momentum distributions and azimuthal asymmetries, depending on the momentum imbalance of the pair. Analytical expressions are presented for these observables and for analogous ones in Higgs plus jet and quarkonium plus photon production in unpolarized proton-proton scattering experiments. It is shown how the proposed measurements, to be performed at a future EIC and at the LHC, could provide important information on the size and shape of gluon TMDs, as well as on other fundamental properties such as their process and energy scale dependences.

  20. Electrolyte Imbalance in Patients with Sheehan's Syndrome

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    Chur Hoan Lim

    2015-12-01

    Full Text Available BackgroundWe investigated the prevalence of electrolyte imbalance and the relationship between serum electrolyte and anterior pituitary hormone levels in patients with Sheehan's syndrome.MethodsIn a retrospective study, we investigated 78 patients with Sheehan's syndrome. We also included 95 normal control subjects who underwent a combined anterior pituitary hormone stimulation test and showed normal hormonal responses.ResultsIn patients with Sheehan's syndrome, the serum levels of sodium, potassium, ionized calcium, magnesium, and inorganic phosphate were significantly lower than those in control subjects. The prevalence of hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, and hypophosphatemia in patients with Sheehan's syndrome was 59.0% (n=46, 26.9% (n=21, 35.9% (n=28, 47.4% (n=37, and 23.1% (n=18, respectively. Levels of sodium and ionized calcium in serum were positively correlated with levels of all anterior pituitary hormones (all P<0.05. Levels of potassium in serum were positively correlated with adrenocorticotrophic hormone (ACTH and growth hormone (GH levels (all P<0.05. Levels of inorganic phosphate in serum were positively correlated with levels of thyroid-stimulating hormone, prolactin, and GH (all P<0.05, and levels of magnesium in serum were positively correlated with delta ACTH (P<0.01.ConclusionElectrolyte imbalance was common in patients with Sheehan's syndrome. Furthermore, the degree of anterior pituitary hormone deficiency relates to the degree of electrolyte disturbance in patients with this disease.

  1. Assignment of SNP allelic configuration in polyploids using competitive allele-specific PCR: application to citrus triploid progeny

    Science.gov (United States)

    Cuenca, José; Aleza, Pablo; Navarro, Luis; Ollitrault, Patrick

    2013-01-01

    Background Polyploidy is a major component of eukaryote evolution. Estimation of allele copy numbers for molecular markers has long been considered a challenge for polyploid species, while this process is essential for most genetic research. With the increasing availability and whole-genome coverage of single nucleotide polymorphism (SNP) markers, it is essential to implement a versatile SNP genotyping method to assign allelic configuration efficiently in polyploids. Scope This work evaluates the usefulness of the KASPar method, based on competitive allele-specific PCR, for the assignment of SNP allelic configuration. Citrus was chosen as a model because of its economic importance, the ongoing worldwide polyploidy manipulation projects for cultivar and rootstock breeding, and the increasing availability of SNP markers. Conclusions Fifteen SNP markers were successfully designed that produced clear allele signals that were in agreement with previous genotyping results at the diploid level. The analysis of DNA mixes between two haploid lines (Clementine and pummelo) at 13 different ratios revealed a very high correlation (average = 0·9796; s.d. = 0·0094) between the allele ratio and two parameters [θ angle = tan−1 (y/x) and y′ = y/(x + y)] derived from the two normalized allele signals (x and y) provided by KASPar. Separated cluster analysis and analysis of variance (ANOVA) from mixed DNA simulating triploid and tetraploid hybrids provided 99·71 % correct allelic configuration. Moreover, triploid populations arising from 2n gametes and interploid crosses were easily genotyped and provided useful genetic information. This work demonstrates that the KASPar SNP genotyping technique is an efficient way to assign heterozygous allelic configurations within polyploid populations. This method is accurate, simple and cost-effective. Moreover, it may be useful for quantitative studies, such as relative allele-specific expression analysis and bulk segregant analysis

  2. Operating a redox flow battery with a negative electrolyte imbalance

    Science.gov (United States)

    Pham, Quoc; Chang, On; Durairaj, Sumitha

    2015-03-31

    Loss of flow battery electrode catalyst layers during self-discharge or charge reversal may be prevented by establishing and maintaining a negative electrolyte imbalance during at least parts of a flow battery's operation. Negative imbalance may be established and/or maintained actively, passively or both. Actively establishing a negative imbalance may involve detecting an imbalance that is less negative than a desired threshold, and processing one or both electrolytes until the imbalance reaches a desired negative level. Negative imbalance may be effectively established and maintained passively within a cell by constructing a cell with a negative electrode chamber that is larger than the cell's positive electrode chamber, thereby providing a larger quantity of negative electrolyte for reaction with positive electrolyte.

  3. Muscular Imbalance Correction in the Power Fitness Training

    Directory of Open Access Journals (Sweden)

    Olga E. Aftimichuk

    2013-09-01

    Full Text Available Muscular imbalance is one of the manifestations of pathological-biomechanical changes in muscular-skeletal system. It is the result of tonus-power imbalance of short and relaxed muscles. Muscle shortening is the most striking sign of muscular imbalance. Hypodynamia and passive lifestyle can cause such results. The paper justifies the experimental technique of women muscular imbalances correction by means of power training. Selection of exercises, weights and machines was made, taking into account the anatomical and physiological characteristics of the body of women of second maturity. The indexes, obtained as a result of fitness programs testing, developed within the frameworks of correctional methods.

  4. Cooperation of Adhesin Alleles in Salmonella-Host Tropism

    Science.gov (United States)

    De Masi, Leon; Yue, Min; Hu, Changmin; Rakov, Alexey V.; Rankin, Shelley C.

    2017-01-01

    ABSTRACT Allelic combinations and host specificities for three fimbrial adhesins, FimH, BcfD, and StfH, were compared for 262 strains of Salmonella enterica serovar Newport, a frequent human and livestock pathogen. Like FimH, BcfD had two major alleles (designated A and B), whereas StfH had two allelic groups, each with two alleles (subgroup A1 and A2 and subgroup B1 and B2). The most prevalent combinations of FimH/BcfD/StfH alleles in S. Newport were A/A/A1 and B/B/B1. The former set was most frequently found in bovine and porcine strains, whereas the latter combination was most frequently found in environmental and human isolates. Bacteria genetically engineered to express Fim, Bcf, or Stf fimbriae on their surface were tested with the different alleles for binding to human, porcine, and bovine intestinal epithelial cells. The major allelic combinations with bovine and porcine strains (A/A/A1) or with human isolates (B/B/B1) provided at least two alleles capable of binding significantly better than the other alleles to an intestinal epithelial cell line from the respective host(s). However, each combination of alleles kept at least one allele mediating binding to an intestinal epithelial cell from another host. These findings indicated that allelic variation in multiple adhesins of S. Newport contributes to bacterial adaptation to certain preferential hosts without losing the capacity to maintain a broad host range. IMPORTANCE Salmonella enterica remains a leading foodborne bacterial pathogen in the United States; infected livestock serve often as the source of contaminated food products. A study estimated that over a billion Salmonella gastroenteritis cases and up to 33 million typhoid cases occur annually worldwide, with 3.5 million deaths. Although many Salmonella strains with a broad host range present preferential associations with certain host species, it is not clear what determines the various levels of host adaptation. Here, causal properties of host

  5. Mechanism for Corrective Action on Budget Imbalances

    Directory of Open Access Journals (Sweden)

    Ion Lucian CATRINA

    2014-02-01

    Full Text Available The European Fiscal Compact sets the obligation for the signatory states to establish an automatic mechanism for taking corrective action on budget imbalances. Nevertheless, the European Treaty says nothing about the tools that should be used in order to reach the desired equilibrium of budgets, but only that it should aim at correcting deviations from the medium-term objective or the adjustment path, including their cumulated impact on government debt dynamics. This paper is aiming at showing that each member state has to build the correction mechanism according to the impact of the chosen tools on economic growth and on general government revenues. We will also emphasize that the correction mechanism should be built not only exacerbating the corrective action through spending/ tax based adjustments, but on a high quality package of economic policies as well.

  6. Allelic exclusion of immunoglobulin genes: models and mechanisms.

    Science.gov (United States)

    Vettermann, Christian; Schlissel, Mark S

    2010-09-01

    The allelic exclusion of immunoglobulin (Ig) genes is one of the most evolutionarily conserved features of the adaptive immune system and underlies the monospecificity of B cells. While much has been learned about how Ig allelic exclusion is established during B-cell development, the relevance of monospecificity to B-cell function remains enigmatic. Here, we review the theoretical models that have been proposed to explain the establishment of Ig allelic exclusion and focus on the molecular mechanisms utilized by developing B cells to ensure the monoallelic expression of Ig kappa and Ig lambda light chain genes. We also discuss the physiological consequences of Ig allelic exclusion and speculate on the importance of monospecificity of B cells for immune recognition.

  7. Characterization of a surface membrane molecule expressed by natural killer cells in most inbred mouse strains: monoclonal antibody C9.1 identifies an allelic form of the 2B4 antigen

    Science.gov (United States)

    Kubota, K; Katoh, H; Muguruma, K; Koyama, K

    1999-01-01

    A newly generated monoclonal antibody (mAb C9.1) described in this study identifies a surface membrane molecule that is involved in the lytic programme of activated natural killer (NK) cells. This conclusion is based on the facts that, first, this antigen was expressed on the vast majority of surface immunoglobulin (sIg)− CD3− CD4− CD8− spleen lymphocytes, albeit it was also present on minor subsets of sIg+ B (≈7%) and CD3+ T (≈2%) lymphocytes; second, that all splenic NK activity was contained within the C9.1+ cell population, and was almost totally abolished by treatment of spleen cells with mAb C9.1 and complement; third, that mAb C9.1 was capable of increasing interleukin-2-cultured and in vivo polyinosinic:polycytidylic acid-activated, NK cell-mediated, antibody-redirected lysis, but not freshly isolated NK cell-mediated killing. Furthermore, the strain distribution of the C9.1 antigen was shown to be antithetical to that of the 2B4 antigen already described as a molecule associated with major histocompatibility complex-unrestricted killing mediated by activated NK cells. The gene encoding C9.1 antigen was linked to the Akp1 isozyme locus on chromosome 1 close to the 2B4 gene. Although C9.1 and 2B4 were monomeric glycoproteins of 78 000 MW and 66 000 MW, respectively, removal of N-linked sugars from both antigens by endoglycosidase F yielded identical protein backbones of 38 000 MW. Thus, all of these results suggest that mAb C9.1 recognizes an allelic form of the 2B4 antigen. However, the detection of mAb C9.1-reactive antigen on a minor subset of B cells may suggest a possible reactivity of mAb C9.1 with some product of other members of the 2B4 family genes. PMID:10233732

  8. Effort reward imbalance, and salivary cortisol in the morning

    DEFF Research Database (Denmark)

    Eller, Nanna Hurwitz; Nielsen, Søren Feodor; Blønd, Morten

    2012-01-01

    Effort reward imbalance (ERI) is suggested to increase risk for stress and is hypothesized to increase cortisol levels, especially the awakening cortisol response, ACR.......Effort reward imbalance (ERI) is suggested to increase risk for stress and is hypothesized to increase cortisol levels, especially the awakening cortisol response, ACR....

  9. Population and mass imbalance in atomic Fermi gases

    NARCIS (Netherlands)

    Baarsma, J E; Gubbels, K.B.; Stoof, H.T.C.

    2010-01-01

    We develop an accurate theory of resonantly interacting Fermi mixtures with both spin and mass imbalance. We consider Fermi mixtures with arbitrary mass imbalances but focus, in particular, on the experimentally available Li6-K40 mixture. We determine the phase diagram of the mixture for different i

  10. Laterality and imbalance of muscle stiffness relate to personality.

    Science.gov (United States)

    Nakaya, Naoki; Kumano, Hiroaki; Minoda, Keiji; Kanazawa, Motoyori; Fukudo, Shin

    2004-01-01

    The authors' purpose in this study was to test the hypothesis that laterality and imbalance of muscle stiffness relate to personality. The authors selected 23 healthy volunteers and divided them into two groups based on the predominance of muscle stiffness on the left or right side. Imbalance of muscle stiffness was calculated as the absolute value of the difference of muscle stiffness between the right and left sides. The authors evaluated personality with the Japanese version of the Eysenck Personality Questionnaire. Subjects with left predominant muscle stiffness of the rectal abdominis had significantly higher neuroticism score than those with right predominant muscle stiffness. Subjects with more imbalance of muscle stiffness in the latissimus dorsi and in the trapezius had significantly higher neuroticism and psychoticism scores than those with less imbalance. The findings suggest that laterality and imbalance of muscle stiffness relate to personality.

  11. Inflammation Activation Contributes to Adipokine Imbalance in Patients with Acute Coronary Syndrome.

    Science.gov (United States)

    Li, Rong; Chen, Lu-zhu; Zhao, Shui-ping; Huang, Xian-sheng

    2016-01-01

    Inflammation can be activated as a defensive response by the attack of acute coronary syndrome (ACS) for ischemic tissue injury. The aim of the present study was to investigate the impact of ACS-activated inflammation on adipokine imbalance and the effects of statins on the crosstalk between inflammation and adipokine imbalance during ACS. In this study, 586 subjects were categorized into: (1) control group; (2) SA (stable angina) group; and (3) ACS group. Circulating levels of hs-CRP, adiponectin and resistin were measured by ELISA. Furthermore, forty C57BL/6 mice were randomized into: sham, AMI, low-statin (atorvastatin, 2 mg/kg/day) and high-statin (atorvastatin, 20 mg/kg/day) group. After 3 weeks, AMI models were established by surgical coronary artery ligation. Circulating levels and adipose expressions of adiponectin and resistin were assessed in animals. Besides, we investigate the effects of atorvastatin on ox-LDL-induced adipokine imbalance in vitro. As a result, we found that ACS patients had higher hs-CRP and resistin levels and lower adiponectin levels. Our correlation analysis demonstrated hs-CRP concentrations were positively correlated with resistin but negatively with adiponectin levels in humans. Our animal findings indicated higher circulating hs-CRP and resistin levels and lower adiponectin levels in AMI mice. Atorvastatin pre-treatment dose-dependently decreased hs-CRP and resistin levels but increased adiponectin levels in mice. The consistent findings were observed about the adipose expressions of resistin and adiponectin in mice. In study in vitro, ox-LDL increased cellular resistin expressions and otherwise for adiponectin expressions, which dose-dependently reversed by the addition of atorvastatin. Therefore, our study indicates that the ACS attack activates inflammation leading to adipokine imbalance that can be ameliorated by anti-inflammation of atorvastatin.

  12. Inflammation Activation Contributes to Adipokine Imbalance in Patients with Acute Coronary Syndrome.

    Directory of Open Access Journals (Sweden)

    Rong Li

    Full Text Available Inflammation can be activated as a defensive response by the attack of acute coronary syndrome (ACS for ischemic tissue injury. The aim of the present study was to investigate the impact of ACS-activated inflammation on adipokine imbalance and the effects of statins on the crosstalk between inflammation and adipokine imbalance during ACS. In this study, 586 subjects were categorized into: (1 control group; (2 SA (stable angina group; and (3 ACS group. Circulating levels of hs-CRP, adiponectin and resistin were measured by ELISA. Furthermore, forty C57BL/6 mice were randomized into: sham, AMI, low-statin (atorvastatin, 2 mg/kg/day and high-statin (atorvastatin, 20 mg/kg/day group. After 3 weeks, AMI models were established by surgical coronary artery ligation. Circulating levels and adipose expressions of adiponectin and resistin were assessed in animals. Besides, we investigate the effects of atorvastatin on ox-LDL-induced adipokine imbalance in vitro. As a result, we found that ACS patients had higher hs-CRP and resistin levels and lower adiponectin levels. Our correlation analysis demonstrated hs-CRP concentrations were positively correlated with resistin but negatively with adiponectin levels in humans. Our animal findings indicated higher circulating hs-CRP and resistin levels and lower adiponectin levels in AMI mice. Atorvastatin pre-treatment dose-dependently decreased hs-CRP and resistin levels but increased adiponectin levels in mice. The consistent findings were observed about the adipose expressions of resistin and adiponectin in mice. In study in vitro, ox-LDL increased cellular resistin expressions and otherwise for adiponectin expressions, which dose-dependently reversed by the addition of atorvastatin. Therefore, our study indicates that the ACS attack activates inflammation leading to adipokine imbalance that can be ameliorated by anti-inflammation of atorvastatin.

  13. The effect of load imbalances on the performance of Monte Carlo algorithms in LWR analysis

    Energy Technology Data Exchange (ETDEWEB)

    Siegel, A.R., E-mail: siegela@mcs.anl.gov [Argonne National Laboratory, Nuclear Engineering Division (United States); Argonne National Laboratory, Mathematics and Computer Science Division (United States); Smith, K., E-mail: kord@mit.edu [Massachusetts Institute of Technology, Department of Nuclear Science and Engineering (United States); Romano, P.K., E-mail: romano7@mit.edu [Massachusetts Institute of Technology, Department of Nuclear Science and Engineering (United States); Forget, B., E-mail: bforget@mit.edu [Massachusetts Institute of Technology, Department of Nuclear Science and Engineering (United States); Felker, K., E-mail: felker@mcs.anl.gov [Argonne National Laboratory, Mathematics and Computer Science Division (United States)

    2013-02-15

    A model is developed to predict the impact of particle load imbalances on the performance of domain-decomposed Monte Carlo neutron transport algorithms. Expressions for upper bound performance “penalties” are derived in terms of simple machine characteristics, material characterizations and initial particle distributions. The hope is that these relations can be used to evaluate tradeoffs among different memory decomposition strategies in next generation Monte Carlo codes, and perhaps as a metric for triggering particle redistribution in production codes.

  14. Golden Jubilee Photos: A Universal Imbalance

    CERN Multimedia

    2004-01-01

    http://www.cern.ch/cern50/ View along the NA48 beamline with the detector in the distance. No one is sure why the Universe wound up the way it has: all matter and no antimatter. According to prevailing theories, the early universe had equal amounts of matter and antimatter. However, whenever such opposites meet, they annihilate and become a burst of energy. This would seem to leave the Universe with neither matter nor antimatter - and thus no stars, planets, or physicists. If nature shows a bias for matter over antimatter, this could explain why the Universe is all matter. To see what might be missing from the theories, physicists search for the rare cases in which matter and antimatter behave differently. One such imbalance, called direct CP violation, showed up in the NA 31 experiment at CERN. The results from this experiment, first presented in 1993, showed that when K mesons and their antimatter cousins decay, they show a slight preference for matter over antimatter. Later experiments with neutral K mes...

  15. Large Genomic Imbalances in Brugada Syndrome

    Science.gov (United States)

    Riuró, Helena; Mates, Jesus; Pérez-Serra, Alexandra; Coll, Mònica; Porres, José Manuel; del Olmo, Bernat; Iglesias, Anna; Selga, Elisabet; Picó, Ferran; Pagans, Sara; Ferrer-Costa, Carles; Sarquella-Brugada, Geòrgia; Arbelo, Elena; Cesar, Sergi; Brugada, Josep; Campuzano, Óscar; Brugada, Ramon

    2016-01-01

    Purpose Brugada syndrome (BrS) is a form of cardiac arrhythmia which may lead to sudden cardiac death. The recommended genetic testing (direct sequencing of SCN5A) uncovers disease-causing SNVs and/or indels in ~20% of cases. Limited information exists about the frequency of copy number variants (CNVs) in SCN5A in BrS patients, and the role of CNVs in BrS-minor genes is a completely unexplored field. Methods 220 BrS patients with negative genetic results were studied to detect CNVs in SCN5A. 63 cases were also screened for CNVs in BrS-minor genes. Studies were performed by Multiplex ligation-dependent probe amplification or Next-Generation Sequencing (NGS). Results The detection rate for CNVs in SCN5A was 0.45% (1/220). The detected imbalance consisted of a duplication from exon 15 to exon 28, and could potentially explain the BrS phenotype. No CNVs were found in BrS-minor genes. Conclusion CNVs in current BrS-related genes are uncommon among BrS patients. However, as these rearrangements may underlie a portion of cases and they undergo unnoticed by traditional sequencing, an appealing alternative to conventional studies in these patients could be targeted NGS, including in a single experiment the study of SNVs, indels and CNVs in all the known BrS-related genes. PMID:27684715

  16. Polymorphism of Mhc-DRB alleles in Cercopithecus aethiops (green monkey): generation and functionality.

    Science.gov (United States)

    Rosal-Sánchez, M; Paz-Artal, E; Moreno-Pelayo, M A; Martínez-Quiles, N; Martínez-Laso, J; Martín-Villa, J M; Arnaiz-Villena, A

    1998-05-01

    DRB genes have been studied for the first time in green monkeys (Cercopithecus aethiops). Eleven new DRB alleles (exon 2, exon 3) have been obtained and sequenced from cDNA. A limited number of lineages have been identified: DRB1*03 (4 alleles), DRB1*07 (3 alleles), DRB5 (1 allele), DRB*w6 (1 allele), and DRB*w7 (2 alleles). The existence of Ceae-DRB1 duplications is supported by the finding of 3 DRB1 alleles in 3 different individuals. Ceae-DRB1*0701 may be non-functional because it bears serine at position 82, which hinders molecule surface expression in mice; the allele is only found in Ceae-DRB duplicated haplotypes. Base changes in cDNA Ceae-DRB alleles are consistent with the generation of polymorphism by point mutations or short segment exchanges between alleles. The eleven green monkey DRB alleles meet the requirements for functionality as antigen-presenting molecules (perhaps, excluding DRB1*0701), since: 1) they have been isolated from cDNA and do not present deletions, insertions or stop codons: 2) structural motifs necessary for a correct folding of the molecule, for the formation of DR/DR dimers and for CD4 interactions are conserved, and 3) the number of non-synonymous substitutions is higher than the number of synonymous substitutions in the peptide binding region (PBR), while the contrary holds true for the non-PBR region.

  17. T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis.

    Science.gov (United States)

    Wang, Chenggong; Liao, Qiande; Hu, Yihe; Zhong, DA

    2015-01-01

    Ankylosing spondylitis is a chronic inflammatory rheumatic disease, which is characterized by inflammation of the spine and the sacroiliac joints. To date, the disease etiology remains unclear. In the present study, the correlation of T lymphocyte subset changes with the progression of ankylosing spondylitis was investigated. A total of 55 patients with ankylosing spondylitis (22 severe and 23 mild cases) and 20 healthy individuals were selected. Firstly, the punctured cells in the lesions and the serum were collected, and the lymphocytes and the peripheral blood mononuclear cells were prepared. Secondly, quantitative PCR, ELISA and flow cytometry analyses were carried out to detect the levels of a series of immunoglobulins, complements, helper T cells, cytotoxic T cells, regulatory cells and cytokines. The expression levels of α-globulin, γ-globulin, immunoglobulin (Ig)G, IgA, IgM, serum complement C3, and complement C4 were found to be significantly increased in ankylosing spondylitis patients. In addition, the percentage of Th1 and Th17 cells was found to be significantly higher in the ankylosing spondylitis groups (mild and severe) compared with the healthy individuals. As a result, the Th1/Th2 and Th17/Treg ratios were significantly higher in patients with ankylosing spondylitis. In addition, T lymphocyte subset ratio imbalances contributed to an increased expression of immune mediators, including interferon (IFN)-γ and interleukin (IL)-17A. The mRNA and protein expression levels of IFN-γ and IL-17A were found to be higher in the ankylosing spondylitis groups compared with the control group. The present study provided further evidence on the function and underlying mechanism of T lymphocyte subsets, which may be useful in the diagnosis and treatment of ankylosing spondylitis.

  18. CD4+T细胞亚群表达失衡在妊娠期哮喘发病中的作用及意义%Role and significance of the CD4+T cells subsets' expressing imbalance in the pathogenesis of gestation asthma

    Institute of Scientific and Technical Information of China (English)

    马佳佳; Nick Lu; 陈必良

    2012-01-01

    目的:观察妊娠期哮喘小鼠模型中Th17及Treg细胞活性分布和表达变化,探讨Th17/Treg细胞免疫平衡在妊娠期哮喘小鼠发病中的作用机制.方法:24只6~8周龄,雌性BALB/c小鼠随机分为4组,每组6只.以OVA/Al (OH)3混悬液致敏与激发构建妊娠期哮喘组(AP组)和非妊娠期哮喘组(ANP组)小鼠模型;健康妊娠组(HP组)和健康非妊娠组(HNP组)小鼠致敏与激发均以只含Al(OH)3的生理盐水混悬液替代.光镜下观察小鼠支气管肺泡灌洗液(BALF)中细胞计数及分类;HE染色评价小鼠气道炎症程度及肺组织病理学变化;流式细胞术测定小鼠外周血Th17及Treg细胞所占CD4+T细胞比例,计算Th17/Treg细胞比值;RT-PCR检测小鼠肺组织中Th17及Treg细胞相关因子表达.结果:妊娠期哮喘小鼠BALF中炎症细胞分类及计数、肺组织病理学表现和活体肺功能气道高反应性Penh值等客观指标证实,妊娠哮喘小鼠模型构建成功.外周血中,AP组CD4+IL-17+T细胞(Th17)显著升高(P<0.01);Foxp3+T细胞( Treg)显著降低(P<0.01);与HP,HNP组相比,存在Th17/Treg比例失衡(P<0.01).AP组小鼠肺组织中IL-17、IL-23,IL-10 mRNA表达水平均显著高于HP组及HNP组(P<0.01);IFN-γ mRNA则显著低于HP组及HNP组(P<0.01);ANP组各因子mRNA水平变化与AP组一致,组间无显著差异.结论:妊娠期哮喘小鼠存在细胞免疫功能失调;Th17、Treg细胞数量及免疫平衡状态发生改变,可能是妊娠期哮喘发病过程中一个重要的决定因素.%Objective:To observe the activity distribution of Thl7 and Treg cells and expression changes in mouse model of pregnancy asthma, and to study the role of Thl7/Treg cell's immune imbalance in the pathogenesis of asthma during pregnancy. Methods: 24 female BALB/c mice,6 ~8w old,were randomly divided into 4 groups(n= 6). Ovalbumin (OVA) was used to sensitize, challenge and construct the asthma during pregnancy group ( AP group

  19. Imbalance of endogenous prostanoids in moderate-to-severe asthma

    Directory of Open Access Journals (Sweden)

    Masaya Takemura

    2017-01-01

    Conclusions: An imbalance in production, breakdown, or both between prostaglandin E2 and other prostanoids possibly due to epithelial damage may be involved in the pathogenesis of moderate-to-severe asthma.

  20. An Analysis of Public Service Structural Imbalances in Rural China

    Institute of Scientific and Technical Information of China (English)

    林万龙

    2008-01-01

    Rectifying the structural imbalance between the provision of and demand for rural public services can effectively boost the efficiency of public funds utilization and the level of public service provision. Based on the findings of a field survey, this article presents a summary of the structural imbalance between the provision of and demand for rural public services. This paper holds that the structural imbalance is primarily reflected in the dislocation between provision and demand, the unsuitable mode of provision, the monolithic provision mechanism, the excessive focus on construction at the expense of governance and the overemphasis of counties and townships at the cost of villages. Such structural imbalance is principally because of the limited financial strength of government at the grass-roots level due to treasury centralization and the over-dependence of public services on special funds allocated by government at or above provincial level.

  1. Early Proximal Junctional Failure in Patients with Preoperative Sagittal Imbalance

    OpenAIRE

    2013-01-01

    Study Type Retrospective review. Introduction Sagittal imbalance has been associated with lower health-related quality of life outcomes, and restoration of imbalance is associated with improved outcomes.1 2 3 The long constructs used in adult spinal deformity have potential consequences such as proximal junctional kyphosis (PJK). Clinically, the development of PJK may not be as important as failure of the construct or vertebrae at the proximal end. As PJK does not lead to worse clinical outco...

  2. Effort-reward imbalance and depression in Japanese medical residents.

    Science.gov (United States)

    Sakata, Yumi; Wada, Koji; Tsutsumi, Akizumi; Ishikawa, Hiroyasu; Aratake, Yutaka; Watanabe, Mayumi; Katoh, Noritada; Aizawa, Yoshiharu; Tanaka, Katsutoshi

    2008-01-01

    The effort-reward imbalance is an important psychosocial factor which is related to poor health among employees. However, there are few studies that have evaluated effort-reward imbalance among medical residents. The present study was done to determine the association between psychosocial factors at work as defined by the effort-reward imbalance model and depression among Japanese medical residents. We distributed a questionnaire to 227 medical residents at 16 teaching hospitals in Japan at the end of August 2005. We asked participants to answer questions which included demographic information, depressive symptoms, effort-reward imbalance, over-commitment and social support. Depression was evaluated using the Japanese version of the Center for Epidemiologic Studies-Depression (CES-D) scale. The effort-reward imbalance and over-commitment were assessed by the Effort-Reward Imbalance (ERI) questionnaire which Siegrist developed. Social support was determined on a visual analog scale. Logistic regression analysis was performed to determine the associations between effort-reward imbalance and depressive symptoms. Depressive symptoms were found in 35 (29.2%) 1st-year residents and 21 (27.6%) 2nd-year residents. The effort-reward ratio >1 (OR, 8.83; 95% CI, 2.87-27.12) and low social support score (OR, 2.77, 95% CI, 1.36-5.64) were associated with depressive symptoms among medical residents. Effort-reward imbalance was independently related to depression among Japanese medical residents. The present study suggests that balancing between effort and reward at work is important for medical residents' mental health.

  3. Chiral Imbalance in QCD and its consequences

    Directory of Open Access Journals (Sweden)

    Andrianov Alexander

    2016-01-01

    Full Text Available Under extreme conditions of high temperature and/or large quark (baryon density, the vacuum of QCD changes its properties, and deconfinement, chiral symmetry restoration as well as chiral symmetry breaking take place. These transitions (phases are accompanied by the rapid change in the rate and nature of topological transitions connecting different topological sectors. The heavy ion collisions (HIC program opens a possibility to study these phenomena in so-called non-Abelian Quark-gluon plasma (QGP. In these phases the currents of light quarks (vector and axial-vector can be independently examined for right-handed (RH and left-handed (LH quarks. To describe such a quark matter chiral chemical potential can be introduced to quantify the presence of chirality imbalance (ChI i.e. the difference between the average numbers of RH and LH quarks in the fireball after HIC. In this review talk we will focus our attention on the discussion of the ChI related developments in heavy ion physics at central collisions and the plans for the future experiments aimed at establishing (or falsifying the presence of Local spacial Parity Breaking (LPB in heavy ion data. We describe some of experimental observables in detecting the signal of LPB. A number of measurements is proposed that allow to reach a definite conclusion on the occurrence of LPB effects in non-Abelian QGP produced in central heavy ion collisions and its simulation within a number of QCD-inspired models is outlined. Based on the effective meson theory in the presence of Chern-Simons interaction it is found that the spectrum of massive vector mesons splits into three polarization components with different effective masses. Moreover a resonance broadening occurs that leads to an increase of spectral contribution to the dilepton production as compared to the vacuum state. The asymmetry in production of longitudinally and transversely polarized states of ρ and ω mesons for various values of the

  4. Chiral Imbalance in QCD and its consequences

    Science.gov (United States)

    Andrianov, Alexander; Andrianov, Vladimir; Espriu, Domenec

    2016-10-01

    Under extreme conditions of high temperature and/or large quark (baryon) density, the vacuum of QCD changes its properties, and deconfinement, chiral symmetry restoration as well as chiral symmetry breaking take place. These transitions (phases) are accompanied by the rapid change in the rate and nature of topological transitions connecting different topological sectors. The heavy ion collisions (HIC) program opens a possibility to study these phenomena in so-called non-Abelian Quark-gluon plasma (QGP). In these phases the currents of light quarks (vector and axial-vector) can be independently examined for right-handed (RH) and left-handed (LH) quarks. To describe such a quark matter chiral chemical potential can be introduced to quantify the presence of chirality imbalance (ChI) i.e. the difference between the average numbers of RH and LH quarks in the fireball after HIC. In this review talk we will focus our attention on the discussion of the ChI related developments in heavy ion physics at central collisions and the plans for the future experiments aimed at establishing (or falsifying) the presence of Local spacial Parity Breaking (LPB) in heavy ion data. We describe some of experimental observables in detecting the signal of LPB. A number of measurements is proposed that allow to reach a definite conclusion on the occurrence of LPB effects in non-Abelian QGP produced in central heavy ion collisions and its simulation within a number of QCD-inspired models is outlined. Based on the effective meson theory in the presence of Chern-Simons interaction it is found that the spectrum of massive vector mesons splits into three polarization components with different effective masses. Moreover a resonance broadening occurs that leads to an increase of spectral contribution to the dilepton production as compared to the vacuum state. The asymmetry in production of longitudinally and transversely polarized states of ρ and ω mesons for various values of the dilepton

  5. PCR bias in amplification of androgen receptor alleles, a trinucleotide repeat marker used in clonality studies.

    Science.gov (United States)

    Mutter, G L; Boynton, K A

    1995-04-25

    Trinucleotide CAG repeats in the X-linked human androgen receptor gene (HUMARA) have proved a useful means of determining X chromosome haplotypes, and when combined with methylation analysis of nearby cytosine residues permits identification of non-random X inactivation in tumors of women. Co-amplification of two alleles in a heterozygote generates PCR products which differ in the number of CAG units, and thus their melting and secondary structure characteristics. We have shown that under optimal conditions amplification efficiency of two HUMARA alleles is near-equivalent, generating PCR products in a ratio proportional to that of the genomic template. In contrast, reduction of template quantity, damage of template by ultraviolet irradiation or addition of monovalent salts (sodium chloride, sodium acetate or ammonium acetate) produces highly variable imbalances of allelic PCR products, with a strong tendency to preferentially amplify lower molecular weight alleles. Variability and biasing was diminished by substitution of 7-deaza-2'-dGTP for dGTP during amplification, an intervention which reduces stability of intramolecular and intermolecular GC base pairing. We conclude that DNA which is scanty, damaged or salt contaminated may display amplification bias of GC-rich PCR targets, potentially confounding accurate interpretation or reproducibility of assays which require co-amplification of alleles.

  6. Fitness costs associated with evolved herbicide resistance alleles in plants.

    Science.gov (United States)

    Vila-Aiub, Martin M; Neve, Paul; Powles, Stephen B

    2009-12-01

    Predictions based on evolutionary theory suggest that the adaptive value of evolved herbicide resistance alleles may be compromised by the existence of fitness costs. There have been many studies quantifying the fitness costs associated with novel herbicide resistance alleles, reflecting the importance of fitness costs in determining the evolutionary dynamics of resistance. However, many of these studies have incorrectly defined resistance or used inappropriate plant material and methods to measure fitness. This review has two major objectives. First, to propose a methodological framework that establishes experimental criteria to unequivocally evaluate fitness costs. Second, to present a comprehensive analysis of the literature on fitness costs associated with herbicide resistance alleles. This analysis reveals unquestionable evidence that some herbicide resistance alleles are associated with pleiotropic effects that result in plant fitness costs. Observed costs are evident from herbicide resistance-endowing amino acid substitutions in proteins involved in amino acid, fatty acid, auxin and cellulose biosynthesis, as well as enzymes involved in herbicide metabolism. However, these resistance fitness costs are not universal and their expression depends on particular plant alleles and mutations. The findings of this review are discussed within the context of the plant defence trade-off theory and herbicide resistance evolution.

  7. Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder.

    Science.gov (United States)

    Lopez, A Y; Wang, X; Xu, M; Maheshwari, A; Curry, D; Lam, S; Adesina, A M; Noebels, J L; Sun, Q-Q; Cooper, E C

    2016-12-13

    ANK3, encoding the adaptor protein Ankyrin-G (AnkG), has been implicated in bipolar disorder by genome-wide association studies. ANK3 has multiple alternative first exons, and a bipolar disorder-associated ANK3 variant has been shown to reduce the expression of exon 1b. Here we identify mechanisms through which reduced ANK3 exon 1b isoform expression disrupts neuronal excitation-inhibition balance. We find that parvalbumin (PV) interneurons and principal cells differentially express ANK3 first exon subtypes. PV interneurons express only isoforms containing exon 1b, whereas excitatory principal cells express exon 1e alone or both 1e and 1b. In transgenic mice deficient for exon 1b, PV interneurons lack voltage-gated sodium channels at their axonal initial segments and have increased firing thresholds and diminished action potential dynamic range. These mice exhibit an Ank3 gene dosage-dependent phenotype including behavior changes modeling bipolar disorder, epilepsy and sudden death. Thus ANK3's important association with human bipolar susceptibility may arise from imbalance between AnkG function in interneurons and principal cells and resultant excessive circuit sensitivity and output. AnkG isoform imbalance is a novel molecular endophenotype and potential therapeutic target.Molecular Psychiatry advance online publication, 13 December 2016; doi:10.1038/mp.2016.233.

  8. Allelic imbalance analysis using a single-nucleotide polymorphism microarray for the detection of bladder cancer recurrence.

    NARCIS (Netherlands)

    Coenen, M.J.H.; Ploeg, M.; Schijvenaars, M.M.V.A.P.; Cornel, E.B.; Karthaus, H.F.M.; Scheffer, H.; Witjes, J.A.M.; Franke, B.; Kiemeney, L.A.L.M.

    2008-01-01

    PURPOSE: Non-muscle-invasive bladder cancer is a frequently occurring cancer, with an extremely high recurrence risk. Recurrence detection is based on cytology and urethrocystoscopy. A previous study suggested that a single-nucleotide polymorphism (SNP) array may be effective for noninvasive detecti

  9. A fast and accurate method to detect allelic genomic imbalances underlying mosaic rearrangements using SNP array data

    Directory of Open Access Journals (Sweden)

    Pique-Regi Roger

    2011-05-01

    Full Text Available Abstract Background Mosaicism for copy number and copy neutral chromosomal rearrangements has been recently identified as a relatively common source of genetic variation in the normal population. However its prevalence is poorly defined since it has been only studied systematically in one large-scale study and by using non optimal ad-hoc SNP array data analysis tools, uncovering rather large alterations (> 1 Mb and affecting a high proportion of cells. Here we propose a novel methodology, Mosaic Alteration Detection-MAD, by providing a software tool that is effective for capturing previously described alterations as wells as new variants that are smaller in size and/or affecting a low percentage of cells. Results The developed method identified all previously known mosaic abnormalities reported in SNP array data obtained from controls, bladder cancer and HapMap individuals. In addition MAD tool was able to detect new mosaic variants not reported before that were smaller in size and with lower percentage of cells affected. The performance of the tool was analysed by studying simulated data for different scenarios. Our method showed high sensitivity and specificity for all assessed scenarios. Conclusions The tool presented here has the ability to identify mosaic abnormalities with high sensitivity and specificity. Our results confirm the lack of sensitivity of former methods by identifying new mosaic variants not reported in previously utilised datasets. Our work suggests that the prevalence of mosaic alterations could be higher than initially thought. The use of appropriate SNP array data analysis methods would help in defining the human genome mosaic map.

  10. Allelic imbalance and fine mapping of the 17p13.3 subregion in sporadic breast carcinomas

    DEFF Research Database (Denmark)

    Hoff, C; Mollenhauer, J; Waldau, B;

    2001-01-01

    .3. This region is suspected to harbor another tumor suppressor gene. In order to get more information concerning the pattern of AIs in 17p13.3, we performed analysis of AI of 49 breast carcinomas at 6 polymorphic loci in 17p13.3. Eighty-six percent of the tumors present AI at least at one marker in 17p13...

  11. Allele Imbalance or Loss of Heterozygosity, in Normal Appearing Breast Epithelium as a Novel Biomarker to Predict Future Breast Cancer

    Science.gov (United States)

    2011-07-10

    were either in cassettes too large to fit a standard microtome [7/22] or were in large wax blocks [15/22]. We requested that the tissue be re...review Initially unuseable Not Poor Poor TDLUs TDLUs ɛ Stroma Too Histo Large Cassettes enough quality quality too lost TDLUs only many logically wax ...biopsies lacked atypia, and who had no fa mily history of breast cancer. 10-μ sections were cut from paraffin blocks and TDLUs were removed by laser

  12. An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models

    LENUS (Irish Health Repository)

    Donatello, Simona

    2011-04-26

    Abstract Background Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Methods Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. Results Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. Conclusions Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.

  13. Cell surface expression level variation between two common Human Leukocyte Antigen alleles, HLA-A2 and HLA-B8, is dependent on the structure of the C terminal part of the alpha 2 and the alpha 3 domains

    DEFF Research Database (Denmark)

    Dellgren, Christoffer; Nehlin, Jan O; Barington, Torben

    2015-01-01

    Constitutive cell surface expression of Human Leukocyte Antigen (HLA) class I antigens vary extremely from tissue to tissue and individual antigens may differ widely in expression levels. Down-regulation of class I expression is a known immune evasive mechanism used by cancer cells and viruses....... Moreover, recent observations suggest that even minor differences in expression levels may influence the course of viral infections and the frequency of complications to stem cell transplantation. We have shown that some human multipotent stem cells have high expression of HLA-A while HLA-B is only weakly...... expressed, and demonstrate here that this is also the case for the human embryonic kidney cell line HEK293T. Using quantitative flow cytometry and quantitative polymerase chain reaction we found expression levels of endogenous HLA-A3 (median 71,204 molecules per cell) 9.2-fold higher than the expression of...

  14. Subfunctionalization reduces the fitness cost of gene duplication in humans by buffering dosage imbalances

    Directory of Open Access Journals (Sweden)

    Fernández Ariel

    2011-12-01

    Full Text Available Abstract Background Driven essentially by random genetic drift, subfunctionalization has been identified as a possible non-adaptive mechanism for the retention of duplicate genes in small-population species, where widespread deleterious mutations are likely to cause complementary loss of subfunctions across gene copies. Through subfunctionalization, duplicates become indispensable to maintain the functional requirements of the ancestral locus. Yet, gene duplication produces a dosage imbalance in the encoded proteins and thus, as investigated in this paper, subfunctionalization must be subject to the selective forces arising from the fitness bottleneck introduced by the duplication event. Results We show that, while arising from random drift, subfunctionalization must be inescapably subject to selective forces, since the diversification of expression patterns across paralogs mitigates duplication-related dosage imbalances in the concentrations of encoded proteins. Dosage imbalance effects become paramount when proteins rely on obligatory associations to maintain their structural integrity, and are expected to be weaker when protein complexation is ephemeral or adventitious. To establish the buffering effect of subfunctionalization on selection pressure, we determine the packing quality of encoded proteins, an established indicator of dosage sensitivity, and correlate this parameter with the extent of paralog segregation in humans, using species with larger population -and more efficient selection- as controls. Conclusions Recognizing the role of subfunctionalization as a dosage-imbalance buffer in gene duplication events enabled us to reconcile its mechanistic nonadaptive origin with its adaptive role as an enabler of the evolution of genetic redundancy. This constructive role was established in this paper by proving the following assertion: If subfunctionalization is indeed adaptive, its effect on paralog segregation should scale with the dosage

  15. Different Approaches in Addressing Internal and External Economic Imbalances

    Institute of Scientific and Technical Information of China (English)

    郭树清

    2008-01-01

    This article analyzes the internal and external imbalances of China’s economy from a global perspective. The author believes that trade surplus and savings surplus are not the absolute metrics to define a country’s economic strength. China’s balance of payments has continued to maintain a big surplus, which shows China’s unique economic structure and growth model and exposes deep contradictions in income distribution, factor prices and resource allocation. While stimulating rapid growth, the imbalance of China’s economy, at the same time, has long delayed the upgrading of industrial structure, aggravating the threat of inflation and heightening concerns of an asset bubble. Although the external and internal imbalances are closely linked to each other, they are quite different in nature. This similar global economic imbalance has existed for a long time, and to a great extent, is inevitable and rational. However, internal imbalances caused by its own systems and policies, if lasted, would have severe and negative impacts not only on China’s economy, but on the global economy as a whole.

  16. How gender disparities drive imbalances in health care leadership

    Directory of Open Access Journals (Sweden)

    Hoss MAK

    2011-11-01

    Full Text Available Mary Ann Keogh Hoss1, Paula Bobrowski2, Kathryn J McDonagh3, Nancy M Paris41Health Services Administration, Eastern Washington University, College of Business and Public Administration, Spokane, WA, USA; 2College of Liberal Arts, Auburn University, Auburn, AL, USA; 3Executive Relations, Hospira Inc, Lake Forest, IL, USA; 4Georgia Center for Oncology Research and Education, Atlanta, GA, USAAbstract: Low female representation in US hospital chief executive officer positions has persisted for decades. This article addresses gender disparity in professional development, the rationale for gender differences, and practical strategies to address this imbalance. The health care workforce consists of 75% women, but according to two recent surveys, ie, a state survey and a survey of the top 100 US hospitals, women hold only about 12% of chief executive officer positions in US hospitals. Significant and dedicated efforts by both individuals and organizations are necessary to rectify this imbalance.Keywords: gender, imbalance, leadership, United States, hospitals

  17. Adjustment of Global Imbalances and Its Impact on China's Economy

    Institute of Scientific and Technical Information of China (English)

    Jianhuai Shi

    2006-01-01

    The present paper discusses ways of adjusting the imbalances of the global economy and its impact on China's economy. The analysis in the paper shows that the cut of US fiscal deficits and the appreciation of the currencies of East Asia, including China ' s RMB, are necessary for a smooth adjustment of the global imbalances. The adjustments will have a positive impact on China's economy and will help China realize its external balance. The increase in public spending on the service sector along with the appreciation of RMB will help China realize the internal balance too. The adjustment of the global imbalances will create opportunities and an external pushing force for China in its industrial restructuring and shift in the model of economic growth.

  18. Neoliberalism, trade imbalances, and economic policy in the Eurozone crisis

    Directory of Open Access Journals (Sweden)

    Engelbert Stockhammer

    2016-12-01

    Full Text Available This paper analyzes the causes of the Eurozone crisis. In doing so, it carefully surveys authors from different economic schools of thought. The paper discusses competing explanations for European current account imbalances. Remarkably, opposing views on the relative importance of cost developments and demand developments in explaining current account imbalances can be found in both heterodox and orthodox economics. Regarding the assessment of fiscal and monetary policy there is a clearer polarisation, with heterodox analysis regarding austerity as unhelpful and most of orthodox economics endorsing it. We advocate a post-Keynesian view, which holds that current account imbalances are not a fundamental cause of the sovereign debt crisis. Rather, the economic policy architecture of the Eurozone, which aims at restricting the role of fiscal and monetary policy, is the key to understanding the crisis in Europe.

  19. Effort-reward imbalance and burnout among nurses.

    Science.gov (United States)

    Bakker, A B; Killmer, C H; Siegrist, J; Schaufeli, W B

    2000-04-01

    This study among a sample of 204 German nurses tested the hypothesis that an imbalance of high extrinsic efforts spent (i.e. job demands) and low extrinsic rewards obtained (e.g. poor promotion prospects) are associated with the burnout syndrome: the depletion of nurses' emotional resources. The results of a series of analyses of variances confirmed this hypothesis, by showing that those nurses who experienced an effort-reward imbalance (ERI) reported higher levels on two of the three core dimensions of burnout (i.e. emotional exhaustion and depersonalization) than those who did not experience such an imbalance. Moreover - as additionally hypothesized - significant interaction effects indicated that burnout (i.e. emotional exhaustion and reduced personal accomplishment) was particularly prevalent among those nurses who experienced ERI and put relatively high intrinsic effort into their jobs, as reflected by their strong tendency to be personally in control over job conditions.

  20. Shoulder muscle imbalance and subacromial impingement syndrome in overhead athletes.

    Science.gov (United States)

    Page, Phil

    2011-03-01

    Subacromial impingement is a frequent and painful condition among athletes, particularly those involved in overhead sports such as baseball and swimming. There are generally two types of subacromial impingement: structural and functional. While structural impingement is caused by a physical loss of area in the subacromial space due to bony growth or inflammation, functional impingement is a relative loss of subacromial space secondary to altered scapulohumeral mechanics resulting from glenohumeral instability and muscle imbalance. The purpose of this review is to describe the role of muscle imbalance in subacromial impingement in order to guide sports physical therapy evaluation and interventions.

  1. In-phase and quadrature imbalance modeling, estimation, and compensation

    CERN Document Server

    Li, Yabo

    2013-01-01

    This book provides a unified IQ imbalance model and systematically reviews the existing estimation and compensation schemes. It covers the different assumptions and approaches that lead to many models of IQ imbalance. In wireless communication systems, the In-phase and Quadrature (IQ) modulator and demodulator are usually used as transmitter (TX) and receiver (RX), respectively. For Digital-to-Analog Converter (DAC) and Analog-to-Digital Converter (ADC) limited systems, such as multi-giga-hertz bandwidth millimeter-wave systems, using analog modulator and demodulator is still a low power and l

  2. The U.S. Dollar and Global Imbalances

    OpenAIRE

    Liu, Kai; Zhou, Xuan

    2015-01-01

    Global Imbalances are mainly featured by the massive and long-lasting U.S. trade deficit. Since the Breton Woods system collapsed and was replaced by the Jamaica Agreement, the U.S. trade deficit has been lasting for about 40 years. This paper proves that permanent global imbalances can be sustainable due to the special role of the U.S. dollar, by building a two-country cash-in-advance growth model with a dollar standard in the international trade. The permanent U.S. trade deficit is an incre...

  3. GLOBAL IMBALANCES, CRISIS AND THE LACK OF GLOBAL GOVERNANCE

    Directory of Open Access Journals (Sweden)

    VIOLETA GIANINA DRAGOTĂ

    2012-11-01

    Full Text Available While briefly shrinking during the global crisis, global imbalances in trade and financial flows and their underlying systemic causes have not gone away. The current monetary non-order causes developing countries to adopt defensive strategies against fickle markets and allows developed countries to engage in beggar-thy-neighbour strategies, with a reliance on exports serving to offset their failure to manage domestic demand. Global imbalances are a symptom of existing systemic governance shortcomings. They can only be properly addressed by global governance reform and proper international policy coordination.

  4. Analysis of the porcine APOA2 gene expression in liver, polymorphism identification and association with fatty acid composition traits.

    Science.gov (United States)

    Ballester, M; Revilla, M; Puig-Oliveras, A; Marchesi, J A P; Castelló, A; Corominas, J; Fernández, A I; Folch, J M

    2016-10-01

    APOA2 is a protein implicated in triglyceride, fatty acid and glucose metabolism. In pigs, the APOA2 gene is located on pig chromosome 4 (SSC4) in a QTL region affecting fatty acid composition, fatness and growth traits. In this study, we evaluated APOA2 as a candidate gene for meat quality traits in an Iberian × Landrace backcross population. The APOA2:c.131T>A polymorphism, located in exon 3 of APOA2 and determining a missense mutation, was associated with the percentage of hexadecenoic acid [C16:1(n-9)], linoleic acid [C18:2(n-6)], α-linolenic acid [C18:3(n-3)], dihomo-gamma-linolenic acid [C20:3(n-6)] and polyunsaturated fatty acids (PUFAs) in backfat. Furthermore, this SNP was associated with the global mRNA expression levels of APOA2 in liver and was used as a marker to determine allelic expression imbalance by pyrosequencing. We determined an overexpression of the T allele in heterozygous samples with a mean ratio of 2.8 (T/A), observing a high variability in the allelic expression among individuals. This result suggests that complex regulatory mechanisms, beyond a single polymorphism (e.g. epigenetic effects or multiple cis-acting polymorphisms), may be regulating APOA2 gene expression.

  5. [Frequent allelic losses in tumor-associated stromal cells and tumor epitelium of prostate cancer].

    Science.gov (United States)

    Kekeeva, T V; Popova, O P; Shegaĭ, P V; Zavalishina, L E; Andreeva, Iu Iu; Zaletaev, D V; Nemtsova, M V

    2008-01-01

    It has become increasingly clear that tumor microenvironment plays a critical role in carcinogenesis. Accumulation of genetic alterations is typical not only for cancer epithelial cells but tumor-associated fibroblasts as well. Tumor epithelia, tumor-associated stroma from prostatectomy specimens of patients with prostate cancer and cells from prostatic intraepithelial neoplasia (PIN) and adjacent stroma from males with PIN were isolated by using laser capture microdissection. Microsatellite allelotyping was evaluated using 4 highly polymorphic markers for chromosomal regions 8p22, 16q23-24 and 13q14. Incidences of alterations (loss of heterozygosity or allelic imbalance) were 48% for region 8p22, 72% for 16q23 and 37% for 13q14. The LOH frequencies in tumor-associated stroma cells were very similar. Alterations at chromosome 13q were significantly associated with advanced tumor stage, whereas AI at 16q was also associated with high Gleason score and lymph node metastasis. We find some incidences of allelic imbalance in premalignant lesions in epithelial (16-27%) and stromal (7-22%) components. Our results show that the frequencies of genetic aberrations are as high in stromal cells as in tumor cells.

  6. Neuropeptides function in a homeostatic manner to modulate excitation-inhibition imbalance in C. elegans.

    Science.gov (United States)

    Stawicki, Tamara M; Takayanagi-Kiya, Seika; Zhou, Keming; Jin, Yishi

    2013-05-01

    Neuropeptides play crucial roles in modulating neuronal networks, including changing intrinsic properties of neurons and synaptic efficacy. We previously reported a Caenorhabditis elegans mutant, acr-2(gf), that displays spontaneous convulsions as the result of a gain-of-function mutation in a neuronal nicotinic acetylcholine receptor subunit. The ACR-2 channel is expressed in the cholinergic motor neurons, and acr-2(gf) causes cholinergic overexcitation accompanied by reduced GABAergic inhibition in the locomotor circuit. Here we show that neuropeptides play a homeostatic role that compensates for this excitation-inhibition imbalance in the locomotor circuit. Loss of function in genes required for neuropeptide processing or release of dense core vesicles specifically modulate the convulsion frequency of acr-2(gf). The proprotein convertase EGL-3 is required in the cholinergic motor neurons to restrain convulsions. Electrophysiological recordings of neuromuscular junctions show that loss of egl-3 in acr-2(gf) causes a further reduction of GABAergic inhibition. We identify two neuropeptide encoding genes, flp-1 and flp-18, that together counteract the excitation-inhibition imbalance in acr-2(gf) mutants. We further find that acr-2(gf) causes an increased expression of flp-18 in the ventral cord cholinergic motor neurons and that overexpression of flp-18 reduces the convulsion of acr-2(gf) mutants. The effects of these peptides are in part mediated by two G-protein coupled receptors, NPR-1 and NPR-5. Our data suggest that the chronic overexcitation of the cholinergic motor neurons imposed by acr-2(gf) leads to an increased production of FMRFamide neuropeptides, which act to decrease the activity level of the locomotor circuit, thereby homeostatically modulating the excitation and inhibition imbalance.

  7. Global Imbalance:Onus On the United States

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    During the China-U.S. Business Forum held in Beijing February 14-15, Xia Bin, Director of the Financial Research Institute of the Development Research Center under the State Council, makes a speech on the United States' responsibility for global economic imbalances. His main ideas as reported in the China Business News, follow:

  8. Subacromial impingement syndrome: the role of posture and muscle imbalance.

    Science.gov (United States)

    Lewis, Jeremy S; Green, Ann; Wright, Christine

    2005-01-01

    Changes in upper body posture, colloquially termed forward head posture (FHP), are considered to be an etiologic factor in the pathogenesis of subacromial impingement syndrome (SIS). The literature suggests that postural deviations associated with FHP follow distinct patterns involving an increase in the thoracic kyphosis angle and a downwardly rotated, anteriorly tilted, and protracted scapula, which in turn leads to increased compression in the subacromial space. These postural changes are thought to occur concurrently with an imbalance of the musculature, and conservative rehabilitation commonly involves addressing both posture and muscle imbalance. There is a paucity of evidence supporting the hypothesis that posture and muscle imbalance are involved in the etiology of SIS. The purpose of this study was to investigate whether FHP was associated with an increased thoracic kyphosis, an altered position of the scapula; and a reduction in glenohumeral elevation range. Selected sagittal and frontal plane postural measurements were made in 60 asymptomatic subjects and 60 subjects with SIS. The findings suggested that upper body posture does not follow the set patterns described in the literature, and further research is required to determine whether upper body and scapular posture and muscle imbalance are involved in the pathogenesis of SIS.

  9. Private consumption-savings behavior and macroeconomic imbalances

    NARCIS (Netherlands)

    de Castro Campos, M.

    2016-01-01

    Between the signing of the Maastricht Treaty in 1991 and 2007 many of the existing macroeconomic theories were applied to support the claim that the euro area was an optimal currency union and to argue that increasing macroeconomic imbalances were a logical part of the financial integration process.

  10. Prism adaptation improves postural imbalance in neglect patients

    NARCIS (Netherlands)

    Nijboer, Tanja C W; Olthoff, Liselot; Van der Stigchel, Stefan; Visser-Meily, Johanna M a

    2014-01-01

    Several studies have found a negative relation between neglect and postural imbalance. The aim of the current study was to investigate the influence of a single session of prism adaptation on balance [i.e. mediolateral and anteroposterior center of pressure (CoP)] and postural sway (i.e. mean varian

  11. Addressing the pressing need to reduce global and European imbalances

    OpenAIRE

    Cozzi, Giovanni; McKinley, Terry

    2015-01-01

    This Policy Brief is focused on the need to reduce macroeconomic imbalances both globally and within Europe. In doing so, it employs the CAM global macroeconometric model to make projections of trends over roughly the next ten years, i.e., through 2025.

  12. Hypermethylated SUPERMAN epigenetic alleles in arabidopsis.

    Science.gov (United States)

    Jacobsen, S E; Meyerowitz, E M

    1997-08-22

    Mutations in the SUPERMAN gene affect flower development in Arabidopsis. Seven heritable but unstable sup epi-alleles (the clark kent alleles) are associated with nearly identical patterns of excess cytosine methylation within the SUP gene and a decreased level of SUP RNA. Revertants of these alleles are largely demethylated at the SUP locus and have restored levels of SUP RNA. A transgenic Arabidopsis line carrying an antisense methyltransferase gene, which shows an overall decrease in genomic cytosine methylation, also contains a hypermethylated sup allele. Thus, disruption of methylation systems may yield more complex outcomes than expected and can result in methylation defects at known genes. The clark kent alleles differ from the antisense line because they do not show a general decrease in genomic methylation.

  13. Enhancement of allele discrimination by introduction of nucleotide mismatches into siRNA in allele-specific gene silencing by RNAi.

    Directory of Open Access Journals (Sweden)

    Yusuke Ohnishi

    Full Text Available Allele-specific gene silencing by RNA interference (RNAi is therapeutically useful for specifically inhibiting the expression of disease-associated alleles without suppressing the expression of corresponding wild-type alleles. To realize such allele-specific RNAi (ASP-RNAi, the design and assessment of small interfering RNA (siRNA duplexes conferring ASP-RNAi is vital; however, it is also difficult. In a previous study, we developed an assay system to assess ASP-RNAi with mutant and wild-type reporter alleles encoding the Photinus and Renilla luciferase genes. In line with experiments using the system, we realized that it is necessary and important to enhance allele discrimination between mutant and corresponding wild-type alleles. Here, we describe the improvement of ASP-RNAi against mutant alleles carrying single nucleotide variations by introducing base substitutions into siRNA sequences, where original variations are present in the central position. Artificially mismatched siRNAs or short-hairpin RNAs (shRNAs against mutant alleles of the human Prion Protein (PRNP gene, which appear to be associated with susceptibility to prion diseases, were examined using this assessment system. The data indicates that introduction of a one-base mismatch into the siRNAs and shRNAs was able to enhance discrimination between the mutant and wild-type alleles. Interestingly, the introduced mismatches that conferred marked improvement in ASP-RNAi, appeared to be largely present in the guide siRNA elements, corresponding to the 'seed region' of microRNAs. Due to the essential role of the 'seed region' of microRNAs in their association with target RNAs, it is conceivable that disruption of the base-pairing interactions in the corresponding seed region, as well as the central position (involved in cleavage of target RNAs, of guide siRNA elements could influence allele discrimination. In addition, we also suggest that nucleotide mismatches at the 3'-ends of sense

  14. Common Kibra alleles are associated with human memory performance.

    Science.gov (United States)

    Papassotiropoulos, Andreas; Stephan, Dietrich A; Huentelman, Matthew J; Hoerndli, Frederic J; Craig, David W; Pearson, John V; Huynh, Kim-Dung; Brunner, Fabienne; Corneveaux, Jason; Osborne, David; Wollmer, M Axel; Aerni, Amanda; Coluccia, Daniel; Hänggi, Jürgen; Mondadori, Christian R A; Buchmann, Andreas; Reiman, Eric M; Caselli, Richard J; Henke, Katharina; de Quervain, Dominique J-F

    2006-10-20

    Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele-dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.

  15. Segregation of male-sterility alleles across a species boundary.

    Science.gov (United States)

    Weller, S G; Sakai, A K; Culley, T M; Duong, L; Danielson, R E

    2014-02-01

    Hybrid zones may serve as bridges permitting gene flow between species, including alleles influencing the evolution of breeding systems. Using greenhouse crosses, we assessed the likelihood that a hybrid zone could serve as a conduit for transfer of nuclear male-sterility alleles between a gynodioecious species and a hermaphroditic species with very rare females in some populations. Segregation patterns in progeny of crosses between rare females of hermaphroditic Schiedea menziesii and hermaphroditic plants of gynodioecious Schiedea salicaria heterozygous at the male-sterility locus, and between female S. salicaria and hermaphroditic plants from the hybrid zone, were used to determine whether male-sterility was controlled at the same locus in the parental species and the hybrid zone. Segregations of females and hermaphrodites in approximately equal ratios from many of the crosses indicate that the same nuclear male-sterility allele occurs in the parent species and the hybrid zone. These rare male-sterility alleles in S. menziesii may result from gene flow from S. salicaria through the hybrid zone, presumably facilitated by wind pollination in S. salicaria. Alternatively, rare male-sterility alleles might result from a reversal from gynodioecy to hermaphroditism in S. menziesii, or possibly de novo evolution of male sterility. Phylogenetic analysis indicates that some species of Schiedea have probably evolved separate sexes independently, but not in the lineage containing S. salicaria and S. menziesii. High levels of selfing and expression of strong inbreeding depression in S. menziesii, which together should favour females in populations, argue against a reversal from gynodioecy to hermaphroditism in S. menziesii.

  16. NPY antagonism reduces adiposity and attenuates age-related imbalance of adipose tissue metabolism.

    Science.gov (United States)

    Park, Seongjoon; Fujishita, Chika; Komatsu, Toshimitsu; Kim, Sang Eun; Chiba, Takuya; Mori, Ryoichi; Shimokawa, Isao

    2014-12-01

    An orexigenic hormone, neuropeptide Y (NPY), plays a role not only in the hypothalamic regulation of appetite, but also in the peripheral regulation of lipid metabolism. However, the intracellular mechanisms triggered by NPY to regulate lipid metabolism are poorly understood. Here we report that NPY deficiency reduces white adipose tissue (WAT) mass and ameliorates the age-related imbalance of adipose tissue metabolism in mice. Gene expression involved in adipogenesis/lipogenesis was found to decrease, whereas proteins involved in lipolysis increased in gonadal WAT (gWAT) of NPY-knockout mice. These changes were associated with an activated SIRT1- and PPARγ-mediated pathway. Moreover, the age-related decrease of de novo lipogenesis in gWAT and thermogenesis in inguinal WAT was inhibited by NPY deficiency. Further analysis using 3T3-L1 cells showed that NPY inhibited lipolysis through the Y1 receptor and enhanced lipogenesis following a reduction in cAMP response element-binding protein (CREB) and SIRT1 protein expression. Therefore, NPY appears to act as a key regulator of adipose tissue metabolism via the CREB-SIRT1 signaling pathway. Taken together, NPY deficiency reduces adiposity and ameliorates the age-related imbalance of adipose tissue metabolism, suggesting that antagonism of NPY may be a promising target for drug development to prevent age-related metabolic diseases.

  17. Altitude acclimatization improves submaximal cognitive performance in mice and involves an imbalance of the cholinergic system.

    Science.gov (United States)

    Guerra-Narbona, R; Delgado-García, J M; López-Ramos, J C

    2013-06-15

    The aim of this work was to reveal a hypothetical improvement of cognitive abilities in animals acclimatized to altitude and performing under ground level conditions, when looking at submaximal performance, once seen that it was not possible when looking at maximal scores. We modified contrasted cognitive tasks (object recognition, operant conditioning, eight-arm radial maze, and classical conditioning of the eyeblink reflex), increasing their complexity in an attempt to find performance differences in acclimatized animals vs. untrained controls. In addition, we studied, through immunohistochemical quantification, the expression of choline acetyltransferase and acetyl cholinesterase, enzymes involved in the synthesis and degradation of acetylcholine, in the septal area, piriform and visual cortexes, and the hippocampal CA1 area of animals submitted to acute hypobaric hypoxia, or acclimatized to this simulated altitude, to find a relationship between the cholinergic system and a cognitive improvement due to altitude acclimatization. Results showed subtle improvements of the cognitive capabilities of acclimatized animals in all of the tasks when performed under ground-level conditions (although not before 24 h), in the three tasks used to test explicit memory (object recognition, operant conditioning in the Skinner box, and eight-arm radial maze) and (from the first conditioning session) in the classical conditioning task used to evaluate implicit memory. An imbalance of choline acetyltransferase/acetyl cholinesterase expression was found in acclimatized animals, mainly 24 h after the acclimatization period. In conclusion, altitude acclimatization improves cognitive capabilities, in a process parallel to an imbalance of the cholinergic system.

  18. Obesity does not Lead to Imbalance Between Myocardial Phospholamban Phosphorylation and Dephosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Freire, Paula Paccielli, E-mail: freirepp@hotmail.com; Alves, Carlos Augusto Barnabe; Deus, Adriana Fernandes de [Departamento de Clínica Médica - Faculdade de Medicina de Botucatu - Universidade Estadual Paulista, Botucatu, SP (Brazil); Leopoldo, Ana Paula Lima; Leopoldo, André Soares [Centro de Educação Física e Desportos - Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Silva, Danielle Cristina Tomaz da; Tomasi, Loreta Casquel de; Campos, Dijon Henrique Salomé; Cicogna, Antonio Carlos [Departamento de Clínica Médica - Faculdade de Medicina de Botucatu - Universidade Estadual Paulista, Botucatu, SP (Brazil)

    2014-07-15

    The activation of the beta-adrenergic system promotes G protein stimulation that, via cyclic adenosine monophosphate (cAMP), alters the structure of protein kinase A (PKA) and leads to phospholamban (PLB) phosphorylation. This protein participates in the system that controls intracellular calcium in muscle cells, and it is the primary regulator of sarcoplasmic reticulum calcium pump activity. In obesity, the beta-adrenergic system is activated by the influence of increased leptin, therefore, resulting in higher myocardial phospholamban phosphorylation via cAMP-PKA. To investigate the involvement of proteins which regulate the degree of PLB phosphorylation due to beta-adrenergic activation in obesity. In the present study, we hypothesized that there is an imbalance between phospholamban phosphorylation and dephosphorylation, with prevalence of protein phosphorylation. Male Wistar rats were randomly distributed into two groups: control (n = 14), fed with normocaloric diet; and obese (n = 13), fed with a cycle of four unsaturated high-fat diets. Obesity was determined by the adiposity index, and protein expressions of phosphatase 1 (PP-1), PKA, PLB, phosphorylated phospholamban at serine16 (PPLB-Ser16) were assessed by Western blot. Obesity caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, hyperleptinemia and did not alter the protein expression of PKA, PP-1, PLB, PPLB-Ser16. Obesity does not promote an imbalance between myocardial PLB phosphorylation and dephosphorylation via beta-adrenergic system.

  19. Obesity does not Lead to Imbalance Between Myocardial Phospholamban Phosphorylation and Dephosphorylation

    Directory of Open Access Journals (Sweden)

    Paula Paccielli Freire

    2014-07-01

    Full Text Available Background: The activation of the beta-adrenergic system promotes G protein stimulation that, via cyclic adenosine monophosphate (cAMP, alters the structure of protein kinase A (PKA and leads to phospholamban (PLB phosphorylation. This protein participates in the system that controls intracellular calcium in muscle cells, and it is the primary regulator of sarcoplasmic reticulum calcium pump activity. In obesity, the beta-adrenergic system is activated by the influence of increased leptin, therefore, resulting in higher myocardial phospholamban phosphorylation via cAMP-PKA. Objective: To investigate the involvement of proteins which regulate the degree of PLB phosphorylation due to beta-adrenergic activation in obesity. In the present study, we hypothesized that there is an imbalance between phospholamban phosphorylation and dephosphorylation, with prevalence of protein phosphorylation. Methods: Male Wistar rats were randomly distributed into two groups: control (n = 14, fed with normocaloric diet; and obese (n = 13, fed with a cycle of four unsaturated high-fat diets. Obesity was determined by the adiposity index, and protein expressions of phosphatase 1 (PP-1, PKA, PLB, phosphorylated phospholamban at serine16 (PPLB-Ser16 were assessed by Western blot. Results: Obesity caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, hyperleptinemia and did not alter the protein expression of PKA, PP-1, PLB, PPLB-Ser16. Conclusion: Obesity does not promote an imbalance between myocardial PLB phosphorylation and dephosphorylation via beta-adrenergic system.

  20. Caveolin-1 Promotes the Imbalance of Th17/Treg in Patients with Chronic Obstructive Pulmonary Disease.

    Science.gov (United States)

    Sun, Nina; Wei, Xiaofang; Wang, Jingluan; Cheng, Zhaozhong; Sun, Weihong

    2016-12-01

    The imbalance of Th17/Treg cells plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Caveolin-1 (Cav-1) has been regarded as a potential critical regulatory protein in pathological mechanisms of chronic inflammatory respiratory diseases. Therefore, we investigated whether the loss of Cav-1 is involved in the homeostasis of Th17/Treg cells in COPD. We examined the expressions of plasma Cav-1 and circulating Th17, Treg cells, and the related cytokines in patients with COPD. Enzyme-linked immunosorbent assay (ELISA) analyses showed a significant reduction of plasma Cav-1 levels in patients with stable COPD (SCOPD) and acutely exacerbated COPD (AECOPD) compared to smokers without COPD. This loss was associated with an increase in frequency of Treg and decreased in frequency of Th17 cells. To further identify the role of Cav-1, we studied the effects of Cav-1 overexpression or downregulation on frequencies of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects. Interestingly, small interfering RNA (siRNA) downregulation of Cav-1 was accompanied by an augmentation of Treg and reduction of Th17 expression. Together, our study demonstrated that the loss of Cav-1 contributed to the imbalance of Th17/Treg cells in patients with COPD.

  1. 新等位基因人类白细胞抗原B*15:133的鉴定及其原核表达%Identification of a human new allele human leucocyte antigen-B*15:133 and its prokaryotic expression

    Institute of Scientific and Technical Information of China (English)

    王琳; 宋长兴; 张志欣

    2011-01-01

    BACKGROUND: In total 4 633 alleles have been reported in world up to April 2010. More than 200 new alleles have been found in China, most of which need to be further studied.OBJECTIVE: Serologic and genetic studies were performed to confirm the identity of a new human leucocyte antigen (HLA)allele within the Chinese population to construct an expression vector containing the heavy chain of HLA-B*15:133 in a prokaryotic system and to identify its activity.METHODS: During routine typing work, genomic DNA was typed by PCR-SSO and PCR-SBT. An ambiguous result was found and identified as a novel allele by Serologic and DNA sequence analysis. The extra-membrane gene fragment of HLA-B*15:133 (digested with BamH Ⅰ and Hind Ⅲ) was inserted into vector pET 30a(+). The expression vector pET30a(+)-B*15:133 was transfected into the BL21(DE3) cells, and western-blotting was used to identify its expression.RESULTS AND CONCLUSION: A new allele which had one nucleotide substitution at position 419 from C to T (condon116 TCC->TTC) was identified, resulting in an amino acid change from Serine (S) to Phenylalanine (F). Serologic specificity is B71 (70) genetic and serological analysis indicated that the novel HLA-B allele of the donor was inherited from his mother. The restriction endonuclease digestions and PCR suggested the expression vector pET 30a(+)-B*15:133 was constructed successfully. A Western-blot identified the extra-membrane polypeptide chain of HLA-B*15:133. The expression vector pET30a(+)-B*15:133 can express the extra-membrane polypeptide chain of HLA-B*15:133 in BL21 (DE3).%背景:国际上至2010-04共报告人类白细胞抗原4 633个等位基因,中国自2000年至少发现200个新的等位基因,由于资金和时间有限,大部分新等位基因未作血清分型、家系研究以及进一步的功能性研究.目的:在健康志愿者人群中发现新等位基因,并对其进行家系研究,同时构建重链胞外区多肽的原核细胞表达载体,

  2. Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles | Office of Cancer Genomics

    Science.gov (United States)

    Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic.

  3. 氧自由基失衡微环境对骨关节炎进展的影响%Effects of microenvironment imbalance of oxygen free radicals on the progress of osteoarthritis

    Institute of Scientific and Technical Information of China (English)

    李红波; 彭磊

    2016-01-01

    Osteoarthritis ( OA ) mainly manifests as articular cartilage degeneration, secondary osteoarthritis and chronic degenerative diseases involving the joint synovium, joint capsule and other adjoining structures of the joint. Its incidence and progress are more complex. In recent years, with the development of molecular biology, pathology and imaging, the understanding of OA has been deepening. Some factors such as biological stress, hormone metabolism, metal atoms, free radical imbalance and certain cytokines are also gradually considered to be closely related with OA. The imbalance of oxygen free radicals in microenvironment caused by dysfunction of mitochondria is considered to be one of the main causes for the development of OA. The imbalance of oxygen free radicals may aggravate mitochondrial damage under the low expression of antioxidant free radicals, making the microenvironment of oxygen free radicals beyond the self-regulated steady state. It is manifested as inflammatory mediator damage, genetic material damage, weakened repair, disorder of apoptosis and autophagy in the structure and time and weakened role of antioxidant free radical system under the microenvironment imbalance of oxygen free radicals. The series of changes based on microenvironment imbalances will continue through the online response to continuously express the damage effect, which is an important reason for chronic and persistent unhealing of OA. In this paper, under the microenvironment imbalance of oxygen free radicals, the effects of oxygen free radical imbalance on the occurrence and progress of OA are briefly reviewed.

  4. A molecular method for S-allele identification in apple based on allele-specific PCR.

    Science.gov (United States)

    Janssens, G A; Goderis, I J; Broekaert, W F; Broothaerts, W

    1995-09-01

    cDNA sequences corresponding to two self-incompatibility alleles (S-alleles) of the apple cv 'Golden Delicious' have previously been described, and now we report the identification of three additional S-allele cDNAs of apple, one of which was isolated from a pistil cDNA library of cv 'Idared' and two of which were obtained by reverse transcription-PCR (RT-PCR) on pistil RNA of cv 'Queen's Cox'. A comparison of the deduced amino acid sequences of these five S-allele cDNAs revealed an average homology of 69%. Based on the nucleotide sequences of these S-allele cDNAs, we developed a molecular technique for the diagnostic identification of the five different S-alleles in apple cultivars. The method used consists of allele-specific PCR amplification of genomic DNA followed by digestion of the amplification product with an allele-specific restriction endonuclease. Analysis of a number of apple cultivars with known S-phenotype consistently showed coincidence of phenotypic and direct molecular data of the S-allele constitution of the cultivars. It is concluded that the S-allele identification approach reported here provides a rapid and useful method to determine the S-genotype of apple cultivars.

  5. Spinal pedicle subtraction osteotomy for fixed sagittal imbalance patients.

    Science.gov (United States)

    Hyun, Seung-Jae; Kim, Yongjung J; Rhim, Seung-Chul

    2013-11-16

    In addressing spinal sagittal imbalance through a posterior approach, the surgeon now may choose from among a variety of osteotomy techniques. Posterior column osteotomies such as the facetectomy or Ponte or Smith-Petersen osteotomy provide the least correction, but can be used at multiple levels with minimal blood loss and a lower operative risk. Pedicle subtraction osteotomies provide nearly 3 times the per-level correction of Ponte/Smith-Petersen osteotomies; however, they carry increased technical demands, longer operative time, and greater blood loss and associated significant morbidity, including neurological injury. The literature focusing on pedicle subtraction osteotomy for fixed sagittal imbalance patients is reviewed. The long-term overall outcomes, surgical tips to reduce the complications and suggestions for their proper application are also provided.

  6. Progress Towards a Quantum Degenerate Mixture with Extreme Mass Imbalance

    Science.gov (United States)

    Desalvo, B. J.; Johansen, Jacob; Chin, Cheng

    2016-05-01

    We report experimental progress towards a quantum degenerate Bose-Fermi mixture of 133 Cs and 6 Li. Beyond providing the largest mass imbalance of any bi-alkali mixture, this system exhibits multiple interspecies Feshbach resonances allowing wide tuning of the interaction strength and Efimov resonances potentially inducing three-body interactions. The use of a dual-color optical dipole trap in our experiment overcomes the large differential gravitational sag due to the mass imbalance and facilitates mixing the species nano-Kelvin temperatures allowing precision studies of interspecies interactions. Turning from few-body physics to many-body, we will present our efforts to reach simultaneous quantum degeneracy as well as discuss prospects of high resolution imaging of both species.

  7. Thermodynamics of quark matter with a chiral imbalance

    Science.gov (United States)

    Farias, Ricardo L. S.; Duarte, Dyana C.; Krein, Gastão; Ramos, Rudnei O.

    2016-10-01

    We show how a scheme of rewriting a divergent momentum integral can conciliate results obtained with the Nambu-Jona-Lasinio model and recent lattice results for the chiral transition in the presence of a chiral imbalance in quark matter. Purely vacuum contributions are separated from medium-dependent regularized momentum integrals in such a way that one is left with ultraviolet divergent momentum integrals that depend on vacuum quantities only. The scheme is applicable to other commonly used effective models to study quark matter with a chiral imbalance, it allows us to identify the source of their difficulties in reproducing the qualitative features of lattice results, and enhances their predictability and uses in other applications.

  8. Comparison of HLA allelic imputation programs

    Science.gov (United States)

    Shaffer, Christian M.; Bastarache, Lisa; Gaudieri, Silvana; Glazer, Andrew M.; Steiner, Heidi E.; Mosley, Jonathan D.; Mallal, Simon; Denny, Joshua C.; Phillips, Elizabeth J.; Roden, Dan M.

    2017-01-01

    Imputation of human leukocyte antigen (HLA) alleles from SNP-level data is attractive due to importance of HLA alleles in human disease, widespread availability of genome-wide association study (GWAS) data, and expertise required for HLA sequencing. However, comprehensive evaluations of HLA imputations programs are limited. We compared HLA imputation results of HIBAG, SNP2HLA, and HLA*IMP:02 to sequenced HLA alleles in 3,265 samples from BioVU, a de-identified electronic health record database coupled to a DNA biorepository. We performed four-digit HLA sequencing for HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1 using long-read 454 FLX sequencing. All samples were genotyped using both the Illumina HumanExome BeadChip platform and a GWAS platform. Call rates and concordance rates were compared by platform, frequency of allele, and race/ethnicity. Overall concordance rates were similar between programs in European Americans (EA) (0.975 [SNP2HLA]; 0.939 [HLA*IMP:02]; 0.976 [HIBAG]). SNP2HLA provided a significant advantage in terms of call rate and the number of alleles imputed. Concordance rates were lower overall for African Americans (AAs). These observations were consistent when accuracy was compared across HLA loci. All imputation programs performed similarly for low frequency HLA alleles. Higher concordance rates were observed when HLA alleles were imputed from GWAS platforms versus the HumanExome BeadChip, suggesting that high genomic coverage is preferred as input for HLA allelic imputation. These findings provide guidance on the best use of HLA imputation methods and elucidate their limitations. PMID:28207879

  9. Yule-generated trees constrained by node imbalance.

    Science.gov (United States)

    Disanto, Filippo; Schlizio, Anna; Wiehe, Thomas

    2013-11-01

    The Yule process generates a class of binary trees which is fundamental to population genetic models and other applications in evolutionary biology. In this paper, we introduce a family of sub-classes of ranked trees, called Ω-trees, which are characterized by imbalance of internal nodes. The degree of imbalance is defined by an integer 0 ≤ ω. For caterpillars, the extreme case of unbalanced trees, ω = 0. Under models of neutral evolution, for instance the Yule model, trees with small ω are unlikely to occur by chance. Indeed, imbalance can be a signature of permanent selection pressure, such as observable in the genealogies of certain pathogens. From a mathematical point of view it is interesting to observe that the space of Ω-trees maintains several statistical invariants although it is drastically reduced in size compared to the space of unconstrained Yule trees. Using generating functions, we study here some basic combinatorial properties of Ω-trees. We focus on the distribution of the number of subtrees with two leaves. We show that expectation and variance of this distribution match those for unconstrained trees already for very small values of ω.

  10. Grayscale imbalance correction in real-time phase measuring profilometry

    Science.gov (United States)

    Zhu, Lin; Cao, Yiping; He, Dawu; Chen, Cheng

    2016-10-01

    Grayscale imbalance correction in real-time phase measuring profilometry (RPMP) is proposed. In the RPMP, the sufficient information is obtained to reconstruct the 3D shape of the measured object in one over twenty-four of a second. Only one color fringe pattern whose R, G and B channels are coded as three sinusoidal phase-shifting gratings with an equivalent shifting phase of 2π/3 is sent to a flash memory on a specialized digital light projector (SDLP). And then the SDLP projects the fringe patterns in R, G and B channels sequentially onto the measured object in one over seventy-two of a second and meanwhile a monochrome CCD camera captures the corresponding deformed patterns synchronously with the SDLP. Because the deformed patterns from three color channels are captured at different time, the color crosstalk is avoided completely. But due to the monochrome CCD camera's different spectral sensitivity to R, G and B tricolor, there will be grayscale imbalance among these deformed patterns captured at R, G and B channels respectively which may result in increasing measuring errors or even failing to reconstruct the 3D shape. So a new grayscale imbalance correction method based on least square method is developed. The experimental results verify the feasibility of the proposed method.

  11. Comparison of muscle strength imbalance in powerlifters and jumpers.

    Science.gov (United States)

    Luk, Hui-Ying; Winter, Christa; O'Neill, Elizabeth; Thompson, Brian A

    2014-01-01

    The purpose of the study was to examine the bilateral and unilateral force production difference in powerlifters (bilateral) and field jumpers (unilateral) to determine the existence of leg dominance. Nineteen powerlifters (PL; n = 11) and field jumpers (J; n = 8) were included in the study. Five different no arm swing countermovement jumps were randomized for testing: (a) double-leg jump; (b) dominant leg-specified double-leg jump; (c) nondominant leg-specified double-leg jump; (d) dominant leg-specified single-leg jump; and (e) nondominant leg-specified single-leg jump. The force, velocity, and power were measured via a forceplate. The Limb Symmetry Index (LSI% = (1 - ND limb/D limb) × 100%) was calculated for force imbalance between the dominant (N) and nondominant (ND) limb between PL and J. Based on the analysis, PL (mean = 2.75 ± 2.45%) had a lower LSI (p imbalance force production between limbs. This phenomenon is important for the strength coach to acknowledge, to perform an appropriate strength balance test during the off-season, and to implement a training program to reduce the force disparity between limbs. Neglecting the development of force imbalance between limbs may predispose healthy players to injury.

  12. Positional Nystagmus in Patients Evaluated for Dizziness and Imbalance

    Directory of Open Access Journals (Sweden)

    Richard A. Roberts

    2016-01-01

    Full Text Available There is variability in the literature regarding the presence of positional nystagmus in healthy participants with reportedly normal vestibular and central nervous system function. This ranges from 7.5% to 88% and raises an important clinical question. If 88% of healthy participants have positional nystagmus then how is the clinician to interpret the presence of positional nystagmus in a patient presenting with dizziness and/or disequilibrium? The primary purpose of this investigation was to examine the prevalence and characteristics of positional nystagmus in patients evaluated specifically for dizziness and imbalance. Data was collected using retrospective chart review. 200 charts were randomly selected from all patients seen for evaluation of dizziness and imbalance over a period of eight months. Clinicians independently reviewed the data from positional testing for each chart. Nystagmus was present if there was a clear slow and fast phase component and there were three beats in a 10 s time window. Nystagmus direction and intensity data were collected. Results indicate positional nystagmus is present in 10.5% to 21% of patients evaluated for dizziness and imbalance. Use of liberal criteria for determining presence of positional nystagmus (i.e., 3 beats in 20 sec may account for higher prevalence rates across other studies.

  13. Money and age in schools: Bullying and power imbalances.

    Science.gov (United States)

    Chaux, Enrique; Castellanos, Melisa

    2015-05-01

    School bullying continues to be a serious problem around the world. Thus, it seems crucial to clearly identify the risk factors associated with being a victim or a bully. The current study focused in particular on the role that age and socio-economic differences between classmates could play on bullying. Logistic and multilevel analyses were conducted using data from 53,316 5th and 9th grade students from a representative sample of public and private Colombian schools. Higher age and better family socio-economic conditions than classmates were risk factors associated with being a bully, while younger age and poorer socio-economic conditions than classmates were associated with being a victim of bullying. Coming from authoritarian families or violent neighborhoods, and supporting beliefs legitimizing aggression, were also associated with bullying and victimization. Empathy was negatively associated with being a bully, and in some cases positively associated with being a victim. The results highlight the need to take into account possible sources of power imbalances, such as age and socio-economic differences among classmates, when seeking to prevent bullying. In particular, interventions focused on peer group dynamics might contribute to avoid power imbalances or to prevent power imbalances from becoming power abuse. Aggr. Behav. 41:280-293, 2015. © 2014 Wiley Periodicals, Inc.

  14. The number of CAG repeats within the normal allele does not influence the age of onset in Huntington's disease.

    Science.gov (United States)

    Klempíř, Jiří; Zidovská, Jana; Stochl, Jan; Ing, Věra Kebrdlová; Uhrová, Tereza; Roth, Jan

    2011-01-01

    Huntington's disease (HD) is caused by the expansion of the number of CAG repeats on the chromosome 4p16.3, which results in elongated glutamine tract of huntingtin. The purpose of this work was to examine the interaction between the normal and mutant alleles of this gene and their effect on the clinical onset of HD. We hypothesized that in patients with identical number of CAG repeats within the mutant allele, the age of onset of HD is influenced by the number of CAG repeats within the normal allele. We analyzed the relations between the number of CAG repeats within the normal and mutant alleles, the age at HD onset, and the character of initial symptoms in 468 patients with clinically expressed HD. Although the Cox regression coefficient of 0.15 was significant (P CAG repeats within normal allele. Within the groups of patients with the same number of CAG repeats of the mutant allele, number of CAG repeats of the normal allele was found uncorrelated to the age at onset. Furthermore, when analyzing subgroups of patients with the same allelic composition on both alleles, we failed to observe any correlation with the age at the onset. Our analysis gives no corroboration to the idea of a normal allele having a share in the modification of the age at HD onset. We believe that with the current state of knowledge it is not possible to devise a mathematical model for HD onset prediction because too many entirely unknown modifying factors are still involved.

  15. Gene dosage imbalance during DNA replication controls bacterial cell-fate decision

    Science.gov (United States)

    Igoshin, Oleg

    Genes encoding proteins in a common regulatory network are frequently located close to one another on the chromosome to facilitate co-regulation or couple gene expression to growth rate. Contrasting with these observations, here we demonstrate a functional role for the arrangement of Bacillus subtilis sporulation network genes on opposite sides of the chromosome. We show that the arrangement of two sporulation network genes, one located close to the origin, the other close to the terminus leads to a transient gene dosage imbalance during chromosome replication. This imbalance is detected by the sporulation network to produce cell-cycle coordinated pulses of the sporulation master regulator Spo0A~P. This pulsed response allows cells to decide between sporulation and continued vegetative growth during each cell-cycle spent in starvation. Furthermore, changes in DNA replication and cell-cycle parameters with decreased growth rate in starvation conditions enable cells to indirectly detect starvation without the need for evaluating specific metabolites. The simplicity of the uncovered coordination mechanism and starvation sensing suggests that it may be widely applicable in a variety of gene regulatory and stress-response settings. This work is supported by National Science Foundation Grants MCB-1244135, EAGER-1450867, MCB-1244423, NIH NIGMS Grant R01 GM088428 and HHMI International Student Fellowship.

  16. Connexin hemichannels explain the ionic imbalance and lead to atrophy in denervated skeletal muscles.

    Science.gov (United States)

    Cisterna, Bruno A; Vargas, Aníbal A; Puebla, Carlos; Sáez, Juan C

    2016-11-01

    Denervated fast skeletal muscles undergo atrophy, which is associated with an increase in sarcolemma permeability and protein imbalance. However, the mechanisms responsible for these alterations remain largely unknown. Recently, a close association between de novo expression of hemichannels formed by connexins 43 and 45 and increase in sarcolemma permeability of denervated fast skeletal myofibers was demonstrated. However, it remains unknown whether these connexins cause the ionic imbalance of denervates fast myofibers. To elucidate the latter and the role of hemichannels formed by connexins (Cx HCs) in denervation-induced atrophy, skeletal myofibers deficient in Cx43 and Cx45 expression (Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice) and control (Cx43(fl/fl)Cx45(fl/fl) mice) were denervated and several muscle features were systematically analyzed at different post-denervation (PD) times (1, 3, 5, 7 and 14days). The following sequence of events was found in denervated myofibers of Cx43(fl/fl)Cx45(fl/fl) mice: 1) from day 3 PD, increase in sarcolemmal permeability, 2) from day 5 PD, increases of intracellular Ca(2+) and Na(+) signals as well as a significant increase in protein synthesis and degradation, yielding a negative protein balance and 3) from day 7 PD, a fall in myofibers cross-section area. All the above alterations were either absent or drastically reduced in denervated myofibers of Cx43(fl/fl)Cx45(fl/fl):Myo-Cre mice. Thus, the denervation-induced Cx HCs expression is an early event that precedes the electrochemical gradient dysregulation across the sarcolemma and critically contributes to the progression of skeletal muscle atrophy. Consequently, Cx HCs could be a therapeutic target to drastically prevent the denervation-induced atrophy of fast skeletal muscles.

  17. TRPV6 alleles do not influence prostate cancer progression

    Directory of Open Access Journals (Sweden)

    Flockerzi Veit

    2009-10-01

    Full Text Available Abstract Background The transient receptor potential, subfamily V, member 6 (TRPV6 is a Ca2+ selective cation channel. Several studies have shown that TRPV6 transcripts are expressed in locally advanced prostatic adenocarcinoma, metastatic and androgen-insensitive prostatic lesions but are undetectable in healthy prostate tissue and benign prostatic hyperplasia. Two allelic variants of the human trpv6 gene have been identified which are transcribed into two independent mRNAs, TRPV6a and TRPV6b. We now asked, whether the trpv6a allele is correlated with the onset of prostate cancer, with the Gleason score and the tumour stage. Methods Genomic DNA of prostate cancer patients and control individuals was isolated from resections of prostatic adenocarcinomas and salivary fluid respectively. Genotyping of SNPs of the TRPV6 gene was performed by restriction length polymorphism or by sequencing analysis. RNA used for RT-PCR was isolated from prostate tissue. Data sets were analyzed by Chi-Square test. Results We first characterized in detail the five polymorphisms present in the protein coding exons of the trpv6 gene and show that these polymorphisms are coupled and are underlying the TRPV6a and the TRPV6b variants. Next we analysed the frequencies of the two TRPV6 alleles using genomic DNA from saliva samples of 169 healthy individuals. The homozygous TRPV6b genotype predominated with 86%, whereas no homozygous TRPV6a carriers could be identified. The International HapMap Project identified a similar frequency for an Utah based population whereas in an African population the a-genotype prevailed. The incidence of prostate cancer is several times higher in African populations than in non-African and we then investigated the TRPV6a/b frequencies in 141 samples of prostatic adenocarcinoma. The TRPV6b allele was found in 87% of the samples without correlation with Gleason score and tumour stage. Conclusion Our results show that the frequencies of trpv6

  18. Diversity of lactase persistence alleles in Ethiopia: signature of a soft selective sweep.

    Science.gov (United States)

    Jones, Bryony L; Raga, Tamiru O; Liebert, Anke; Zmarz, Pawel; Bekele, Endashaw; Danielsen, E Thomas; Olsen, Anders Krüger; Bradman, Neil; Troelsen, Jesper T; Swallow, Dallas M

    2013-09-05

    The persistent expression of lactase into adulthood in humans is a recent genetic adaptation that allows the consumption of milk from other mammals after weaning. In Europe, a single allele (-13910(∗)T, rs4988235) in an upstream region that acts as an enhancer to the expression of the lactase gene LCT is responsible for lactase persistence and appears to have been under strong directional selection in the last 5,000 years, evidenced by the widespread occurrence of this allele on an extended haplotype. In Africa and the Middle East, the situation is more complicated and at least three other alleles (-13907(∗)G, rs41525747; -13915(∗)G, rs41380347; -14010(∗)C, rs145946881) in the same LCT enhancer region can cause continued lactase expression. Here we examine the LCT enhancer sequence in a large lactose-tolerance-tested Ethiopian cohort of more than 350 individuals. We show that a further SNP, -14009T>G (ss 820486563), is significantly associated with lactose-digester status, and in vitro functional tests confirm that the -14009(∗)G allele also increases expression of an LCT promoter construct. The derived alleles in the LCT enhancer region are spread through several ethnic groups, and we report a greater genetic diversity in lactose digesters than in nondigesters. By examining flanking markers to control for the effects of mutation and demography, we further describe, from empirical evidence, the signature of a soft selective sweep.

  19. A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference.

    Science.gov (United States)

    Lombardi, Maria Stella; Jaspers, Leonie; Spronkmans, Christine; Gellera, Cinzia; Taroni, Franco; Di Maria, Emilio; Donato, Stefano Di; Kaemmerer, William F

    2009-06-01

    Use of RNA interference to reduce huntingtin protein (htt) expression in affected brain regions may provide an effective treatment for Huntington disease (HD), but it remains uncertain whether suppression of both wild-type and mutant alleles in a heterozygous patient will provide more benefit than harm. Previous research has shown suppression of just the mutant allele is achievable using siRNA targeted to regions of HD mRNA containing single nucleotide polymorphisms (SNPs). To determine whether more than a minority of patients may be eligible for an allele-specific therapy, we genotyped DNA from 327 unrelated European Caucasian HD patients at 26 SNP sites in the HD gene. Over 86% of the patients were found to be heterozygous for at least one SNP among those tested. Because the sites are genetically linked, one cannot use the heterozygosity rates of the individual SNPs to predict how many sites (and corresponding allele-specific siRNA) would be needed to provide at least one treatment possibility for this percentage of patients. By computing all combinations, we found that a repertoire of allele-specific siRNA corresponding to seven sites can provide at least one allele-specific siRNA treatment option for 85.6% of our sample. Moreover, we provide evidence that allele-specific siRNA targeting these sites are readily identifiable using a high throughput screening method, and that allele-specific siRNA identified using this method indeed show selective suppression of endogenous mutant htt protein in fibroblast cells from HD patients. Therefore, allele-specific siRNA are not so rare as to be impractical to find and use therapeutically.

  20. What is the Imbalance of Water in Nature?

    Science.gov (United States)

    Kontar, V. A.

    2011-12-01

    Look at any lake. Water comes into the lake from the atmosphere, from surface and groundwater sources. Water leaves the lake to the atmosphere, surface and underground drains, as well as for consumption by human society, wild plants and animals if they are within the boundaries of the lake's system. If quantity of water coming into the lake is equally of the quantity of water which flow from the lake, so the lake level has not changed and we have a state of equilibration or balance. The bookkeeper's book also has name "balance". But this is just a play on words. If the water is coming into the lake more than the water is coming away from lake, therefore the lake level will increase and we have a state of the imbalance of the increase type. If the water is coming into the lake less than the water is coming away from lake, therefore the lake level will decrease and we have a state of the imbalance of the decrease type. Everyone knows that the lake level rises or falls, for example during the year. Sometimes it is happened some balance. But the state of balance is rare and in of the short duration. The lake is of most the time in the conditions of the imbalance increases or the imbalance decreases type. The balance as a state of equilibrium, in the language of mathematics, is the point of the extremum between the periods of rise and fall. The balance is a special condition, which is existing very rare and a very short period of time. The people sometimes to do the great efforts for maintain the constant level of the lakes. But these facts don't change the situation. On the contrary, the human's struggle for maintain the lake in constant level just shows how difficult and expensive to go against the natural laws of Nature. When water was plentiful, these facts could be ignored. But now when the global water shortage is quickly growing, many previously ignored details are becoming crucial. There are very important to do the correct definitions of the borders and

  1. Dopamine receptor and Gα(olf expression in DYT1 dystonia mouse models during postnatal development.

    Directory of Open Access Journals (Sweden)

    Lin Zhang

    Full Text Available DYT1 dystonia is a heritable, early-onset generalized movement disorder caused by a GAG deletion (ΔGAG in the DYT1 gene. Neuroimaging studies and studies using mouse models suggest that DYT1 dystonia is associated with dopamine imbalance. However, whether dopamine imbalance is key to DYT1 or other forms of dystonia continues to be debated.We used Dyt1 knock out (Dyt1 KO, Dyt1 ΔGAG knock-in (Dyt1 KI, and transgenic mice carrying one copy of the human DYT1 wild type allele (DYT1 hWT or human ΔGAG mutant allele (DYT1 hMT. D1R, D2R, and Gα(olf protein expression was analyzed by western blot in the frontal cortex, caudate-putamen and ventral midbrain in young adult (postnatal day 60; P60 male mice from all four lines; and in the frontal cortex and caudate putamen in juvenile (postnatal day 14; P14 male mice from the Dyt1 KI and KO lines. Dopamine receptor and Gα(olf protein expression were significantly decreased in multiple brain regions of Dyt1 KI and Dyt1 KO mice and not significantly altered in the DYT1 hMT or DYT1 hWT mice at P60. The only significant change at P14 was a decrease in D1R expression in the caudate-putamen of the Dyt1 KO mice.We found significant decreases in key proteins in the dopaminergic system in multiple brain regions of Dyt1 KO and Dyt1 KI mouse lines at P60. Deletion of one copy of the Dyt1 gene (KO mice produced the most pronounced effects. These data offer evidence that impaired dopamine receptor signaling may be an early and significant contributor to DYT1 dystonia pathophysiology.

  2. Forensic Loci Allele Database (FLAD): Automatically generated, permanent identifiers for sequenced forensic alleles.

    Science.gov (United States)

    Van Neste, Christophe; Van Criekinge, Wim; Deforce, Dieter; Van Nieuwerburgh, Filip

    2016-01-01

    It is difficult to predict if and when massively parallel sequencing of forensic STR loci will replace capillary electrophoresis as the new standard technology in forensic genetics. The main benefits of sequencing are increased multiplexing scales and SNP detection. There is not yet a consensus on how sequenced profiles should be reported. We present the Forensic Loci Allele Database (FLAD) service, made freely available on http://forensic.ugent.be/FLAD/. It offers permanent identifiers for sequenced forensic alleles (STR or SNP) and their microvariants for use in forensic allele nomenclature. Analogous to Genbank, its aim is to provide permanent identifiers for forensically relevant allele sequences. Researchers that are developing forensic sequencing kits or are performing population studies, can register on http://forensic.ugent.be/FLAD/ and add loci and allele sequences with a short and simple application interface (API).

  3. Behavior of Poverty in Mexico: A Review of the Imbalances

    OpenAIRE

    Barrón-Pérez, María Antonieta

    2015-01-01

    Behavior of Poverty in Mexico: A Review of the Imbalances AbstractIntroduction: The persistence of poverty in Mexico leads to the question, what are the elements that keep 53.3 million people, accounting for 45.5% of the population, at some level of poverty? The purpose of this article is therefore to show how social spending in Mexico has been unable to reduce poverty levelsin the country’s most backward entities, which is directly related to the criteria for allocation of social spending an...

  4. Early proximal junctional failure in patients with preoperative sagittal imbalance.

    Science.gov (United States)

    Smith, Micah W; Annis, Prokopis; Lawrence, Brandon D; Daubs, Michael D; Brodke, Darrel S

    2013-10-01

    Study Type Retrospective review. Introduction Sagittal imbalance has been associated with lower health-related quality of life outcomes, and restoration of imbalance is associated with improved outcomes.123 The long constructs used in adult spinal deformity have potential consequences such as proximal junctional kyphosis (PJK). Clinically, the development of PJK may not be as important as failure of the construct or vertebrae at the proximal end. As PJK does not lead to worse clinical outcomes,45 we define the term early proximal junctional failure (EPJF) as fracture, implant failure, or myelopathy due to stenosis at the upper instrumental vertebra (UIV) or UIV + 1 within 6 months of surgery. Objective The purpose of this study is to report the incidence of EPJF in patients who are sagittally imbalanced preoperatively and to identify risk factors postoperatively that correlate with EPJF using commonly reported sagittal balance parameters. Methods We reviewed 197 patients with preoperative sagittal imbalance by at least one of the following: sagittal vertical axis more than 5 cm, global sagittal alignment more than 45 degrees, pelvic incidence-lumbar lordosis more than 10 degrees, or spine-sacral angle less than 120 degrees. Radiographic measurements also included proximal junctional angle, thoracic kyphosis, lumbar lordosis, pelvic parameters, and sagittal balance parameters/formulas, as well as UIV angle, UIV spinosacral angle, and UIV plumb line to assess as potential risk factors. EPJF incidence was calculated postoperatively for each of the accepted sagittal balance parameters/formulas. Results EPJF was observed in 49 of 197 patients (25%) with preoperative sagittal imbalance and was more common in fusions with UIV in the lower thoracic spine (TS) (35%) than in those with UIV in the upper TS (10%) or lumbar (25%) (p = 0.007). Of the 49 EPJF patients, 16 patients (33%) required revision surgery within the first year, for an overall early revision

  5. Examining Nuclear Effects in Neutrino Interactions with Transverse Kinematic Imbalance

    Science.gov (United States)

    Pickering, Luke

    We present a Monte Carlo truth study examining nuclear effects in charged-current neutrino interactions using observables constructed in the transverse plane. Three distributions are introduced that show very weak dependence on neutrino flux and its associated uncertainty. Measurements comparing these distributions between quasi-elastic-like and single charged pion final states will provide new constraints of nuclear effects. It is suggested that the on-axis position in the NuMI beam provides the correct flux to take advantage of this reduced energy dependence in measuring nuclear effect-generated transverse imbalances.

  6. Evolutionary dynamics of sporophytic self-incompatibility alleles in plants

    DEFF Research Database (Denmark)

    Schierup, M H; Vekemans, X; Christiansen, F B

    1997-01-01

    The stationary frequency distribution and allelic dynamics in finite populations are analyzed through stochastic simulations in three models of single-locus, multi-allelic sporophytic self-incompatibility. The models differ in the dominance relationships among alleles. In one model, alleles act c...

  7. Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration.

    Science.gov (United States)

    Koike, Masato; Nojiri, Hidetoshi; Ozawa, Yusuke; Watanabe, Kenji; Muramatsu, Yuta; Kaneko, Haruka; Morikawa, Daichi; Kobayashi, Keiji; Saita, Yoshitomo; Sasho, Takahisa; Shirasawa, Takuji; Yokote, Koutaro; Kaneko, Kazuo; Shimizu, Takahiko

    2015-06-25

    Mechanical stress and aging are major risk factors of cartilage degeneration. Human studies have previously reported that oxidative damage increased, while SOD2 protein was reciprocally downregulated in osteoarthritic degenerated cartilage. However, it remains unclear whether mitochondrial superoxide imbalance in chondrocytes causes cartilage degeneration. We herein demonstrate that mechanical loading promoted mitochondrial superoxide generation and selective Sod2 downregulation in chondrocytes in vivo and that mitochondrial superoxide inducer also downregulated Sod2 expression in chondrocytes in vitro. A genetically manipulated model revealed that Sod2 deficiency in chondrocytes also resulted in mitochondrial superoxide overproduction and dysfunction, thus leading to cartilage degeneration. Intra-articular injection of a permeable antioxidant effectively suppressed the mechanical loading-induced mitochondrial superoxide generation and cartilage degeneration in mice. Our findings demonstrate that mitochondrial superoxide plays a pivotal role in the development and progression of osteoarthritis, and the mitochondrial superoxide balance may therefore be a promising target for the treatment of cartilage degeneration.

  8. rDNA genetic imbalance and nucleolar chromatin restructuring is induced by distant hybridization between Raphanus sativus and Brassica alboglabra.

    Science.gov (United States)

    Long, Hong; Chen, Chunli; Wang, Bing; Feng, Yanni

    2015-01-01

    The expression of rDNA in hybrids inherited from only one progenitor refers to nucleolar dominance. The molecular basis for choosing which genes to silence remains unclear. We report genetic imbalance induced by distant hybridization correlates with formation of rDNA genes (NORs) in the hybrids between Raphanus sativus L. and Brassica alboglabra Bailey. Moreover, increased CCGG methylation of rDNA in F1 hybrids is concomitant with Raphanus-derived rDNA gene silencing and rDNA transcriptional inactivity revealed by nucleolar configuration restriction. Newly formed rDNA gene locus occurred through chromosomal in F1 hybrids via chromosomal imbalance. NORs are gained de novo, lost, and/or transposed in the new genome. Inhibition of methyltransferases leads to changes in nucleolar architecture, implicating a key role of methylation in control of nucleolar dominance and vital nucleolar configuration transition. Our findings suggest that gene imbalance and methylation-related chromatin restructuring is important for rDNA gene silencing that may be crucial for synthesis of specific proteins.

  9. Mangiferin Attenuates Th1/Th2 Cytokine Imbalance in an Ovalbumin-Induced Asthmatic Mouse Model

    Science.gov (United States)

    Hou, Guang-Han; Du, Jun; Huang, Xin; Lu, Yi; Keller, Evan T.; Zhang, Jian; Deng, Jia-Gang

    2014-01-01

    Mangiferin is a major bioactive ingredient in Mangifera indica Linn. (Anacardiaceae) leaves. Aqueous extract of such leaves have been used as an indigenous remedy for respiratory diseases like asthma and coughing in traditional Chinese medicine. However, underlying molecular mechanisms of mangiferin on anti-asthma remain unclear. In our present study, we investigated the anti-asthmatic effect of mangiferin on Th1/Th2 cytokine profiles and explored its underlying immunoregulatory mechanism in mouse model of allergic asthma. Mangiferin significantly reduced the total inflammatory cell counts and eosinophil infiltration, decreased the production of ovalbumin-specific IgE in serum and PGD2 in BALF. The antibody array analysis showed that mangiferin down-regulated the levels of one group of cytokines/chemokines including Th2-related IL-4, IL-5, IL-13, and others IL-3, IL-9, IL-17, RANTES, TNF-α, but simultaneously up-regulated Th1-related IFN-γ, IL-2 and IL-10 and IL-12 expression in serum. Thus it attenuates the imbalance of Th1/Th2 cells ratio by diminishing the abnormal mRNA levels of Th1 cytokines (IFN-γ and IL-12) and Th2 cytokines (IL-4, IL-5 and IL-13). Finally, mangiferin substantially inhibited the activation and expression of STAT-6 and GATA-3 in excised lung tissues. Our results suggest that mangiferin can exert anti-asthmatic effect. The underlying mechanism may attribute to the modulation of Th1/Th2 cytokine imbalance via inhibiting the STAT6 signaling pathway. PMID:24955743

  10. Mangiferin attenuates TH1/TH2 cytokine imbalance in an ovalbumin-induced asthmatic mouse model.

    Directory of Open Access Journals (Sweden)

    Hong-Wei Guo

    Full Text Available Mangiferin is a major bioactive ingredient in Mangifera indica Linn. (Anacardiaceae leaves. Aqueous extract of such leaves have been used as an indigenous remedy for respiratory diseases like asthma and coughing in traditional Chinese medicine. However, underlying molecular mechanisms of mangiferin on anti-asthma remain unclear. In our present study, we investigated the anti-asthmatic effect of mangiferin on Th1/Th2 cytokine profiles and explored its underlying immunoregulatory mechanism in mouse model of allergic asthma. Mangiferin significantly reduced the total inflammatory cell counts and eosinophil infiltration, decreased the production of ovalbumin-specific IgE in serum and PGD2 in BALF. The antibody array analysis showed that mangiferin down-regulated the levels of one group of cytokines/chemokines including Th2-related IL-4, IL-5, IL-13, and others IL-3, IL-9, IL-17, RANTES, TNF-α, but simultaneously up-regulated Th1-related IFN-γ, IL-2 and IL-10 and IL-12 expression in serum. Thus it attenuates the imbalance of Th1/Th2 cells ratio by diminishing the abnormal mRNA levels of Th1 cytokines (IFN-γ and IL-12 and Th2 cytokines (IL-4, IL-5 and IL-13. Finally, mangiferin substantially inhibited the activation and expression of STAT-6 and GATA-3 in excised lung tissues. Our results suggest that mangiferin can exert anti-asthmatic effect. The underlying mechanism may attribute to the modulation of Th1/Th2 cytokine imbalance via inhibiting the STAT6 signaling pathway.

  11. Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments

    Directory of Open Access Journals (Sweden)

    Jill R. Crittenden

    2011-09-01

    Full Text Available The striatum is composed principally of GABAergic, medium spiny projection neurons (MSNs that can be categorized based on their gene expression, electrophysiological profiles and input-output circuits. Major subdivisions of MSN populations include 1 those in ventromedial and dorsolateral striatal regions, 2 those giving rise to the direct and indirect pathways, and 3 those that lie in the striosome and matrix compartments. The first two classificatory schemes have enabled advances in understanding of how basal ganglia circuits contribute to disease. However, despite the large number of molecules that are differentially expressed in the striosomes or the extra-striosomal matrix, and the evidence that these compartments have different input-output connections, our understanding of how this compartmentalization contributes to striatal function is still not clear. A broad view is that the matrix contains the direct and indirect pathway MSNs that form parts of sensorimotor and associative circuits, whereas striosomes contain MSNs that receive input from parts of limbic cortex and project directly or indirectly to the dopamine-containing neurons of the substantia nigra, pars compacta. Striosomes are widely distributed within the striatum and are thought to exert global, as well as local, influences on striatal processing by exchanging information with the surrounding matrix, including through interneurons that send processes into both compartments. It has been suggested that striosomes exert and maintain limbic control over behaviors driven by surrounding sensorimotor and associative parts of the striatal matrix. Consistent with this possibility, imbalances between striosome and matrix functions have been reported in relation to neurological disorders, including Huntington’s disease, L-DOPA-induced dyskinesias, dystonia and drug addiction. Here, we consider how signaling imbalances between the striosomes and matrix might relate to symptomatology in

  12. Imbalance Between Th17 Cells and Regulatory T Cells During Monophasic Experimental Autoimmune Uveitis.

    Science.gov (United States)

    Zhang, Lian; Wan, Fangzhu; Song, Jike; Tang, Kai; Zheng, Fengming; Guo, Junguo; Guo, Dadong; Bi, Hongsheng

    2016-02-01

    The aim of this study is to explore the dynamic changes in IL-17-expressing T cells (Th17)/Treg expression in monophasic experimental autoimmune uveitis (mEAU). mEAU was induced in Lewis rats with IRBP1177-1191 peptide and evaluated clinically and pathologically on days 9, 13, 18, 23, 28, 35, and 48. Lymphocytes isolated from inguinal lymph nodes were subjected to flow cytometry to analyze the frequency of Th17/Treg cells. The levels of cytokines (IL-17, IL-6, IL-10, transforming growth factor (TGF)-β) in serum were detected by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative PCR (RT-PCR) was used for measuring the levels of IL-17, IL-6, TGF-β, and Foxp3. Clinical and histopathologic assessment showed that mEAU began on day 9, peaked on day 13, and decreased to normal on day 18. The frequency of Th17 cells increased obviously on day 9, peaking on day 13, while the frequency of Treg cells increased on day 13, peaked on day 18, and remained at a high level until day 48. In the serum, the levels of IL-17 and IL-6 peaked on day 9 and gradually decreased to normal on day 28. The level of TGF-β increased on day 9, peaked on day 13, and decreased to normal on day 35. Meanwhile, the level of IL-10 increased on day 9 and stayed at a high level until day 48. Additionally, the above results were further confirmed by RT-PCR. The imbalance between Th17 and Treg cells contributes to the onset and progression of mEAU, and a compartmental imbalance of Treg over Th17 exists in the recovery phase of mEAU.

  13. Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice.

    Directory of Open Access Journals (Sweden)

    Marnie E Blewitt

    2006-04-01

    Full Text Available There is increasing evidence in both plants and animals that epigenetic marks are not always cleared between generations. Incomplete erasure at genes associated with a measurable phenotype results in unusual patterns of inheritance from one generation to the next, termed transgenerational epigenetic inheritance. The Agouti viable yellow (A(vy allele is the best-studied example of this phenomenon in mice. The A(vy allele is the result of a retrotransposon insertion upstream of the Agouti gene. Expression at this locus is controlled by the long terminal repeat (LTR of the retrotransposon, and expression results in a yellow coat and correlates with hypomethylation of the LTR. Isogenic mice display variable expressivity, resulting in mice with a range of coat colours, from yellow through to agouti. Agouti mice have a methylated LTR. The locus displays epigenetic inheritance following maternal but not paternal transmission; yellow mothers produce more yellow offspring than agouti mothers. We have analysed the DNA methylation in mature gametes, zygotes, and blastocysts and found that the paternally and maternally inherited alleles are treated differently. The paternally inherited allele is demethylated rapidly, and the maternal allele is demethylated more slowly, in a manner similar to that of nonimprinted single-copy genes. Interestingly, following maternal transmission of the allele, there is no DNA methylation in the blastocyst, suggesting that DNA methylation is not the inherited mark. We have independent support for this conclusion from studies that do not involve direct analysis of DNA methylation. Haplo-insufficiency for Mel18, a polycomb group protein, introduces epigenetic inheritance at a paternally derived A(vy allele, and the pedigrees reveal that this occurs after zygotic genome activation and, therefore, despite the rapid demethylation of the locus.

  14. Attenuation of IL-7 receptor signaling is not required for allelic exclusion.

    Science.gov (United States)

    Will, Wynette M; Aaker, Joshua D; Burchill, Matthew A; Harmon, Ian R; O'Neil, Jennifer J; Goetz, Christine A; Hippen, Keli L; Farrar, Michael A

    2006-03-15

    Allelic exclusion prevents pre-B cells from generating more than one functional H chain, thereby ensuring the formation of a unique pre-BCR. The signaling processes underlying allelic exclusion are not clearly understood. IL-7R-dependent signals have been clearly shown to regulate the accessibility of the Ig H chain locus. More recent work has suggested that pre-BCR-dependent attenuation of IL-7R signaling returns the H chain loci to an inaccessible state; this process has been proposed to underlie allelic exclusion. Importantly, this model predicts that preventing pre-BCR-dependent down-regulation of IL-7R signaling should interfere with allelic exclusion. To test this hypothesis, we made use of transgenic mice that express a constitutively active form of STAT5b (STAT5b-CA). STAT5b-CA expression restores V(D)J recombination in IL-7R(-/-) B cells, demonstrating that IL-7 regulates H chain locus accessibility and V(D)J recombination via STAT5 activation. To examine the effects of constitutively active STAT5b on allelic exclusion, we crossed STAT5b-CA mice (which express the IgM(b) allotype) to IgM(a) allotype congenic mice. We found no difference in the percentage of IgM(a)/IgM(b)-coexpressing B cells in STAT5b-CA vs littermate control mice; identical results were observed when crossing STAT5b-CA mice with hen egg lysozyme (HEL) H chain transgenic mice. The HEL transgene enforces allelic exclusion, preventing rearrangement of endogenous H chain genes; importantly, rearrangement of endogenous H chain genes was suppressed to a similar degree in STAT5b-CA vs HEL mice. Thus, attenuation of IL-7R/STAT5 signaling is not required for allelic exclusion.

  15. Online Feature Selection of Class Imbalance via PA Algorithm

    Institute of Scientific and Technical Information of China (English)

    Chao Han; Yun-Kun Tan; Jin-Hui Zhu; Yong Guo; Jian Chen; Qing-Yao Wu

    2016-01-01

    Imbalance classification techniques have been frequently applied in many machine learning application domains where the number of the majority (or positive) class of a dataset is much larger than that of the minority (or negative) class. Meanwhile, feature selection (FS) is one of the key techniques for the high-dimensional classification task in a manner which greatly improves the classification performance and the computational efficiency. However, most studies of feature selection and imbalance classification are restricted to off-line batch learning, which is not well adapted to some practical scenarios. In this paper, we aim to solve high-dimensional imbalanced classification problem accurately and efficiently with only a small number of active features in an online fashion, and we propose two novel online learning algorithms for this purpose. In our approach, a classifier which involves only a small and fixed number of features is constructed to classify a sequence of imbalanced data received in an online manner. We formulate the construction of such online learner into an optimization problem and use an iterative approach to solve the problem based on the passive-aggressive (PA) algorithm as well as a truncated gradient (TG) method. We evaluate the performance of the proposed algorithms based on several real-world datasets, and our experimental results have demonstrated the effectiveness of the proposed algorithms in comparison with the baselines.

  16. The effect of spinal manipulation on imbalances in leg strength.

    Science.gov (United States)

    Chilibeck, Philip D; Cornish, Stephen M; Schulte, Al; Jantz, Nathan; Magnus, Charlene R A; Schwanbeck, Shane; Juurlink, Bernhard H J

    2011-09-01

    We hypothesized that spinal manipulation (SM) would reduce strength imbalances between legs. Using an un-blinded randomized design, 28 males and 21 females (54 ± 19y) with at least a 15% difference in isometric strength between legs for hip flexion, extension, abduction, or knee flexion were randomized to treatment or placebo (mock spinal manipulation). Strength of the stronger and weaker legs for hip flexion, extension, abduction, and/or knee flexion was assessed before and after the intervention. SM reduced the relative strength difference between legs for knee flexion (mean ± SD 57 ± 53 to 5 ± 14%) and hip flexion (24 ± 12 to 11 ± 15%) compared to placebo (34 ± 29 to 24 ± 36%, and 20 ± 18 to 22 ± 26%, respectively) (p = 0.05). SM also improved strength in the weak leg for hip abduction (104 ± 43 to 116 ± 43 Nm) compared to placebo (84 ± 24 to 85 ± 31 Nm) (p = 0.03). This study suggests that spinal manipulation may reduce imbalances in strength between legs for knee and hip flexion.

  17. Shoulder strength imbalances as injury risk in handball.

    Science.gov (United States)

    Edouard, P; Degache, F; Oullion, R; Plessis, J-Y; Gleizes-Cervera, S; Calmels, P

    2013-07-01

    This study was conducted to analyze whether internal (IR) and external (ER) rotator shoulder muscles weakness and/or imbalance collected through a preseason assessment could be predictors of subsequent shoulder injury during a season in handball players. In preseason, 16 female elite handball players (HPG) and 14 healthy female nonathletes (CG) underwent isokinetic IR and ER strength test with use of a Con-Trex® dynamometer in a seated position with 45° shoulder abduction in scapular plane, at 60, 120 and 240°/s in concentric and at 60°/s in eccentric, for both sides. An imbalanced muscular strength profile was determined using -statistically selected cut-offs from CG values. For HPG, all newly incurred shoulder injuries were reported during the season. There were significant differences between HPG and CG only for dominant eccentric IR strength, ER/IR ratio at 240°/s and for IRecc/ERcon ratio. In HPG, IR and ER strength was higher, and ER/IR ratios lower for dominant than for nondominant side. The relative risk was 2.57 (95%CI: 1.60-3.54; Pmuscle strength increases on the dominant side without ER/IR imbalances; and higher injury risk was associated with imbalanced muscular strength profile.

  18. TEMPOL increases NAD+ and improves redox imbalance in obese mice

    Directory of Open Access Journals (Sweden)

    Mayumi Yamato

    2016-08-01

    Full Text Available Continuous energy conversion is controlled by reduction–oxidation (redox processes. NAD+ and NADH represent an important redox couple in energy metabolism. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL is a redox-cycling nitroxide that promotes the scavenging of several reactive oxygen species (ROS and is reduced to hydroxylamine by NADH. TEMPOL is also involved in NAD+ production in the ascorbic acid–glutathione redox cycle. We utilized the chemical properties of TEMPOL to investigate the effects of antioxidants and NAD+/NADH modulators on the metabolic imbalance in obese mice. Increases in the NAD+/NADH ratio by TEMPOL ameliorated the metabolic imbalance when combined with a dietary intervention, changing from a high-fat diet to a normal diet. Plasma levels of the superoxide marker dihydroethidium were higher in mice receiving the dietary intervention compared with a control diet, but were normalized with TEMPOL consumption. These findings provide novel insights into redox regulation in obesity.

  19. Effects of imbalance and geometric error on precision grinding machines

    Energy Technology Data Exchange (ETDEWEB)

    Bibler, J.E.

    1997-06-01

    To study balancing in grinding, a simple mechanical system was examined. It was essential to study such a well-defined system, as opposed to a large, complex system such as a machining center. The use of a compact, well-defined system enabled easy quantification of the imbalance force input, its phase angle to any geometric decentering, and good understanding of the machine mode shapes. It is important to understand a simple system such as the one I examined given that imbalance is so intimately coupled to machine dynamics. It is possible to extend the results presented here to industrial machines, although that is not part of this work. In addition to the empirical testing, a simple mechanical system to look at how mode shapes, balance, and geometric error interplay to yield spindle error motion was modelled. The results of this model will be presented along with the results from a more global grinding model. The global model, presented at ASPE in November 1996, allows one to examine the effects of changing global machine parameters like stiffness and damping. This geometrically abstract, one-dimensional model will be presented to demonstrate the usefulness of an abstract approach for first-order understanding but it will not be the main focus of this thesis. 19 refs., 36 figs., 10 tables.

  20. Allelic Variation of Cytochrome P450s Drives Resistance to Bednet Insecticides in a Major Malaria Vector.

    Directory of Open Access Journals (Sweden)

    Sulaiman S Ibrahim

    2015-10-01

    Full Text Available Scale up of Long Lasting Insecticide Nets (LLINs has massively contributed to reduce malaria mortality across Africa. However, resistance to pyrethroid insecticides in malaria vectors threatens its continued effectiveness. Deciphering the detailed molecular basis of such resistance and designing diagnostic tools is critical to implement suitable resistance management strategies. Here, we demonstrated that allelic variation in two cytochrome P450 genes is the most important driver of pyrethroid resistance in the major African malaria vector Anopheles funestus and detected key mutations controlling this resistance. An Africa-wide polymorphism analysis of the duplicated genes CYP6P9a and CYP6P9b revealed that both genes are directionally selected with alleles segregating according to resistance phenotypes. Modelling and docking simulations predicted that resistant alleles were better metabolizers of pyrethroids than susceptible alleles. Metabolism assays performed with recombinant enzymes of various alleles confirmed that alleles from resistant mosquitoes had significantly higher activities toward pyrethroids. Additionally, transgenic expression in Drosophila showed that flies expressing resistant alleles of both genes were significantly more resistant to pyrethroids compared with those expressing the susceptible alleles, indicating that allelic variation is the key resistance mechanism. Furthermore, site-directed mutagenesis and functional analyses demonstrated that three amino acid changes (Val109Ile, Asp335Glu and Asn384Ser from the resistant allele of CYP6P9b were key pyrethroid resistance mutations inducing high metabolic efficiency. The detection of these first DNA markers of metabolic resistance to pyrethroids allows the design of DNA-based diagnostic tools to detect and track resistance associated with bednets scale up, which will improve the design of evidence-based resistance management strategies.

  1. Self-incompatibility of Prunus tenella and evidence that reproductively isolated species of Prunus have different SFB alleles coupled with an identical S-RNase allele.

    Science.gov (United States)

    Surbanovski, Nada; Tobutt, Kenneth R; Konstantinović, Miroslav; Maksimović, Vesna; Sargent, Daniel J; Stevanović, Vladimir; Bosković, Radovan I

    2007-05-01

    Many species of Prunus display an S-RNase-based gametophytic self-incompatibility (SI), controlled by a single highly polymorphic multigene complex termed the S-locus. This comprises tightly linked stylar- and pollen-expressed genes that determine the specificity of the SI response. We investigated SI of Prunus tenella, a wild species found in small, isolated populations on the Balkan peninsula, initially by pollination experiments and identifying stylar-expressed RNase alleles. Nine P. tenella S-RNase alleles (S(1)-S(9)) were cloned; their sequence analysis showed a very high ratio of non-synonymous to synonymous nucleotide substitutions (K(a)/K(s)) and revealed that S-RNase alleles of P. tenella, unlike those of Prunus dulcis, show positive selection in all regions except the conserved regions and that between C2 and RHV. Remarkably, S(8)-RNase, was found to be identical to S(1)-RNase from Prunus avium, a species that does not interbreed with P. tenella and, except for just one amino acid, to S(11) of P. dulcis. However, the corresponding introns and S-RNase-SFB intergenic regions showed considerable differences. Moreover, protein sequences of the pollen-expressed SFB alleles were not identical, harbouring 12 amino-acid replacements between those of P. tenella SFB(8) and P. avium SFB(1). Implications of this finding for hypotheses about the evolution of new S-specificities are discussed.

  2. An allele of the crm gene blocks cyanobacterial circadian rhythms.

    Science.gov (United States)

    Boyd, Joseph S; Bordowitz, Juliana R; Bree, Anna C; Golden, Susan S

    2013-08-20

    The SasA-RpaA two-component system constitutes a key output pathway of the cyanobacterial Kai circadian oscillator. To date, rhythm of phycobilisome associated (rpaA) is the only gene other than kaiA, kaiB, and kaiC, which encode the oscillator itself, whose mutation causes completely arrhythmic gene expression. Here we report a unique transposon insertion allele in a small ORF located immediately upstream of rpaA in Synechococcus elongatus PCC 7942 termed crm (for circadian rhythmicity modulator), which results in arrhythmic promoter activity but does not affect steady-state levels of RpaA. The crm ORF complements the defect when expressed in trans, but only if it can be translated, suggesting that crm encodes a small protein. The crm1 insertion allele phenotypes are distinct from those of an rpaA null; crm1 mutants are able to grow in a light:dark cycle and have no detectable oscillations of KaiC phosphorylation, whereas low-amplitude KaiC phosphorylation rhythms persist in the absence of RpaA. Levels of phosphorylated RpaA in vivo measured over time are significantly altered compared with WT in the crm1 mutant as well as in the absence of KaiC. Taken together, these results are consistent with the hypothesis that the Crm polypeptide modulates a circadian-specific activity of RpaA.

  3. Mosaicism for FMR1 gene full mutation and intermediate allele in a female foetus: a postzygotic retraction event.

    Science.gov (United States)

    Ferreira, Susana Isabel; Pires, Luís Miguel; Ferrão, José; Sá, Joaquim; Serra, Armando; Carreira, Isabel Marques

    2013-09-15

    Fragile X syndrome is caused by the expansion of an unstable CGG repeat in the 5'UTR of FMR1 gene. The occurrence of mosaicism is not uncommon, especially in male patients, whereas in females it is not so often reported. Here we report a female foetus that was subject to prenatal diagnosis, because of her mother being a premutation carrier. The foetus was identified as being a mosaic for an intermediate allele and a full mutation of FMR1 gene, in the presence of a normal allele. The mosaic status was confirmed in three different tissues of the foetus--amniotic fluid, skin biopsy and blood--the last two obtained after pregnancy termination. Karyotype analysis and X-chromosome STR markers analysis do not support the mosaicism as inheritance of both maternal alleles. Oligonucleotide array-CGH excluded an imbalance that could contain the primer binding site with a different repeat size. The obtained results give compelling evidence for a postzygotic expansion mechanism where the foetus mosaic pattern originated from expansion of the mother's premutation into a full mutation and consequent regression to an intermediate allele in a proportion of cells. These events occurred in early embryogenesis before the commitment of cells into the different tissues, as the three tested tissues of the foetus have the same mosaic pattern. The couple has a son with Fragile X mental retardation syndrome and choose to terminate this pregnancy after genetic counselling.

  4. Quantification of Allele Dosage in tetraploid Roses

    NARCIS (Netherlands)

    Vukosavljev, M.; Guardo, Di M.; Weg, van de W.E.; Arens, P.; Smulders, M.J.M.

    2012-01-01

    Many important crops (wheat, potato, strawberry, rose, etc.) are polyploid. This complicates genetic analyses, as the same locus can be present on multiple homologous or homoeologous chromosomes. SSR markers are suitable for mapping in segregating populations of polyploids as they are multi-allelic,

  5. Estimating the probability of allelic drop-out of STR alleles in forensic genetics

    DEFF Research Database (Denmark)

    Tvedebrink, Torben; Eriksen, Poul Svante; Mogensen, Helle Smidt;

    2009-01-01

    In crime cases with available DNA evidence, the amount of DNA is often sparse due to the setting of the crime. In such cases, allelic drop-out of one or more true alleles in STR typing is possible. We present a statistical model for estimating the per locus and overall probability of allelic drop......-out using the results of all STR loci in the case sample as reference. The methodology of logistic regression is appropriate for this analysis, and we demonstrate how to incorporate this in a forensic genetic framework....

  6. New Adaptive Method for IQ Imbalance Compensation of Quadrature Modulators in Predistortion Systems

    Directory of Open Access Journals (Sweden)

    Hassan Zareian

    2009-01-01

    Full Text Available Imperfections in quadrature modulators (QMs, such as inphase and quadrature (IQ imbalance, can severely impact the performance of power amplifier (PA linearization systems, in particular in adaptive digital predistorters (PDs. In this paper, we first analyze the effect of IQ imbalance on the performance of a memory orthogonal polynomials predistorter (MOP PD, and then we propose a new adaptive algorithm to estimate and compensate the unknown IQ imbalance in QM. Unlike previous compensation techniques, the proposed method was capable of online IQ imbalance compensation with faster convergence, and no special calibration or training signals were needed. The effectiveness of the proposed IQ imbalance compensator was validated by simulations. The results clearly show the performance of the MOP PD to be enhanced significantly by adding the proposed IQ imbalance compensator.

  7. New Adaptive Method for IQ Imbalance Compensation of Quadrature Modulators in Predistortion Systems

    Science.gov (United States)

    Zareian, Hassan; Vakili, Vahid Tabataba

    2009-12-01

    Imperfections in quadrature modulators (QMs), such as inphase and quadrature (IQ) imbalance, can severely impact the performance of power amplifier (PA) linearization systems, in particular in adaptive digital predistorters (PDs). In this paper, we first analyze the effect of IQ imbalance on the performance of a memory orthogonal polynomials predistorter (MOP PD), and then we propose a new adaptive algorithm to estimate and compensate the unknown IQ imbalance in QM. Unlike previous compensation techniques, the proposed method was capable of online IQ imbalance compensation with faster convergence, and no special calibration or training signals were needed. The effectiveness of the proposed IQ imbalance compensator was validated by simulations. The results clearly show the performance of the MOP PD to be enhanced significantly by adding the proposed IQ imbalance compensator.

  8. Effects of specific muscle imbalance improvement training on the balance ability in elite fencers

    OpenAIRE

    Kim, Taewhan; Kil, Sekee; Chung, Jinwook; Moon, Jeheon; Oh, Eunyoung

    2015-01-01

    [Purpose] The lunge Motion that occurs frequently in fencing training and matches results in imbalance of the upper and lower limbs muscles. This research focuses on the improvement of the imbalance that occurs in the national team fencers of the Republic of Korea through specific muscle imbalance improvement training. [Subjects] The subjects of this research were limited to right-handed male fencers. Nine male, right-handed national fencing athletes were selected for this study (4 epee, 5 sa...

  9. Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

    Directory of Open Access Journals (Sweden)

    Lu Wang

    2016-08-01

    Full Text Available Fragile X syndrome (FXS is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP, the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO mice, the factors released by astrocytes are still unclear. We cultured wild type (WT cortical neurons in astrocyte-conditioned medium (ACM from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA levels using high-performance liquid chromatography (HPLC. The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB, a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment.

  10. Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

    Science.gov (United States)

    Wang, Lu; Wang, Yan; Zhou, Shimeng; Yang, Liukun; Shi, Qixin; Li, Yujiao; Zhang, Kun; Yang, Le; Zhao, Minggao; Yang, Qi

    2016-01-01

    Fragile X syndrome (FXS) is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO) mice, the factors released by astrocytes are still unclear. We cultured wild type (WT) cortical neurons in astrocyte-conditioned medium (ACM) from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA) levels using high-performance liquid chromatography (HPLC). The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T) expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB), a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment. PMID:27517961

  11. HLA-B alleles of the Cayapa of Ecuador: New B39 and B15 alleles

    Energy Technology Data Exchange (ETDEWEB)

    Garber, T.L.; Butler, L.M.; Watkins, D.I. [Univ. of Wisconsin, Madison, WI (United States)] [and others

    1995-05-01

    Recent data suggest that HLA-B locus alleles can evolve quickly in native South American populations. To investigate further this phenomenon of new HLA-B variants among Amerindians, we studied samples from another South American tribe, the Cayapa from Ecuador. We selected individuals for HLA-B molecular typing based upon their HLA class II typing results. Three new variants of HLA-B39 and one new variant of HLA-B15 were found in the Cayapa: HLA-B*3905, HLA-B*3906, HLA-B*3907, and HLA-B*1522. A total of thirteen new HLA-B alleles have now been found in the four South American tribes studied. Each of these four tribes studied, including the Cayapa, had novel alleles that were not found in any of the other tribes, suggesting that many of these new HLA-B alleles may have evolved since the Paleo-Indians originally populated South America. Each of these 13 new alleles contained predicted amino acid replacements that were located in the peptide binding site. These amino acid replacements may affect the sequence motif of the bound peptides, suggesting that these new alleles have been maintained by selection. New allelic variants have been found for all common HLA-B locus antigenic groups present in South American tribes with the exception of B48. In spite of its high frequency in South American tribes, no evidence for variants of B48 has been found in all the Amerindians studied, suggesting that B48 may have unique characteristics among the B locus alleles. 70 refs., 2 figs., 2 tabs.

  12. HLA-B alleles of the Cayapa of Ecuador: new B39 and B15 alleles.

    Science.gov (United States)

    Garber, T L; Butler, L M; Trachtenberg, E A; Erlich, H A; Rickards, O; De Stefano, G; Watkins, D I

    1995-01-01

    Recent data suggest that HLA-B locus alleles can evolve quickly in native South American populations. To investigate further this phenomenon of new HLA-B variants among Amerindians, we studied samples from another South American tribe, the Cayapa from Ecuador. We selected individuals for HLA-B molecular typing based upon their HLA class II typing results. Three new variants of HLA-B39 and one new variant of HLA-B15 were found in the Cayapa: HLA-B*3905, HLA-B*3906, HLA-B*3907, and HLA-B*1522. A total of thirteen new HLA-B alleles have now been found in the four South American tribes studied. Each of these four tribes studied, including the Cayapa, had novel alleles that were not found in any of the other tribes, suggesting that many of these new HLA-B alleles may have evolved since the Paleo-Indians originally populated South America. Each of these 13 new alleles contained predicted amino acid replacements that were located in the peptide binding site. These amino acid replacements may affect the sequence motif of the bound peptides, suggesting that these new alleles have been maintained by selection. New allelic variants have been found for all common HLA-B locus antigenic groups present in South American tribes with the exception of B48. In spite of its high frequency in South American tribes, no evidence for variants of B48 has been found in all the Amerindians studied, suggesting that B48 may have unique characteristics among the B locus alleles.

  13. Interaction between Current Imbalance and Magnetization in LHC Cables

    CERN Document Server

    Bottura, L; Kuijper, A; den Ouden, A; ten Haken, B; ten Kate, H H J

    2001-01-01

    The quality of the magnetic field in superconducting accelerator magnets is associated with the properties of the superconducting cable. Current imbalances due to coupling currents DI, as large as 100 A, are induced by spatial variations of the field sweep rate and contact resistances. During injection at a constant field all magnetic field components show a decay behavior. The decay is caused by a diffusion of coupling currents into the whole magnet. This results in a redistribution of the transport current among the strands and causes a demagnetization of the superconducting cable. As soon as the field is ramped up again after the end of injection, the magnetization rapidly recovers from the decay and follows the course of the original hysteresis curve. In order to clarify the interactions between the changes in current and magnetization during injection we performed a number of experiments. A magnetic field with a spatially periodic pattern was applied to a superconducting wire in order to simulate the cou...

  14. FDI Inflows and Trade Imbalances: Evidence from Developing Asia

    Directory of Open Access Journals (Sweden)

    Thi Anh-Dao Tran

    2014-06-01

    Full Text Available The present paper examines the effects of FDI inflows on external imbalances in the developing and transition countries in Asia during the period 1991-2011. To this end, we extend the conventional trade balance model by reformulating the determinants of exports and imports. Our empirical findings suggest that current FDI inflows increase trade deficits, leading to negative consequences for the host country’s macroeconomic stability. However, the coefficient estimated becomes negative when we lag the FDI variable, implying that FDI inflows worsen the trade balance first and then improve it. We also find that a real depreciation tends to worsen trade balances because the usual Marshall-Lerner constraint is magnified by the import content of exports. Lastly, higher domestic absorption and larger productive capacity in the manufacturing sector improve the trade balance. Thelatter result supports the export-investment nexus, one of the most distinctive features of Asia.

  15. Redox Imbalance in T Cell-Mediated Skin Diseases

    Directory of Open Access Journals (Sweden)

    Saveria Pastore

    2010-01-01

    Full Text Available The skin is permanently exposed to physical, chemical, and biological aggression by the environment. In addition, acute and chronic inflammatory events taking place in the skin are accompanied by abnormal release of pro-oxidative mediators. In this paper, we will briefly overview the homeostatic systems active in the skin to maintain the redox balance and also to counteract abnormal oxidative stress. We will concentrate on the evidence that a local and/or systemic redox dysregulation accompanies the chronic inflammatory disorder events associated to psoriasis, contact dermatitis, and atopic dermatitis. We will also discuss the fact that several well-established treatments for the therapy of chronic inflammatory skin disorders are based on the application of strong physical or chemical oxidants onto the skin, indicating that, in selected conditions, a further increase of the oxidative imbalance may lead to a beneficial outcome.

  16. Bose polaron problem: Effect of mass imbalance on binding energy

    Science.gov (United States)

    Ardila, L. A. Peña; Giorgini, S.

    2016-12-01

    By means of quantum Monte Carlo methods we calculate the binding energy of an impurity immersed in a Bose-Einstein condensate at T =0 . The focus is on the attractive branch of the Bose polaron and on the role played by the mass imbalance between the impurity and the surrounding particles. For an impurity resonantly coupled to the bath, we investigate the dependence of the binding energy on the mass ratio and on the interaction strength within the medium. In particular, we determine the equation of state in the case of a static (infinite mass) impurity, where three-body correlations are irrelevant and the result is expected to be a universal function of the gas parameter. For the mass ratio corresponding to 40K impurities in a gas of 87Rb atoms, we provide an explicit comparison with the experimental findings of a recent study carried out at JILA.

  17. A case of myotonic dystrophy with electrolyte imbalance.

    Science.gov (United States)

    Ko, Weon-Jin; Kim, Kwang-Yeol; Kim, So-Mi; Hong, Seung-Jae; Lee, Sang-Hoon; Song, Ran; Yang, Hyung-In; Lee, Yeon-Ah

    2013-07-01

    Type 1 myotonic dystrophy (DM1) is an autosomal-dominant inherited disorder with a multisystem involvement, caused by an abnormal expansion of the CTG sequence of the dystrophic myotonia protein kinase (DMPK) gene. DM1 is a variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being reported. But, Electrolytes imbalance is a very rare condition in patients with DM1 yet. Herein we present a 42-yr-old Korean male of DM1 with abnormally elevated serum sodium and potassium. The patient had minimum volume of maximally concentrated urine without water loss. It was only cured by normal saline hydration. The cause of hypernatremia was considered by primary hypodipsia. Hyperkalemic conditions such as renal failure, pseudohyperkalemia, cortisol deficiency and hyperkalemic periodic paralysis were excluded. Further endocrine evaluation suggested selective hyperreninemic hypoaldosteronism as a cause of hyperkalemia.

  18. The genetic variation of RELN expression in schizophrenia and bipolar disorder.

    Science.gov (United States)

    Ovadia, Galit; Shifman, Sagiv

    2011-01-01

    Reelin plays an important role in the development and function of the brain and has been linked to different neuropsychiatric diseases. To further clarify the connection between reelin and psychiatric disorders, we studied the factors that influence the expression of reelin gene (RELN) and its different isoforms. We examined the total expression of RELN, allelic expression, and two alternative RELN isoforms in postmortem brain samples from patients with schizophrenia and bipolar disorder, as well as unaffected controls. We did not find a significant reduction in the total expression of RELN in schizophrenia or bipolar disorder. However, we did find a significant reduction of the proportion of the short RELN isoform, missing the C-terminal region in bipolar disorder, and imbalance in the allelic expression of RELN in schizophrenia. In addition, we tested the association between variation in RELN expression and rs7341475, an intronic SNP that was found to be associated with schizophrenia in women. We did not find an association between rs7341474 and the total expression of RELN either in women or in the entire sample. However, we observed a nominally significant effect of genotype-by-sex interaction on the variation in microexon skipping. Women with the risk genotype of rs7341475 (GG) had a higher proportion of microexon skipping, which is the isoform predominant in tissues outside the brain, while men had the opposite trend. Finally, we tested 83 SNPs in the gene region for association with expression variation of RELN, but none were significant. Our study further supports the connection between RELN dysfunction and psychiatric disorders, and provides a possible functional role for a schizophrenia associated SNP. Nevertheless, the positive associations observed in this study needs further replication as it may have implications for understanding the biological causes of schizophrenia and bipolar disorder.

  19. Propensity to obesity impacts the neuronal response to energy imbalance

    Directory of Open Access Journals (Sweden)

    Marc-Andre eCornier

    2015-02-01

    Full Text Available The mechanisms responsible for the propensity to gain weight or remain normal weight are poorly understood. The objective of this study was to study the neuronal response to visual food cues during short-term energy imbalance in healthy adults recruited as obesity-resistant (OR or obesity-prone (OP based on self-identification, BMI, and personal/family weight history. 25 OR and 28 OP subjects were studied in underfed (UF and overfed (OF as compared to eucaloric (EU conditions in a randomized crossover design. Each study phase included a 3 day run-in diet, 1 day of controlled feeding (basal energy needs for EU, 40% above/below basal energy needs for OF/UF, and a test day. On the test day fMRI was performed in the acute fed stated (30 minutes after a test meal while subjects viewed images of foods of high hedonic value and neutral non-food objects. Measures of appetite and hormones were also performed before and every 30 minutes after the test meal. UF was associated with significantly increased activation of insula, somatosensory cortex, inferior and medial prefrontal cortex, parahippocampus, precuneus, cingulate and visual cortex in OR. However, UF had no impact in OP. As a result, UF was associated with significantly greater activation, specifically in the insula, inferior prefrontal cortex, and somatosensory cortex in OR as compared to OP. While OF was overall associated with reduced activation of inferior visual cortex, no group interaction was observed with OF. In summary, these findings suggest that individuals resistant to weight gain and obesity are more sensitive to short-term energy imbalance, particularly with UF, than those prone to weight gain. The inability to sense or adapt to changes in energy balance may represent an important mechanism contributing to excess energy intake and risk for obesity.

  20. Convulsion following gastroenteritis in children without severe electrolyte imbalance.

    Science.gov (United States)

    Ghorashi, Ziaaedin; Nezami, Nariman; Soltani-Ahari, Hassan; Ghorashi, Sona

    2010-01-01

    Three to five million children from among one billion with gastroenteritis die annually worldwide. The etiologic agent in developed countries is viral in 15-60% of cases, while in developing countries, bacteria and parasites are frequently reported as the etiologic factors. Neurologic signs including convulsion are seen in some cases of diarrhea. This study aimed to investigate the etiology, risk factors and short-term prognosis of gastroenteritis with convulsion. During a case-control study, 100 patients with gastroenteritis were enrolled into the case and control groups on the basis of convulsion or no convulsion development, respectively. This study was conducted in Tabriz Children's Hospital from March 2004 to March 2007. The age of patients ranged from 2 months to 7 years, and the groups were age- and sex-matched. Body temperature (BT), severity and type of dehydration, stool exam and culture, past history of convulsion in the patient and first-degree relatives, electrolyte imbalance, and short-term prognosis were studied and compared. The mean weight of groups was not different, while the frequency of fever at the time of admission, past history of febrile convulsion in first-degree relatives and severity of dehydration were significantly higher in the case group (p convulsion in the patient, shigellosis and antibiotic usage were also significantly higher in the case group (p = 0.025, p = 0.014 and p = 0.001). Convulsion mostly occurred in mild gastroenteritis accompanied with fever and positive history of febrile convulsion in first-degree relatives. History of febrile convulsion in the patient and shigellosis were associated with development of convulsion in patients with gastroenteritis. No significant electrolyte imbalance was observed in patients with gastroenteritis experiencing febrile convulsion.

  1. Expression

    Directory of Open Access Journals (Sweden)

    Wang-Xia Wang

    2014-02-01

    Full Text Available The miR-15/107 family comprises a group of 10 paralogous microRNAs (miRNAs, sharing a 5′ AGCAGC sequence. These miRNAs have overlapping targets. In order to characterize the expression of miR-15/107 family miRNAs, we employed customized TaqMan Low-Density micro-fluid PCR-array to investigate the expression of miR-15/107 family members, and other selected miRNAs, in 11 human tissues obtained at autopsy including the cerebral cortex, frontal cortex, primary visual cortex, thalamus, heart, lung, liver, kidney, spleen, stomach and skeletal muscle. miR-103, miR-195 and miR-497 were expressed at similar levels across various tissues, whereas miR-107 is enriched in brain samples. We also examined the expression patterns of evolutionarily conserved miR-15/107 miRNAs in three distinct primary rat brain cell preparations (enriched for cortical neurons, astrocytes and microglia, respectively. In primary cultures of rat brain cells, several members of the miR-15/107 family are enriched in neurons compared to other cell types in the central nervous system (CNS. In addition to mature miRNAs, we also examined the expression of precursors (pri-miRNAs. Our data suggested a generally poor correlation between the expression of mature miRNAs and their precursors. In summary, we provide a detailed study of the tissue and cell type-specific expression profile of this highly expressed and phylogenetically conserved family of miRNA genes.

  2. Muscle activation imbalance and low-back injury in varsity athletes.

    Science.gov (United States)

    Reeves, N Peter; Cholewicki, Jacek; Silfies, Sheri P

    2006-06-01

    There are conflicting findings in the literature regarding erector spinae activation imbalance in people with low-back pain (LBP). Some studies have found asymmetric recruitment between muscle pairs in people with LBP, whilst other studies have not; some reported people with LBP recruit more lumbar muscles whilst other have reported greater thoracic activity. Using 242 varsity athletes, EMG activity of thoracic and lumbar erector spinae pairs was recorded during an isometric trunk extension. Activation imbalance among muscle pairs and levels was compared between athletes with and without a history of low-back injury (HxLBI). There were no group differences in the imbalance between sides, but the HxLBI group had greater activation imbalance between lumbar and thoracic levels than the No HxLBI group. Activation imbalance between levels was similar for individuals with No HxLBI and those who sustained first time injury suggesting that imbalance does not cause LBI. There was no difference between the athletes with single and multiple episode LBI, nor between short and long symptom duration suggesting that the presence of imbalance is not an impairment. Interestingly, activation imbalance occurred in both directions, meaning more thoracic activity for some, and more lumbar activity for others, which might be a functional adaptation related to pathology.

  3. Codigestion of manure and industrial organic waste at centralized biogas plants: process imbalances and limitations

    DEFF Research Database (Denmark)

    Bangsø Nielsen, Henrik; Angelidaki, Irini

    2008-01-01

    The present study focuses on process imbalances in Danish centralized biogas plants treating manure in combination with industrial waste. Collection of process data from various full-scale plants along with a number of interviews showed that imbalances occur frequently. High concentrations...

  4. The state line of solution of imbalances problem the wholesale electricity market of Ukraine

    Directory of Open Access Journals (Sweden)

    А.S. Kolesnichenko

    2011-10-01

    Full Text Available This article deals with the problem of formation and dynamics of imbalances of the wholesale electricity market (WEM of Ukraine. The features and prospects of imbalance control in the context of reforming the wholesale electricity market are analyzed.

  5. Theoretical predictions of transverse kinematic imbalance in neutrino-nucleus interactions

    CERN Document Server

    Pickering, Luke

    2016-01-01

    Distributions of transverse kinematic imbalance in neutrino-nucleus interactions in the few GeV regime are sensitive to nuclear effects. We present a study comparing the latest predictions of transverse kinematic imbalance from the interaction simulations, NuWro and GENIE. We dis- cuss the differences between the model predictions.

  6. A comparison of imbalance settlement designs and results of Germany and the Netherlands

    NARCIS (Netherlands)

    Van der Veen, R.A.C.; Abbasy, A.; Hakvoort, R.A.

    2010-01-01

    Imbalance settlement is a vital part of the balancing market, i.e. the institutional arrangement that establishes market-based balance management in liberalized electricity markets. We investigate the impact of the imbalance settlement design on the behaviour of Balance Responsible Parties and there

  7. Imbalance of Interleukin 18 and Interleukin 18 Binding Protein in Patients with Lupus Nephritis

    Institute of Scientific and Technical Information of China (English)

    Dong Liang; Wenfeng Ma; Cuiwei Yao; Huafeng Liu; Xiaowen Chen

    2006-01-01

    To evaluate the balance status of interleukin 18 (IL-18) and interleukin 18 binding protein (IL-18BP) in circulation in patients with lupus nephritis (LN) and primary nephrotic syndrome (PNS), plasma levels as well as mRNA expression in peripheral blood mononuclear cells (PBMCs) of IL-18 and IL-18BP were measured by ELISA and RT-PCR respectively. The ratio of IL-18/IL-18BP was also calculated. Both plasma IL-18 and IL-18BP increased significantly in LN patients while only IL-18BP increased in PNS, which resulted in an elevated ratio of IL-18/IL-18BP in LN but not in PNS patients when compared with normal controls. In contrast, increased level of IL-18 mRNA was only detected in LN but not in PNS group, although IL-18BP mRNA expressions in PBMCs in both groups were higher than that in control. The imbalance of IL-18 and IL-18BP might be involved in the pathogenesis of LN, based on which a therapeutic approach is valuable to be developed for LN. Cellular & Molecular Immunology. 2006;3(4):303-306.

  8. A Hidden Markov Model to estimate population mixture and allelic copy-numbers in cancers using Affymetrix SNP arrays

    Directory of Open Access Journals (Sweden)

    Torring Niels

    2007-11-01

    Full Text Available Abstract Background Affymetrix SNP arrays can interrogate thousands of SNPs at the same time. This allows us to look at the genomic content of cancer cells and to investigate the underlying events leading to cancer. Genomic copy-numbers are today routinely derived from SNP array data, but the proposed algorithms for this task most often disregard the genotype information available from germline cells in paired germline-tumour samples. Including this information may deepen our understanding of the "true" biological situation e.g. by enabling analysis of allele specific copy-numbers. Here we rely on matched germline-tumour samples and have developed a Hidden Markov Model (HMM to estimate allelic copy-number changes in tumour cells. Further with this approach we are able to estimate the proportion of normal cells in the tumour (mixture proportion. Results We show that our method is able to recover the underlying copy-number changes in simulated data sets with high accuracy (above 97.71%. Moreover, although the known copy-numbers could be well recovered in simulated cancer samples with more than 70% cancer cells (and less than 30% normal cells, we demonstrate that including the mixture proportion in the HMM increases the accuracy of the method. Finally, the method is tested on HapMap samples and on bladder and prostate cancer samples. Conclusion The HMM method developed here uses the genotype calls of germline DNA and the allelic SNP intensities from the tumour DNA to estimate allelic copy-numbers (including changes in the tumour. It differentiates between different events like uniparental disomy and allelic imbalances. Moreover, the HMM can estimate the mixture proportion, and thus inform about the purity of the tumour sample.

  9. Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Streit, Sylvia; Bange, Johannes; Fichtner, Alexander; Ihrler, Stephan; Issing, Wolfgang; Ullrich, Axel

    2004-08-20

    Fibroblast growth factor receptors (FGFRs) have been implicated in various forms of human hyperproliferative disorders such as cancers of the cervix and bladder. We investigated the expression pattern of FGFR4 and the clinical significance of the recently identified Gly/Arg polymorphism (388) in head and neck squamous cell carcinomas (HNSCCs) of the oral cavity and the oropharynx. Sections from 104 paraffin-embedded tumors were analyzed by a restriction fragment length polymorphism-based method to determine the FGFR4 genotypes. Protein expression was investigated immunohistochemically and graded into a low, intermediate, or high degree of staining. FGFR4 expression was scored as high in 17, as intermediate in 59 and as low in 28 cases. The FGFR4 Arg388 allele was found in 59 tumors, 46 of them having heterozygous and 13 homozygous genotypes. High expression of the FGFR4 Arg388 allele was significantly associated with reduced overall survival (p = 0.032) and with an advanced tumor stage (p = 0.023), whereas expression of the FGFR4 Gly388 had no impact on disease progression. Our findings indicate that high expression of FGFR4 in connection with the Arg388 allele is associated with poor clinical outcome and support the significance of FGFR4 as a diagnostic marker and a target for therapeutic intervention in human HNSCC.

  10. Chromosomal imbalances revealed in primary rhabdomyosarcomas by comparative genomic hybridization

    Institute of Scientific and Technical Information of China (English)

    LI Qiao-xin; LIU Chun-xia; CHUN Cai-pu; QI Yan; CHANG Bin; LI Xin-xia; CHEN Yun-zhao; NONG Wei-xia; LI Hong-an; LI Feng

    2009-01-01

    Background Previous cytogenetic studies revealed aberrations varied among the throe subtypes of rhabdomyosarcoma. We profiled chromosomal imbalances in the different subtypes and investigated the relationships between clinical parameters and genomic aberrations.Methods Comparative genomic hybridization was used to investigate genomic imbalances in 25 cases of primary rhabdomyosarcomas and two rhabdomyosarcoma cell lines. Specimens were reviewed to determine histological type, pathological grading and clinical staging.Results Changes involving one or more regions of the genome were seen in all rhabdomyosarcomal patients. For rhabdomyosarcoma, DNA sequence gains were most frequently (>30%) seen in chromosomes 2p, 12q, 6p, 9q, 10q, 1p,2q, 6q, 8q, 15q and 18q; losses from 3p, 11p and 6p. In aggressive alveolar rhabdomyosarcoma, frequent gains were seen on chromosomes 12q, 2p, 6p, 2q, 4q, 10q and 15q; losses from 3p, 6p, 1q and 5q. For embryonic rhabdomyosarcoma, frequent gains were on 7p, 9q, 2p, 18q, 1p and 8q; losses only from 11p. Frequently gained chromosome arms of translocation associated with rhabdomyosarcoma were 12q, 2, 6, 10q, 4q and 15q; losses from 3p,6p and 5q. The frequently gained chromosome arms of nontranslocation associated with rhabdomyosarcoma were 2p,9q and 18q, while 11p and 14q were the frequently lost chromosome arms. Gains on chromosome 12q were significantly correlated with translocation type. Gains on chromosome 9q were significantly correlated with clinical staging. Conclusions Gains on chromosomes 2p, 12q, 6p, 9q, 10q, 1p, 2q, 6q, 8q, 15q and 18q and losses on chromosomes 3p, 11p and 6p may be related to rhabdomyosarcomal carcinogenesis. Furthermore, gains on chromosome 12q may be correlated with translocation and gains on chromosome 9q with the early stages of rhabdomyosarcoma.

  11. Identification of β-globin haplotypes linked to sickle hemoglobin (Hb S) alleles in Mazandaran province, Iran.

    Science.gov (United States)

    Aghajani, Faeghe; Mahdavi, Mohammad Reza; Kosaryan, Mehrnoush; Mahdavi, Mehrad; Hamidi, Mohaddese; Jalali, Hossein

    2016-12-21

    Carrier frequency of the β(S) allele has been reported to be 0.19% in Mazandaran province, northern Iran. Haplotype analysis of the β(S) allele helps trace the origin of its encoded hemoglobin (Hb) variant, Hb S, in a region. The aim of this study was to investigate the haplotypes associated with β(S) alleles in Mazandaran province. Capillary electrophoresis was carried out to detect individuals suspected to have a βS allele(s). DNA analysis (PCR-RFLP) was used for final confirmation. To identify 5\\' to 3\\' β-globin gene cluster haplotypes associated with β(S) alleles, family linkage analysis was applied. Six polymorphic sites (HincII 5' to ε, XmnI 5' to (G)γ, HindIII in (G)γ, HindIII in (A)γ, HincII 3' to ψβ and AvaII in β) were investigated using the PCR-RFLP method. Five different haplotypes were linked to β(S) alleles, while β(A) alleles were associated with nine haplotypes. Among the β(S) alleles, 53.9% were associated with the Benin (----++) haplotype, and the Arab-Indian (+++-++) haplotype had the second-highest frequency (23%). Unlike southern provinces, where the Arab-Indian haplotype is prominent, the Benin haplotype is the most frequent haplotype in northern Iran, and this may represent a founder effect. Since the Benin haplotype does not carry the XmnI polymorphism 5' to the (G)γ gene, which is responsible for high expression of Hb F, a severe form of sickle cell disease can be anticipated in patients that are homozygous for the β(S) allele in the northern region.

  12. Two domain-disrupted hda6 alleles have opposite epigenetic effects on transgenes and some endogenous targets

    KAUST Repository

    Zhang, ShouDong

    2015-12-15

    HDA6 is a RPD3-like histone deacetylase. In Arabidopsis, it mediates transgene and some endogenous target transcriptional gene silencing (TGS) via histone deacetylation and DNA methylation. Here, we characterized two hda6 mutant alleles that were recovered as second-site suppressors of the DNA demethylation mutant ros1–1. Although both alleles derepressed 35S::NPTII and RD29A::LUC in the ros1–1 background, they had distinct effects on the expression of these two transgenes. In accordance to expression profiles of two transgenes, the alleles have distinct opposite methylation profiles on two reporter gene promoters. Furthermore, both alleles could interact in vitro and in vivo with the DNA methyltransferase1 with differential interactive strength and patterns. Although these alleles accumulated different levels of repressive/active histone marks, DNA methylation but not histone modifications in the two transgene promoters was found to correlate with the level of derepression of the reporter genes between the two had6 alleles. Our study reveals that mutations in different domains of HDA6 convey different epigenetic status that in turn controls the expression of the transgenes as well as some endogenous loci.

  13. Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques.

    Directory of Open Access Journals (Sweden)

    Joseph L Mankowski

    Full Text Available Human immunodeficiency virus (HIV infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS disease using a well-characterized simian immunodeficiency (SIV/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5. Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001. Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease.

  14. The acylphosphatase (Acyp) alleles associate with male hybrid sterility in Drosophila.

    Science.gov (United States)

    Michalak, Pawel; Ma, Daina

    2008-06-15

    Hybrid defects are believed to result from genetic incompatibilities between genes that have evolved in separate parental lineages. These genetic dysfunctions on the hybrid genomic background, also known as Dobzhansky-Muller incompatibilities, can be an incipient signature of speciation, and as such - a subject of active research. Here we present evidence that Acyp locus (CG16870) that encodes acylphosphatase, a small enzyme that catalyzes the hydrolysis of acylphosphates and participates in ion transport across biological membranes, is involved in genetic incompatibilities leading to male sterility in hybrids between Drosophila simulans and D. mauritiana. There is a strong association between Acyp alleles (genotype) and the sterility/fertility pattern (phenotype), as well as between the phenotype, the genotype and its transcriptional activity. Allele-specific expression in hybrids heterozygous for Acyp suggests a cis-type regulation of this gene, where an allele from one of the parental species (D. simulans) is consistently overexpressed.

  15. Dideoxy single allele-specific PCR - DSASP new method to discrimination allelic

    Directory of Open Access Journals (Sweden)

    Eleonidas Moura Lima

    2015-06-01

    Full Text Available Gastric cancer (GC is a multifactorial disease with a high mortality rate in Brazil and worldwide. This work aimed to evaluate single nucleotide polymorphisms (SNP rs1695, in the Glutathione S-Transferase Pi (GSTP1 gene in GC samples by comparative analysis Specific PCR - ASP and Dideoxy Single Allele-Specific PCR - DSASP methods. The DSASP is the proposed new method for allelic discrimination. This work analyzed 60 GC samples, 26 diffuse and 34 intestinal types. The SNP rs1695 of the GSTP1 gene was significantly associated with GC analyzed by DSASP method (χ2 = 9.7, P 0.05. These results suggest that the SNP rs1695 of the GSTP1 gene was a risk factor associated with gastric carcinogens is and the DSASP method was a new successfully low-cost strategy to study allelic discrimination.

  16. Determination of DQB1 alleles using PCR amplification and allele-specific primers.

    Science.gov (United States)

    Lepage, V; Ivanova, R; Loste, M N; Mallet, C; Douay, C; Naoumova, E; Charron, D

    1995-10-01

    Molecular genotyping of HLA class II genes is commonly carried out using polymerase chain reaction (PCR) in combination with sequence-specific oligotyping (PCR-SSO) or a combination of the PCR and restriction fragment length polymorphism methods (PCR-RFLP). However, the identification of the DQB1 type by PCR-SSO and PCR-RFLP is very time-consuming which is disadvantageous for the typing of cadaveric organ donors. We have developed a DQB1 typing method using PCR in combination with allele-specific amplification (PCR-ASA), which allows the identification of the 17 most frequent alleles in one step using seven amplification mixtures. PCR allele-specific amplification HLA-DQB1 typing is easy to perform, and the results are easy to interpret in routine clinical practice. The PCR-ASA method is therefore better suited to DQB1 typing for organ transplantation than other methods.

  17. The man-made creators of the imbalance of water in Nature

    Science.gov (United States)

    Shlafman, L. M.; Kontar, V. A.

    2013-12-01

    At 2011 we have described the imbalance of water in Nature as the system [1]. At 2012 we have described water and carbon and the glaciers [2], [3] as creators of the imbalance of Nature. Now we are describing some man-made creators of the imbalance of Nature. The photosynthesis is a powerful creator of the imbalance of Nature. The photosynthesis significantly increases the complexity of the structures and reduces the entropy. Earth's hydrosphere contains water less than it was flowed via photosynthesis. This is an example of the imbalance of involving when the return of water has delayed because water is involved into the processes of life and other processes. People widely use photosynthesis and create not only an additional man-made imbalance of water in Nature, but also the man-made changing the albedo, and a lot of other important parameters of the planet of Earth. All of these processes are significantly imbalanced. The fossil hydrocarbons have accumulated during millions of years, but now are burned. This is an example of the imbalance delay by time. The man-made burning of the hydrocarbons is creating the imbalances of impact or explosive type, because of the burning processes is in millions of times faster than the accumulation processes. Please pay attention to the imbalance of redeployment by places. For example, oil and gas are extracted in one places, and burned in others. During combustion is standing out not only water, but energy, and other components. The temperature in the centers of big cities is always higher and there is dominating the rising air. It pollutes the environment, changes circulations, create greenhouse effect, etc. Other examples of the imbalance of relocation are shown in the production and consumption of food. The irrigation systems transfer water from one place to another. This transfer of water creates a lot of imbalances in change climate, ecosystems, etc in places where water was took and where the water was brought. Usually

  18. Osteogensis imperfecta type I is commonly due to a COLIAI null allel of type I collagen

    Energy Technology Data Exchange (ETDEWEB)

    Willing, M.C.; Pruchno, C.J. (Univ. of Iowa, Iowa City, IA (United States)); Atkinson, M.; Byers, P.H. (Univ. of Washington, Seattle, WA (United States))

    1992-09-01

    Dermal fibroblasts from most individuals with osteogenesis imperfecta (OI) type I produce about half the normal amount of type I procollagen, as a result of decreased synthesis of one of its constituent chains, pro[alpha](I). To test the hypothesis that decreased synthesis of pro[alpha](I) chains results from mutations in the COL1A1 gene, the authors used primer extension with nucleotide-specific chain termination to measure the contribution of individual COL1A1 alleles to the mRNA pool in fibroblasts from affected individuals. A polymorphic Mn/I restriction endonuclease site in the 3'-untranslated region of COL1A1 was used to distinguish the transcripts of the two alleles in heterozygous individuals. Twenty-three individuals from 21 unrelated families were studied. In each case there was marked diminution in steady-state mRNA levels from one COL1A2 allele. Loss of an allele through deletion or rearrangement was not the cause of the diminished COL1A1 mRNA levels. Primer extension with nucleotide-specific chain termination allows identification of the mutant COL1A1 allele in cell strains that are heterozygous for an expressed polymorphism. It is applicable to sporadic cases, to small families, and to large families in whom key individuals are uninformative at the polymorphic sites used in linkage analysis, making it a useful adjunct to the biochemical screening of collagenous proteins for OI. 40 refs., 3 figs., 1 tab.

  19. Molecular characterization of glutenin alleles at the Glu-Dl locus

    Directory of Open Access Journals (Sweden)

    Vapa Ljiljana B.

    2003-01-01

    Full Text Available It is well known that the composition of high-molecular-weight (HMW glutenin subunits impacts the bread making quality. The HMW subunits 1Dx5-1Dyl0 are typically associated with high dough strength and good bread making quality contrary to 1Dx2-lDyl2 subunits. Bread wheat cultivars from Institute of Field and Vegetable Crops in Novi Sad have been screened for the alleles present at Glu-Dl locus using traditional SDS PAG electrophoresis method and a new PCR based approach. The Glu-Dl locus was screened for two main x-type alleles which code for HMW glutenins 2 and 5, and two main y-type alleles which code for HMW glutenin subunits 10 and 12. Among the analyzed cultivars 55.6% expressed the presence of 1Dx5 and 1Dy10 alleles at the Glu-Dl locus. These results confirmed that by using marker-assisted selection (MAS it is possible to identify genotypes with alleles for good bread making quality which could be successfully used in wheat breeding programs.

  20. Allelic genealogies in sporophytic self-incompatibility systems in plants

    DEFF Research Database (Denmark)

    Schierup, M H; Vekemans, X; Christiansen, F B

    1998-01-01

    Expectations for the time scale and structure of allelic genealogies in finite populations are formed under three models of sporophytic self-incompatibility. The models differ in the dominance interactions among the alleles that determine the self-incompatibility phenotype: In the SSIcod model...... action, and the most recessive extant allele is likely to be the most recent common ancestor. Despite these asymmetries, the expected shape of the allele genealogies does not deviate markedly from the shape of a neutral gene genealogy. The application of the results to sequence surveys of alleles...

  1. To be or not to be the odd one out - Allele-specific transcription in pentaploid dogroses (Rosa L. sect. Caninae (DC. Ser

    Directory of Open Access Journals (Sweden)

    Theißen Günter

    2011-02-01

    Full Text Available Abstract Background Multiple hybridization events gave rise to pentaploid dogroses which can reproduce sexually despite their uneven ploidy level by the unique canina meiosis. Two homologous chromosome sets are involved in bivalent formation and are transmitted by the haploid pollen grains and the tetraploid egg cells. In addition the egg cells contain three sets of univalent chromosomes which are excluded from recombination. In this study we investigated whether differential behavior of chromosomes as bivalents or univalents is reflected by sequence divergence or transcription intensity between homeologous alleles of two single copy genes (LEAFY, cGAPDH and one ribosomal DNA locus (nrITS. Results We detected a maximum number of four different alleles of all investigated loci in pentaploid dogroses and identified the respective allele with two copies, which is presumably located on bivalent forming chromosomes. For the alleles of the ribosomal DNA locus and cGAPDH only slight, if any, differential transcription was determined, whereas the LEAFY alleles with one copy were found to be significantly stronger expressed than the LEAFY allele with two copies. Moreover, we found for the three marker genes that all alleles have been under similar regimes of purifying selection. Conclusions Analyses of both molecular sequence evolution and expression patterns did not support the hypothesis that unique alleles probably located on non-recombining chromosomes are less functional than duplicate alleles presumably located on recombining chromosomes.

  2. Thyroid Function Test Imbalance in Epileptic Children Under Anticonvulsive Therapy

    Directory of Open Access Journals (Sweden)

    Mohammad TORKAMAN

    2012-03-01

    Full Text Available How to Cite this Article: Ravi Torkaman M, Amirsalari S, Saburi A. Thyroid Function Test Imbalance in Epileptic ChildrenUnder Anticonvulsive Therapy. Iranian Journal of Child Neurology 2012;6(1:43-44. Dear Editor,There have been many studies regarding the impact of antiepileptic drugs(AEDs on thyroid function. There are some challenging scopes which must beconsidered for conducting the study adressing the focused question. “Which oneof the thyroid hormones is related to the AEDs consumption?”. Some studiesdemonstrated that there may be alterations in all thyroid function tests (T3, T4 andTSH after antiepileptic therapy in children (1. Some studies concluded that longtermprescription of anticonvulsive medications resulted in a decline in serum T4levels, although it had no effect on serum TSH levels. However, changes in serumT3 level was challenging and it must be investigated further (2.There were some confounding factors which may interfere with the conclusion.One of them is the type of the study. There are various study plans for this purposesuch as cross-sectional, case-control, experimental, self-controlled cohort anddouble-blind randomized clinical trial studies. It seems that the proper protocol ofstudy for this propose is a double-blind randomized clinical trial study. By usingother designs, the authors cannot interpret the effect of AEDs on thyroid function;however, they can discuss the prevalence of thyroid hormone imbalance and thecoordination among T3, T4 and TSH.Moreover, one of the confounding factors is the thyroid binding globulin (TBGeffect. It has appeared that some of the AEDs may change the amount of TBGand in this way may affect the amount of thyroid hormones (3. Clonazepamand valproic acid do not have any enzyme inducing effects, but phenobarbital,carbamazepine, phenytoin and primidone may induce the hepatic enzyme (4-6. Therefore, it seems necessary to analyze each group of patients based on thetype of drug which is

  3. EMPIRICAL ANALYSIS OF EMPLOYEES WITH TERTIARY EDUCATION OCCUPATIONAL IMBALANCES

    Directory of Open Access Journals (Sweden)

    Andrei B. Ankudinov

    2013-01-01

    Full Text Available High percentage of graduates (among the highest in the world with university degrees combined with unacceptably low level of utilization of acquired qualifications and generally low quality of education in the majority of Russian universities result in huge structural imbalances. The article presents quantitative estimates of disproportions between the educational levels of employees with higher education and their professional occupation for different branches of economy. A logit models based analysis is performed of how much the professional functions performed by employees match their professional qualifications, levels of education and the extent to which their previously acquired expertise and skills are put into use. The sample used represents working population of Russia with tertiary education. The results obtained allow to the conclusion that worst disproportions between education levels attained and job requirements are observed in trade and services sector, transport and communications, housing and utilities, consumer goods and food industries. The matters are compounded by inert and informationally inefficient labor market, incapable of sending proper signals to national system of tertiary education.

  4. Diagnosis of nutrient imbalances with vector analysis in agroforestry systems.

    Science.gov (United States)

    Isaac, Marney E; Kimaro, Anthony A

    2011-01-01

    Agricultural intensification has had unintended environmental consequences, including increased nutrient leaching and surface runoff and other agrarian-derived pollutants. Improved diagnosis of on-farm nutrient dynamics will have the advantage of increasing yields and will diminish financial and environmental costs. To achieve this, a management support system that allows for site-specific rapid evaluation of nutrient production imbalances and subsequent management prescriptions is needed for agroecological design. Vector diagnosis, a bivariate model to depict changes in yield and nutritional response simultaneously in a single graph, facilitates identification of nutritional status such as growth dilution, deficiency, sufficiency, luxury uptake, and toxicity. Quantitative data from cocoa agroforestry systems and pigeonpea intercropping trials in Ghana and Tanzania, respectively, were re-evaluated with vector analysis. Relative to monoculture, biomass increase in cocoa ( L.) under shade (35-80%) was accompanied by a 17 to 25% decline in P concentration, the most limiting nutrient on this site. Similarly, increasing biomass with declining P concentrations was noted for pigeonpea [ (L). Millsp.] in response to soil moisture availability under intercropping. Although vector analysis depicted nutrient responses, the current vector model does not consider non-nutrient resource effects on growth, such as ameliorated light and soil moisture, which were particularly active in these systems. We revisit and develop vector analysis into a framework for diagnosing nutrient and non-nutrient interactions in agroforestry systems. Such a diagnostic technique advances management decision-making by increasing nutrient precision and reducing environmental issues associated with agrarian-derived soil contamination.

  5. Changes in global net radiative imbalance 1985–2012

    Science.gov (United States)

    Allan, Richard P; Liu, Chunlei; Loeb, Norman G; Palmer, Matthew D; Roberts, Malcolm; Smith, Doug; Vidale, Pier-Luigi

    2014-01-01

    Combining satellite data, atmospheric reanalyses, and climate model simulations, variability in the net downward radiative flux imbalance at the top of Earth's atmosphere (N) is reconstructed and linked to recent climate change. Over the 1985–1999 period mean N (0.34 ± 0.67 Wm−2) is lower than for the 2000–2012 period (0.62 ± 0.43 Wm−2, uncertainties at 90% confidence level) despite the slower rate of surface temperature rise since 2000. While the precise magnitude of N remains uncertain, the reconstruction captures interannual variability which is dominated by the eruption of Mount Pinatubo in 1991 and the El Niño Southern Oscillation. Monthly deseasonalized interannual variability in N generated by an ensemble of nine climate model simulations using prescribed sea surface temperature and radiative forcings and from the satellite-based reconstruction is significantly correlated (r∼0.6) over the 1985–2012 period. PMID:25821270

  6. Does observation of postural imbalance induce a postural reaction?

    Directory of Open Access Journals (Sweden)

    Banty Tia

    Full Text Available BACKGROUND: Several studies bring evidence that action observation elicits contagious responses during social interactions. However automatic imitative tendencies are generally inhibited and it remains unclear in which conditions mere action observation triggers motor behaviours. In this study, we addressed the question of contagious postural responses when observing human imbalance. METHODOLOGY/PRINCIPAL FINDINGS: We recorded participants' body sway while they observed a fixation cross (control condition, an upright point-light display of a gymnast balancing on a rope, and the same point-light display presented upside down. Our results showed that, when the upright stimulus was displayed prior to the inverted one, centre of pressure area and antero-posterior path length were significantly greater in the upright condition compared to the control and upside down conditions. CONCLUSIONS/SIGNIFICANCE: These results demonstrate a contagious postural reaction suggesting a partial inefficiency of inhibitory processes. Further, kinematic information was sufficient to trigger this reaction. The difference recorded between the upright and upside down conditions indicates that the contagion effect was dependent on the integration of gravity constraints by body kinematics. Interestingly, the postural response was sensitive to habituation, and seemed to disappear when the observer was previously shown an inverted display. The motor contagion recorded here is consistent with previous work showing vegetative output during observation of an effortful movement and could indicate that lower level control facilitates contagion effects.

  7. Reduced levels of brain-derived neurotrophic factor contribute to synaptic imbalance during the critical period of respiratory development in rats.

    Science.gov (United States)

    Gao, Xiu-Ping; Liu, Qiuli; Nair, Bindu; Wong-Riley, Margaret T T

    2014-07-01

    Previously, our electrophysiological studies revealed a transient imbalance between suppressed excitation and enhanced inhibition in hypoglossal motoneurons of rats on postnatal days (P) 12-13, a critical period when abrupt neurochemical, metabolic, ventilatory and physiological changes occur in the respiratory system. The mechanism underlying the imbalance is poorly understood. We hypothesised that the imbalance was contributed by a reduced expression of brain-derived neurotrophic factor (BDNF), which normally enhances excitation and suppresses inhibition. We also hypothesised that exogenous BDNF would partially reverse this synaptic imbalance. Immunohistochemistry/single-neuron optical densitometry, real-time quantitative PCR (RT-qPCR) and whole-cell patch-clamp recordings were done on hypoglossal motoneurons in brainstem slices of rats during the first three postnatal weeks. Our results indicated that: (1) the levels of BDNF and its high-affinity tyrosine receptor kinase B (TrkB) receptor mRNAs and proteins were relatively high during the first 1-1.5 postnatal weeks, but dropped precipitously at P12-13 before rising again afterwards; (2) exogenous BDNF significantly increased the normally lowered frequency of spontaneous excitatory postsynaptic currents but decreased the normally heightened amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) during the critical period; (3) exogenous BDNF also decreased the normally heightened frequency of miniature IPSCs at P12-13; and (4) the effect of exogenous BDNF was partially blocked by K252a, a TrkB receptor antagonist. Thus, our results are consistent with our hypothesis that BDNF and TrkB play an important role in the synaptic imbalance during the critical period. This may have significant implications for the mechanism underlying sudden infant death syndrome.

  8. Dynamics of a lipid and metabolic imbalance on the background of a complex programs of rehabilitation at metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Kotenko К.V.

    2013-12-01

    Full Text Available The study aimed the development and assessment of features of corrective action of a medical complex on a lipid imbalance at patients with obesity. Material and methods. For an assessment of features of corrective action of a medical complex on a lipid imbalance at patients with obesity in research I was 50 male patients with obesity and frustration of the reproductive sphere aged from 24 to 68 years were included, middle age was 38,5±6,1 years and 7 healthy persons, men of comparable age without any pathological states, results of which all researches were accepted to values of norm. To all patients included in research, except all-clinical inspection calculation of an index of body weight and the relation of a circle of a waist to a circle of hips, measurement of arterial pressure were applied questioning concerning food and food behavior, anthropometry (growth the body weight, a circle of a waist and hips. Besides all patients conducted laboratory methods the researches including definition of atherogenic fractions of lipids (the general cholesterol, triglycerides, LPNPand LPVP. Researches were conducted before treatment and after a course of treatment. Results. The effective complex program for restoration of reproductive function at patients with obesity is developed. Conclusion. Application of the developed comprehensive program more than its separate components caused the expressed reduction of body weight, mainly due to reduction of fatty tissue and manifestations of visceral obesity in patients with obesity and violation of reproductive function, including due to elimination of metabolic imbalance.

  9. Plasminogen alleles influence susceptibility to invasive aspergillosis.

    Directory of Open Access Journals (Sweden)

    Aimee K Zaas

    2008-06-01

    Full Text Available Invasive aspergillosis (IA is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855 correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn was also identified in the human homolog (PLG; Gene ID 5340. An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection.

  10. Short communication: the beta-casein (CSN2) silent allele C1 is highly spread in goat breeds.

    Science.gov (United States)

    Chessa, S; Rignanese, D; Küpper, J; Pagnacco, G; Erhardt, G; Caroli, A

    2008-11-01

    Several single nucleotide polymorphisms have been identified in the goat milk casein genes, most of them modifying the amino acid sequence of the coded protein. At least 9 variants have been found in goat beta-CN (CSN2); 6 of them were characterized at the DNA level (A, A1, C, E, 0, and 0'), whereas the other 3 variants were described only at the protein level. The recently identified silent A1 allele is characterized by a C-->T transition at the 180th nucleotide of the ninth exon. In the present work, typing results from different breeds (3 Italian, 3 German, and a composite of African breeds for a total of 335 samples) demonstrated that the same mutation is carried by the CSN2*C allele. In addition, the T nucleotide at the 180th nucleotide of the ninth exon was always associated with CSN2*C in all the breeds analyzed. Thus, another silent allele occurs at goat CSN2 and can be named CSN2*C1. The much wider distribution of C1 with respect to the A1 allele indicates that the single nucleotide polymorphisms characterizing the silent mutation originated from CSN2*C. A method for the identification of this allele simultaneously with 5 of the 6 DNA-characterized alleles is also proposed. The mutation involved codifies for the same protein of the C allele; nevertheless, its location in the 3' untranslated region of the gene might affect the specific casein expression.

  11. Imbalance of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1 may contribute to hemorrhage in cerebellar arteriovenous malformations

    Institute of Scientific and Technical Information of China (English)

    Fei Di; Tongyan Chen; Hongli Li; Jizong Zhao; Shuo Wang; Yuanli Zhao; Dong Zhang

    2012-01-01

    In this study,we determined the expression levels of matrix metalloproteinase-2 and -9 and matrix metalloproteinase tissue inhibitor-1 and -2 in brain tissues and blood plasma of patients undergoing surgery for cerebellar arteriovenous malformations or primary epilepsy (control group).Immunohistochemistry and enzyme-linked immunosorbent assay revealed that the expression of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1 was significantly higher in patients with cerebellar arteriovenous malformations than in patients with primary epilepsy.The ratio of matrix metalloproteinase-9 to matrix metalloproteinase tissue inhibitor-1 was significantly higher in patients with hemorrhagic cerebellar arteriovenous malformations compared with those with non-hemorrhagic malformations.Matrix metalloproteinase-2 and matrix metalloproteinase tissue inhibitor-2 levels were not significantly changed.These findings indicate that an imbalance of matrix metalloproteinase-9 and matrix metalloproteinase tissue inhibitor-1,resulting in a relative overabundance of matrix metalloproteinase-9,might be the underlying mechanism of hemorrhage of cerebellar arteriovenous malformations.

  12. An importance of the muscular imbalance in the context of functional disorders of the spine

    OpenAIRE

    JOZOVÁ, Kateřina

    2010-01-01

    ABSTRACT A topic of my thesis is an importance of the muscular imbalance in the context of functional disorders of the spine. The topic has been very up-to-date, because a large proportion of the population suffers from vertebral disorders of functional nature, which are just caused by muscular imbalances. A goal of the first part of the thesis was a theoretic analysis of the problem of muscular imbalances and functional disorders of the spine. A content of that chapter is an introduction to ...

  13. A new strategy to reduce allelic bias in RNA-Seq readmapping

    Science.gov (United States)

    Vijaya Satya, Ravi; Zavaljevski, Nela; Reifman, Jaques

    2012-01-01

    Accurate estimation of expression levels from RNA-Seq data entails precise mapping of the sequence reads to a reference genome. Because the standard reference genome contains only one allele at any given locus, reads overlapping polymorphic loci that carry a non-reference allele are at least one mismatch away from the reference and, hence, are less likely to be mapped. This bias in read mapping leads to inaccurate estimates of allele-specific expression (ASE). To address this read-mapping bias, we propose the construction of an enhanced reference genome that includes the alternative alleles at known polymorphic loci. We show that mapping to this enhanced reference reduced the read-mapping biases, leading to more reliable estimates of ASE. Experiments on simulated data show that the proposed strategy reduced the number of loci with mapping bias by ≥63% when compared with a previous approach that relies on masking the polymorphic loci and by ≥18% when compared with the standard approach that uses an unaltered reference. When we applied our strategy to actual RNA-Seq data, we found that it mapped up to 15% more reads than the previous approaches and identified many seemingly incorrect inferences made by them. PMID:22584625

  14. Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia.

    Science.gov (United States)

    Abeti, Rosella; Uzun, Ebru; Renganathan, Indhushri; Honda, Tadashi; Pook, Mark A; Giunti, Paola

    2015-09-01

    Friedreich's ataxia (FRDA) is an autosomal recessive disorder, caused by reduced levels of the protein frataxin. This protein is located in the mitochondria, where it functions in the biogenesis of iron-sulphur clusters (ISCs), which are important for the function of the mitochondrial respiratory chain complexes. Moreover, disruption in iron biogenesis may lead to oxidative stress. Oxidative stress can be the cause and/or the consequence of mitochondrial energy imbalance, leading to cell death. Fibroblasts from two FRDA mouse models, YG8R and KIKO, were used to analyse two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers. The former have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger the well-known Nrf2 antioxidant pathway. Our results show that the sensitivity to oxidative stress of YG8R and KIKO mouse fibroblasts, resulting in cell death and lipid peroxidation, can be prevented by d4-PUFA and Nrf2-inducers (SFN and TBE-31). The mitochondrial membrane potential (ΔΨm) of YG8R and KIKO fibroblasts revealed a difference in their mitochondrial pathophysiology, which may be due to the different genetic basis of the two models. This suggests that variable levels of reduced frataxin may act differently on mitochondrial pathophysiology and that these two cell models could be useful in recapitulating the observed differences in the FRDA phenotype. This may reflect a different modulatory effect towards cell death that will need to be investigated further.

  15. Assessment of Infantile Mineral Imbalances in Autism Spectrum Disorders (ASDs

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    Toyoharu Tsutsui

    2013-11-01

    Full Text Available The interactions between genes and the environment are now regarded as the most probable explanation for autism. In this review, we summarize the results of a metallomics study in which scalp hair concentrations of 26 trace elements were examined for 1,967 autistic children (1,553 males and 414 females aged 0–15 years-old, and discuss recent advances in our understanding of epigenetic roles of infantile mineral imbalances in the pathogenesis of autism. In the 1,967 subjects, 584 (29.7% and 347 (17.6% were found deficient in zinc and magnesium, respectively, and the incidence rate of zinc deficiency was estimated at 43.5% in male and 52.5% in female infantile subjects aged 0–3 years-old. In contrast, 339 (17.2%, 168 (8.5% and 94 (4.8% individuals were found to suffer from high burdens of aluminum, cadmium and lead, respectively, and 2.8% or less from mercury and arsenic. High toxic metal burdens were more frequently observed in the infants aged 0–3 years-old, whose incidence rates were 20.6%, 12.1%, 7.5%, 3.2% and 2.3% for aluminum, cadmium, lead, arsenic and mercury, respectively. These findings suggest that infantile zinc- and magnesium-deficiency and/or toxic metal burdens may be critical and induce epigenetic alterations in the genes and genetic regulation mechanisms of neurodevelopment in the autistic children, and demonstrate that a time factor “infantile window” is also critical for neurodevelopment and probably for therapy. Thus, early metallomics analysis may lead to early screening/estimation and treatment/prevention for the autistic neurodevelopment disorders.

  16. Association of sympathovagal imbalance with cardiovascular risks in overt hypothyroidism

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    Avupati Naga Syamsunder

    2013-01-01

    Full Text Available Background: Cardiovascular morbidities have been reported in hypothyroidism. Aims: The objective of this study is to investigate the link of sympathovagal imbalance (SVI to cardiovascular risks (CVRs and the plausible mechanisms of CVR in hypothyroidism. Materials and Methods: Age-matched 104 females (50 controls, 54 hypothyroids were recruited and their body mass index (BMI, cardiovascular parameters, autonomic function tests by spectral analysis of heart rate variability (HRV, heart rate response to standing, deep breathing and blood pressure response to isometric handgrip were studied. Thyroid profile, lipid profile, immunological and inflammatory markers were estimated and their association with low-frequency to the high-frequency ratio (LF-HF of HRV, the marker of SVI was assessed by multivariate regression. Results: Increased diastolic pressure, decreased HRV, increased LF-HF, dyslipidemia and increased high-sensitive C-reactive protein (hsCRP were observed in hypothyroid patients and all these parameters had significant correlation with LF-HF. BMI had no significant association with LF-HF. Atherogenic index (β 1.144, P = 0.001 and hsCRP (b 0.578, P = 0.009 had independent contribution to LF-HF. LF-HF could significantly predict hypertension status (odds ratio 2.05, confidence interval 1.110-5.352, P = 0.008 in hypothyroid subjects. Conclusions: SVI due to sympathetic activation and vagal withdrawal occurs in hypothyroidism. Dyslipidemia and low-grade inflammation, but not obesity contribute to SVI and SVI contributes to cardiovascular risks.

  17. Power Imbalances, Food Insecurity, and Children's Rights in Canada.

    Science.gov (United States)

    Blay-Palmer, Alison

    2016-01-01

    Increasingly, food is provided through an industrial food system that separates people from the source of their food and results in high rates of food insecurity, particularly for the most vulnerable in society. A lack of food is a symptom of a lack of power in a system that privileges free market principles over social justice and the protection of human rights. In Canada, the high rates of food insecurity among Canadian children is a reflection of their lack of power and the disregard of their human rights, despite the adoption of the United Nations (UN) Convention on the Rights of the Child in 1991 and ratification of the International Covenant on Social, Economic and Cultural Rights in 1976, which established the right to food for all Canadians. Dueling tensions between human rights and market forces underpin this unacceptable state of affairs in Canada. Gaventa's "power cube" that describes different facets of power - including spaces, levels, and forms - is used to help understand the power imbalances that underlie this injustice. The analysis considers the impact of neoliberal free market principles on the realization of human rights, and the negative impacts this can have on health and well-being for the most vulnerable in society. Canadian case studies from both community organizations provide examples of how power can be shifted to achieve more inclusive, rights-based policy and action. Given increased global pressures toward more open trade markets and national austerity measures that hollow out social supports, Canada provides a cautionary tale for countries in the EU and the US, and for overall approaches to protect the most vulnerable in society.

  18. Carbon and nutrient use efficiencies optimally balance stoichiometric imbalances

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    Manzoni, Stefano; Čapek, Petr; Lindahl, Björn; Mooshammer, Maria; Richter, Andreas; Šantrůčková, Hana

    2016-04-01

    Decomposer organisms face large stoichiometric imbalances because their food is generally poor in nutrients compared to the decomposer cellular composition. The presence of excess carbon (C) requires adaptations to utilize nutrients effectively while disposing of or investing excess C. As food composition changes, these adaptations lead to variable C- and nutrient-use efficiencies (defined as the ratios of C and nutrients used for growth over the amounts consumed). For organisms to be ecologically competitive, these changes in efficiencies with resource stoichiometry have to balance advantages and disadvantages in an optimal way. We hypothesize that efficiencies are varied so that community growth rate is optimized along stoichiometric gradients of their resources. Building from previous theories, we predict that maximum growth is achieved when C and nutrients are co-limiting, so that the maximum C-use efficiency is reached, and nutrient release is minimized. This optimality principle is expected to be applicable across terrestrial-aquatic borders, to various elements, and at different trophic levels. While the growth rate maximization hypothesis has been evaluated for consumers and predators, in this contribution we test it for terrestrial and aquatic decomposers degrading resources across wide stoichiometry gradients. The optimality hypothesis predicts constant efficiencies at low substrate C:N and C:P, whereas above a stoichiometric threshold, C-use efficiency declines and nitrogen- and phosphorus-use efficiencies increase up to one. Thus, high resource C:N and C:P lead to low C-use efficiency, but effective retention of nitrogen and phosphorus. Predictions are broadly consistent with efficiency trends in decomposer communities across terrestrial and aquatic ecosystems.

  19. MASTR: A Technique for Mosaic Mutant Analysis with Spatial and Temporal Control of Recombination Using Conditional Floxed Alleles in Mice

    Directory of Open Access Journals (Sweden)

    Zhimin Lao

    2012-08-01

    Full Text Available Mosaic mutant analysis, the study of cellular defects in scattered mutant cells in a wild-type environment, is a powerful approach for identifying critical functions of genes and has been applied extensively to invertebrate model organisms. A highly versatile technique has been developed in mouse: MASTR (mosaic mutant analysis with spatial and temporal control of recombination, which utilizes the increasing number of floxed alleles and simultaneously combines conditional gene mutagenesis and cell marking for fate analysis. A targeted allele (R26MASTR was engineered; the allele expresses a GFPcre fusion protein following FLP-mediated recombination, which serves the dual function of deleting floxed alleles and marking mutant cells with GFP. Within 24 hr of tamoxifen administration to R26MASTR mice carrying an inducible FlpoER transgene and a floxed allele, nearly all GFP-expressing cells have a mutant allele. The fate of single cells lacking FGF8 or SHH signaling in the developing hindbrain was analyzed using MASTR, and it was revealed that there is only a short time window when neural progenitors require FGFR1 for viability and that granule cell precursors differentiate rapidly when SMO is lost. MASTR is a powerful tool that provides cell-type-specific (spatial and temporal marking of mosaic mutant cells and is broadly applicable to developmental, cancer, and adult stem cell studies.

  20. Molecular identification of rare FY*Null and FY*X alleles in Caucasian thalassemic family from Sardinia.

    Science.gov (United States)

    Manfroi, Silvia; Scarcello, Antonio; Pagliaro, Pasqualepaolo

    2015-10-01

    Molecular genetic studies on Duffy blood group antigens have identified mutations underlying rare FY*Null and FY*X alleles. FY*Null has a high frequency in Blacks, especially from sub-Saharan Africa, while its frequency is not defined in Caucasians. FY*X allele, associated with Fy(a-b+w) phenotype, has a frequency of 2-3.5% in Caucasian people while it is absent in Blacks. During the project of extensive blood group genotyping in patients affected by hemoglobinopathies, we identified FY*X/FY*Null and FY*A/FY*Null genotypes in a Caucasian thalassemic family from Sardinia. We speculate on the frequency of FY*X and FY*Null alleles in Caucasian and Black people; further, we focused on the association of FY*X allele with weak Fyb antigen expression on red blood cells and its identification performing high sensitivity serological typing methods or genotyping.

  1. Integrative Quantitative Proteomics Unveils Proteostasis Imbalance in Human Hepatocellular Carcinoma Developed on Nonfibrotic Livers*

    Science.gov (United States)

    Negroni, Luc; Taouji, Said; Arma, Daniela; Pallares-Lupon, Nestor; Leong, Kristen; Beausang, Lee Anne; Latterich, Martin; Bossé, Roger; Balabaud, Charles; Schmitter, Jean-Marie; Bioulac-Sage, Paulette; Zucman-Rossi, Jessica; Rosenbaum, Jean; Chevet, Eric

    2014-01-01

    Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen®, and AMMP®) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253. PMID:25225353

  2. Integrative quantitative proteomics unveils proteostasis imbalance in human hepatocellular carcinoma developed on nonfibrotic livers.

    Science.gov (United States)

    Negroni, Luc; Taouji, Said; Arma, Daniela; Pallares-Lupon, Nestor; Leong, Kristen; Beausang, Lee Anne; Latterich, Martin; Bossé, Roger; Balabaud, Charles; Schmitter, Jean-Marie; Bioulac-Sage, Paulette; Zucman-Rossi, Jessica; Rosenbaum, Jean; Chevet, Eric

    2014-12-01

    Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen(®), and AMMP(®)) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253.

  3. Correlation between endothelia cells activation and imbalance of cytokines in pulmonary hypertension of congenital heart disease

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twenty patients with simple ventricular septal defect (VSD) were chosen as controls, and 30 patients with PH were studied. Plasma levels of ET-1 and NO were measured by radioimmunoassay or colorimetric method. Before cardiopulmonary bypass was established, the specimens from right lung were fixed with formaldehyde solution, embedded with paraffin and stained by SP immunohistochemistry. Intercellular adhesion molecule-1 (ICAM-1) expression was measured through the determination of the light density with computer imaging technology. Results Compared with that of the patients with simple VSD, the light density of ICAM-1 and plasma level of ET-1 increased in patients with PH; but plasma level of NO decreased (P<0.05). Positive correlation was observed between ICAM-1 and ET-1/NO (P<0.05). Conclusion Endothelia cells activation and imbalance of ET-1/NO might play an important role in the development of PH.

  4. Improving classification of mature microRNA by solving class imbalance problem

    Science.gov (United States)

    Wang, Ying; Li, Xiaoye; Tao, Bairui

    2016-05-01

    MicroRNAs (miRNAs) are ~20–25 nucleotides non-coding RNAs, which regulated gene expression in the post-transcriptional level. The accurate rate of identifying the start sit of mature miRNA from a given pre-miRNA remains lower. It is noting that the mature miRNA prediction is a class-imbalanced problem which also leads to the unsatisfactory performance of these methods. We improved the prediction accuracy of classifier using balanced datasets and presented MatFind which is used for identifying 5‧ mature miRNAs candidates from their pre-miRNA based on ensemble SVM classifiers with idea of adaboost. Firstly, the balanced-dataset was extract based on K-nearest neighbor algorithm. Secondly, the multiple SVM classifiers were trained in orderly using the balance datasets base on represented features. At last, all SVM classifiers were combined together to form the ensemble classifier. Our results on independent testing dataset show that the proposed method is more efficient than one without treating class imbalance problem. Moreover, MatFind achieves much higher classification accuracy than other three approaches. The ensemble SVM classifiers and balanced-datasets can solve the class-imbalanced problem, as well as improve performance of classifier for mature miRNA identification. MatFind is an accurate and fast method for 5‧ mature miRNA identification.

  5. [Different aspects of the cognitive activities of patients with schizophrenia. IV. Imbalance between assertions and negations].

    Science.gov (United States)

    Blein, G; Azorin, J M; Dufour, H; Tissot, R

    1990-12-01

    Not being able to equilibrate affirmations and negations, the schizophrenic patient accedes only exceptionally to the majoring equilibrations of the second and third levels. In the logico-mathematic field, he does not approach the constructive synthetizing generalisations of reasoning. Lacking reflective abstraction, he cannot balance his logico-mathematic reasoning and differentiate what is structurally possible from what is materially possible, thus explaining his inaccessibility to perceive logic necessities, contrasting with the certainties of his delirium. In the logico-experimental domain, he reaches only rarely clause reasoning generalisation, and relapses regularly to the level of inappropriate generalisations of the extended inductive type. It is useless to try to find the "primum movens" of his difficulties, either in his imbalance assimilation/accommodation, or in his impossibility to see his contradictions, or even in his incapacity to equilibrate affirmations and negations. The majoring equilibrations, of which he is unable, are the functional expression of structures which do not follow the linear causality of Laplace's determinism but the circular causality characteristic of teleonomic processes. After a month of neuroleptic treatment, the decompensated schizophrenic's balance between assimilation and accommodation is partially restored.

  6. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    Directory of Open Access Journals (Sweden)

    Jung Yoon Park

    Full Text Available Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W, display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  7. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    Science.gov (United States)

    Park, Jung Yoon; Cho, Mi-Ook; Leonard, Shanique; Calder, Brent; Mian, I Saira; Kim, Woo Ho; Wijnhoven, Susan; van Steeg, Harry; Mitchell, James; van der Horst, Gijsbertus T J; Hoeijmakers, Jan; Cohen, Pinchas; Vijg, Jan; Suh, Yousin

    2008-06-11

    Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD) mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD) mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD) mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD) mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  8. Imbalance of Th17/Treg in Different Subtypes of Autoimmune Thyroid Diseases

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    Cui Li

    2016-11-01

    Full Text Available Aims: To clarify the imbalance of Th17/Treg in different subtypes of autoimmune thyroid diseases (AITDs including Graves' disease(GD, Hashimoto's thyroiditis(HT and Graves' ophthalmopathy (GO. Methods: 47 patients with AITD (including 16 GD, 15 HT, and 16 GO and 12 healthy controls were enrolled in this study. The percentages of Th17 and Treg cells, the ratio of Th17/Treg, as well as their related transcription factors RORγt and Foxp3 mRNA in peripheral blood mononuclear cells (PBMCs were measured by flow cytometry and real-time quantitative PCR Results: Compared with those in control group, the percentage of CD4+IL-17+T cell(Th17 and the mRNA expression of its transcription factor RORγt were higher in PBMCs of AITDs (P+Foxp3+T (Treg cells and its transcription factor Foxp3 mRNA were significantly decreased in PBMCs of GD (PConclusion: Increased Th17 lymphocytes may play a more important role in the pathogenesis of HT and GO while decreased Treg may be greatly involved in GD.

  9. Cytokine Imbalance as a Common Mechanism in Both Psoriasis and Rheumatoid Arthritis

    Science.gov (United States)

    Tan, Yong; Qi, Qiu; Bai, Yanping; Jiang, Chunyan; Wang, Yang

    2017-01-01

    Psoriasis (PS) and rheumatoid arthritis (RA) are immune-mediated inflammatory diseases. Previous studies showed that these two diseases had a common pathogenesis, but the precise molecular mechanism remains unclear. In this study, RNA sequencing of peripheral blood mononuclear cells was employed to explore both the differentially expressed genes (DEGs) of 10 PS and 10 RA patients compared with those of 10 healthy volunteers and the shared DEGs between these two diseases. Bioinformatics network analysis was used to reveal the connections among the shared DEGs and the corresponding molecular mechanism. In total, 120 and 212 DEGs were identified in PS and RA, respectively, and 31 shared DEGs were identified. Bioinformatics analysis indicated that the cytokine imbalance relevant to key molecules (such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), colony-stimulating factor 3 (CSF3), interleukin- (IL-) 6, and interferon gene (IFNG)) and canonical signaling pathways (such as the complement system, antigen presentation, macropinocytosis signaling, nuclear factor-kappa B (NF-κB) signaling, and IL-17 signaling) was responsible for the common comprehensive mechanism of PS and RA. Our findings provide a better understanding of the pathogenesis of PS and RA, suggesting potential strategies for treating and preventing both diseases. This study may also provide a new paradigm for illuminating the common pathogenesis of different diseases.

  10. Imbalance of Th17/Tregs in rats with smoke inhalation-induced acute lung injury

    Science.gov (United States)

    Zhang, Fan; Li, Mian-yang; Lan, Ya-ting; Wang, Cheng-bin

    2016-01-01

    T helper (Th) 17 cells and CD4+ CD25+ regulatory T (Treg) cells are supposed to be critically involved in regulating autoimmune and inflammatory diseases. The aim of this study was to investigate the Th17/Treg pattern in rats with gunpowder smog-induced acute lung injury. Wistar rats were equally randomized to three groups: normal control group, ALI 6 h group (smoke inhalation for 6 h) and ALI 24 h group (smoke inhalation for 24 h). We observed changes in cell counting in bronchoalveolar lavage fluid (BALF), alveolar-capillary membrane permeability and lung tissue pathology. Moreover, rats in ALI 6 h and ALI 24 h group showed increased expression of Th17 cell and related cytokines (IL-17 A, IL-6, TGF-β and IL-23). Meanwhile, Treg prevalence and related cytokines (IL-10, IL-2 and IL-35) were decreased. Consequently, the ratio of Th17/Treg was higher after smoke inhalation. Additionally, Th1 cell decreased while Th2 cell increased at 6 h and 24 h after smoke inhalation. In conclusion, Th17/Treg imbalance exists in rats with smoke inhalation-induced acute lung injury, suggesting its potential role in the pathogenesis of this disease. PMID:26884314

  11. Composition and functional analysis of low-molecular-weight glutenin alleles with Aroona near-isogenic lines of bread wheat

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    Zhang Xiaofei

    2012-12-01

    Full Text Available Abstract Background Low-molecular-weight glutenin subunits (LMW-GS strongly influence the bread-making quality of bread wheat. These proteins are encoded by a multi-gene family located at the Glu-A3, Glu-B3 and Glu-D3 loci on the short arms of homoeologous group 1 chromosomes, and show high allelic variation. To characterize the genetic and protein compositions of LMW-GS alleles, we investigated 16 Aroona near-isogenic lines (NILs using SDS-PAGE, 2D-PAGE and the LMW-GS gene marker system. Moreover, the composition of glutenin macro-polymers, dough properties and pan bread quality parameters were determined for functional analysis of LMW-GS alleles in the NILs. Results Using the LMW-GS gene marker system, 14–20 LMW-GS genes were identified in individual NILs. At the Glu-A3 locus, two m-type and 2–4 i-type genes were identified and their allelic variants showed high polymorphisms in length and nucleotide sequences. The Glu-A3d allele possessed three active genes, the highest number among Glu-A3 alleles. At the Glu-B3 locus, 2–3 m-type and 1–3 s-type genes were identified from individual NILs. Based on the different compositions of s-type genes, Glu-B3 alleles were divided into two groups, one containing Glu-B3a, B3b, B3f and B3g, and the other comprising Glu-B3c, B3d, B3h and B3i. Eight conserved genes were identified among Glu-D3 alleles, except for Glu-D3f. The protein products of the unique active genes in each NIL were detected using protein electrophoresis. Among Glu-3 alleles, the Glu-A3e genotype without i-type LMW-GS performed worst in almost all quality properties. Glu-B3b, B3g and B3i showed better quality parameters than the other Glu-B3 alleles, whereas the Glu-B3c allele containing s-type genes with low expression levels had an inferior effect on bread-making quality. Due to the conserved genes at Glu-D3 locus, Glu-D3 alleles showed no significant differences in effects on all quality parameters. Conclusions This work

  12. Allele-specific PCR detection of sweet cherry self-incompatibility (S) alleles S1 to S16 using consensus and allele-specific primers.

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    Sonneveld, T; Tobutt, K R; Robbins, T P

    2003-10-01

    PCR-based identification of all 13 known self-incompatibility (S) alleles of sweet cherry is reported. Two pairs of consensus primers were designed from our previously published cDNA sequences of S(1) to S(6) S-RNases, the stylar components of self-incompatibility, to reveal length variation of the first and the second introns. With the exception of the first intron of S(13), these also amplified S(7) to S(14) and an allele previously referred to as S(x), which we now label S(16). The genomic PCR products were cloned and sequenced. The partial sequence of S(11) matched that of S(7) and the alleles were shown to have the same functional specificity. Allele-specific primers were designed for S(7) to S(16), so that allele-specific primers are now available for all 13 S alleles of cherry (S(8), S(11) and S(15) are duplicates). These can be used to distinguish between S alleles with introns of similar size and to confirm genotypes determined with consensus primers. The reliability of the PCR with allele-specific primers was improved by the inclusion of an internal control. The use of the consensus and allele-specific primers was demonstrated by resolving conflicting genotypes that have been published recently and by determining genotypes of 18 new cherry cultivars. Two new groups are proposed, Group XXIII (S(3) S(16)), comprising 'Rodmersham Seedling' and 'Strawberry Heart', and Group XXIV (S(6) S(12)), comprising 'Aida' and 'Flamentiner'. Four new self-compatibility genotypes, S(3) S(3)', S(4)' S(6), S(4)' S(9) and S(4)' S(13), were found. The potential use of the consensus primers to reveal incompatibility alleles in other cherry species is also demonstrated.

  13. Apolipoprotein E modulates Alzheimer's Abeta(1-42)-induced oxidative damage to synaptosomes in an allele-specific manner.

    Science.gov (United States)

    Lauderback, Christopher M; Kanski, Jaroslaw; Hackett, Janna M; Maeda, Noboyo; Kindy, Mark S; Butterfield, D Allan

    2002-01-01

    Several functional differences have been reported among the three human e2, e3, and e4 alleles of apolipoprotein E (apoE). One functional difference lies in the antioxidant potential of these alleles; e4 has the poorest potential. Interestingly, e4 also correlates with increased oxidative damage in the Alzheimer's disease (AD) brain, which may explain why the inheritance of the e4 allele is a risk factor for the onset of AD. Beta-amyloid (Abeta) is also intimately involved in AD and promotes oxidative damage in vitro; therefore, we have examined the role of the different apoE alleles in modulating Abeta(1-42)-induced oxidation to synaptosomes. Measurement of specific markers of oxidation in synaptosomes isolated from mice that express one of the human apoE alleles indicates that Abeta-induced increases of these markers can be modulated by apoE in an allele-dependent manner (e2>e3>e4). Increases in reactive oxygen species formation and protein and lipid oxidation were always greatest in e4 synaptosomes as compared to e2 and e3 synaptosomes. Our data support the role of apoE as a modulator of Abeta toxicity and, consistent with the antioxidant potentials of the three alleles, suggest that the e4 allele may not be as effective in this role as the e2 or e3 alleles of apoE. These results are discussed with reference to mechanistic implications for neurodegeneration in the AD brain.

  14. Imbalances in serum angiopoietin concentrations are early predictors of septic shock development in patients with post chemotherapy febrile neutropenia

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    Lorand-Metze Irene

    2010-05-01

    Full Text Available Abstract Background Febrile neutropenia carries a high risk of sepsis complications, and the identification of biomarkers capable to identify high risk patients is a great challenge. Angiopoietins (Ang - are cytokines involved in the control microvascular permeability. It is accepted that Ang-1 expression maintains endothelial barrier integrity, and that Ang-2 acts as an antagonizing cytokine with barrier-disrupting functions in inflammatory situations. Ang-2 levels have been recently correlated with sepsis mortality in intensive care units. Methods We prospectively evaluated concentrations of Ang-1 and Ang-2 at different time-points during febrile neutropenia, and explored the diagnostic accuracy of these mediators as potential predictors of poor outcome in this clinical setting before the development of sepsis complications. Results Patients that evolved with septic shock (n = 10 presented higher levels of Ang-2 measured 48 hours after fever onset, and of the Ang-2/Ang-1 ratio at the time of fever onset compared to patients with non-complicated sepsis (n = 31. These levels correlated with sepsis severity scores. Conclusions Our data suggest that imbalances in the concentrations of Ang-1 and Ang-2 are independent and early markers of the risk of developing septic shock and of sepsis mortality in febrile neutropenia, and larger studies are warranted to validate their clinical usefulness. Therapeutic strategies that manipulate this Ang-2/Ang-1 imbalance can potentially offer new and promising treatments for sepsis in febrile neutropenia.

  15. Rare exonic minisatellite alleles in MUC2 influence susceptibility to gastric carcinoma.

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    Yun Hee Jeong

    Full Text Available BACKGROUND: Mucins are the major components of mucus and their genes share a common, centrally-located region of sequence that encodes tandem repeats. Mucins are well known genes with respect to their specific expression levels; however, their genomic levels are unclear because of complex genomic properties. In this study, we identified eight novel minisatellites from the entire MUC2 region and investigated how allelic variation in these minisatellites may affect susceptibility to gastrointestinal cancer. METHODOLOGY/PRINCIPLE FINDINGS: We analyzed genomic DNA from the blood of normal healthy individuals and multi-generational family groups. Six of the eight minisatellites exhibited polymorphism and were transmitted meiotically in seven families, following Mendelian inheritance. Furthermore, a case-control study was performed that compared genomic DNA from 457 cancer-free controls with DNA from individuals with gastric (455, colon (192 and rectal (271 cancers. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR, 2.56; 95% confidence interval (CI, 1.31-5.04; and p = 0.0047. We focused on an association between rare alleles and gastric cancer. Rare alleles were divided into short (40, 43 and 44 and long (47, 50 and 54, according to their TR (tandem repeats lengths. Interestingly, short rare alleles were associated with gastric cancer (OR = 5.6, 95% CI: 1.93-16.42; p = 0.00036. Moreover, hypervariable MUC2 minisatellites were analyzed in matched blood and cancer tissue from 28 patients with gastric cancer and in 4 cases of MUC2-MS2, minisatellites were found to have undergone rearrangement. CONCLUSIONS/SIGNIFICANCE: Our observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. Additionally, we suggest that minisatellite instability might be associated with MUC2 function in cancer cells.

  16. Sex-specific allelic transmission bias suggests sexual conflict at MC1R.

    Science.gov (United States)

    Ducret, Valérie; Gaigher, Arnaud; Simon, Céline; Goudet, Jérôme; Roulin, Alexandre

    2016-09-01

    Sexual conflict arises when selection in one sex causes the displacement of the other sex from its phenotypic optimum, leading to an inevitable tension within the genome - called intralocus sexual conflict. Although the autosomal melanocortin-1-receptor gene (MC1R) can generate colour variation in sexually dichromatic species, most previous studies have not considered the possibility that MC1R may be subject to sexual conflict. In the barn owl (Tyto alba), the allele MC1RWHITE is associated with whitish plumage coloration, typical of males, and the allele MC1RRUFOUS is associated with dark rufous coloration, typical of females, although each sex can express any phenotype. Because each colour variant is adapted to specific environmental conditions, the allele MC1RWHITE may be more strongly selected in males and the allele MC1RRUFOUS in females. We therefore investigated whether MC1R genotypes are in excess or deficit in male and female fledglings compared with the expected Hardy-Weinberg proportions. Our results show an overall deficit of 7.5% in the proportion of heterozygotes in males and of 12.9% in females. In males, interannual variation in assortative pairing with respect to MC1R explained the year-specific deviations from Hardy-Weinberg proportions, whereas in females, the deficit was better explained by the interannual variation in the probability of inheriting the MC1RWHITE or MC1RRUFOUS allele. Additionally, we observed that sons inherit the MC1RRUFOUS allele from their fathers on average slightly less often than expected under the first Mendelian law. Transmission ratio distortion may be adaptive in this sexually dichromatic species if males and females are, respectively, selected to display white and rufous plumages.

  17. A single-to-differential low-noise amplifier with low differential output imbalance

    Institute of Scientific and Technical Information of China (English)

    Duan Lian; Huang Wei; Ma Chengyan; He Xiaofeng; Jin Yuhua; Ye Tianchun

    2012-01-01

    This paper presents a single-ended input differential output low-noise amplifier intended for GPS applications.We propose a method to reduce the gain/amplitude and phase imbalance of a differential output exploiting the inductive coupling of a transformer or center-tapped differential inductor.A detailed analysis of the theory of imbalance reduction,as well as a discussion on the principle of choosing the dimensions of a transformer,are given.An LNA has been implemented using TSMC 0.18μm technology with ESD-protected.Measurement on board shows a voltage gain of 24.6 dB at 1.575 GHz and a noise figure of 3.2 dB.The gain imbalance is below 0.2 dB and phase imbalance is less than 2 degrees.The LNA consumes 5.2 mA from a 1.8 V supply.

  18. On the consequences of the energy imbalance for calculating surface conductance to water vapour.

    Science.gov (United States)

    Wohlfahrt, Georg; Haslwanter, Alois; Hörtnagl, Lukas; Jasoni, Richard L; Fenstermaker, Lynn F; Arnone, John A; Hammerle, Albin

    2009-09-01

    The Penman-Monteith combination equation, which is most frequently used to derive the surface conductance to water vapour (Gs), implicitly assumes the energy balance to be closed. Any energy imbalance (positive or negative) will thus affect the calculated Gs. Using eddy covariance energy flux data from a temperate grassland and a desert shrub ecosystem we explored five possible approaches of closing the energy imbalance and show that calculated Gs may differ considerably between these five approaches depending on the relative magnitudes of sensible and latent heat fluxes, and the magnitude and sign of the energy imbalance. Based on our limited understanding of the nature of the energy imbalance, we tend to favour an approach which preserves the Bowen-ratio and closes the energy balance on a larger time scale.

  19. An Analysis of Economic Growth, Competitiveness and Macroeconomic Imbalances in the European Union

    Directory of Open Access Journals (Sweden)

    Gheorghe Hurduzeu

    2015-09-01

    Full Text Available Taking into consideration the determinants of the economic crisis and of the sovereign debt crisis, we aim to analyze the dynamics of the European economies and discuss changes related to macroeconomic imbalances, as highlighted by the recent crises as an important factor of the unfavorable dynamics registered during the last years. In this respect we considered both internal and external imbalances, as specified in the macroeconomic imbalance procedure that was implemented for the European Union member states since 2012, as a response to the crises that affected all open economies of the world. The purpose of this article is to provide a comprehensive analysis of economic imbalances in the European Union and to determine their influence on economic growth.

  20. Analysis and compensation of I/Q imbalance in amplify-and-forward cooperative systems

    KAUST Repository

    Qi, Jian

    2012-04-01

    In this paper, dual-hop amplify-and-forward (AF) cooperative systems in the presence of in-phase and quadrature-phase (I/Q) imbalance, which refers to the mismatch between components in I and Q branches, are investigated. First, we analyze the performance of the considered AF cooperative protocol without compensation for I/Q imbalance as the benchmark. Furthermore, a compensation algorithm for I/Q imbalance is proposed, which makes use of the received signals at the destination, from the source and relay nodes, together with their conjugations to detect the transmitted signal. The performance of the AF cooperative system under study is evaluated in terms of average symbol error probability (SEP), which is derived considering transmission over Rayleigh fading channels. Numerical results are provided and show that the proposed compensation algorithm can efficiently mitigate the effect of I/Q imbalance. © 2012 IEEE.

  1. Benchmarking binary classification models on data sets with different degrees of imbalance

    Institute of Scientific and Technical Information of China (English)

    Ligang ZHOU; Kin Keung LAI

    2009-01-01

    In practice, there are many binary classification problems, such as credit risk assessment, medical testing for determining if a patient has a certain disease or not, etc.However, different problems have different characteristics that may lead to different difficulties of the problem. One important characteristic is the degree of imbalance of two classes in data sets. For data sets with different degrees of imbalance, fire the commonly used binary classification methods still feasible? In this study, various binary classifi-cation models, including traditional statistical methods andnewly emerged methods from artificial intelligence, such as linear regression, discriminant analysis, decision tree, neural network, support vector machines, etc., are reviewed, and their performance in terms of the measure of classification accuracy and area under Receiver Operating Characteristic (ROC) curve are tested and compared on fourteen data sets with different imbalance degrees. The results help to select the appropriate methods for problems with different degrees of imbalance.

  2. A Wisp3 Cre-knockin allele produces efficient recombination in spermatocytes during early prophase of meiosis I.

    Directory of Open Access Journals (Sweden)

    Steven Hann

    Full Text Available Individuals with the autosomal recessive skeletal disorder Progressive Pseudorheumatoid Dysplasia have loss-of-function mutations in WISP3, and aberrant WISP3 expression has been detected in tumors from patients with colon and breast cancer. In mice however, neither absence nor over-expression of WISP3 was found to cause a phenotype, and endogenous Wisp3 expression has been difficult to detect. To confirm that Wisp3 knockout mice have no phenotype and to identify potential sites of endogenous Wisp3 expression, we generated mice with a knockin allele (Wisp3 (GFP-Cre designed to express Green Fluorescent Protein (GFP and Cre-recombinase instead of WISP3. Heterozygous and homozygous knockin mice were fertile and indistinguishable from their wild-type littermates, confirming that mice lacking Wisp3 have no phenotype. We could not detect GFP-expression from the knockin allele, but we could detect Cre-expression after crossing mice with the knockin allele to Cre-reporter mice; the double heterozygous offspring had evidence of Cre-mediated recombination in several tissues. The only tissue that had high levels of Cre-mediated recombination was the testis, where recombination in spermatocytes occurred by early prophase of meiosis I. As a consequence, males that were double heterozygous for a Wisp3 (GFP-Cre and a floxed allele only contributed a recombined allele to their offspring. We detected no evidence of Cre-mediated recombination in the female ovary, although when double heterozygous females contributed the reporter allele to their offspring it had recombined ~7% of the time. Wisp3 (GFP-Cre expression therefore occurs less frequently and most likely at a later stage of oocyte development in female mice compared to male mice. We conclude that although WISP3 is dispensable in mice, male mice with a Wisp3 (GFP-Cre allele (Jackson Laboratory stock # 017685 will be useful for studying early prophase of meiosis I and for efficiently recombining floxed

  3. Examination of Potential Benefits of an Energy Imbalance Market in the Western Interconnection

    Energy Technology Data Exchange (ETDEWEB)

    Milligan, M.; Clark, K.; King, J.; Kirby, B.; Guo, T.; Liu, G.

    2013-03-01

    In the Western Interconnection, there is significant interest in improving approaches to wide-area coordinated operations of the bulk electric power system, in part because of the increasing penetration of variable generation. One proposed solution is an energy imbalance market. This study focused on that approach alone, with the goal of identifying the potential benefits of an energy imbalance market in the year 2020.

  4. Widely Linear Blind Adaptive Equalization for Transmitter IQ-Imbalance/Skew Compensation in Multicarrier Systems

    DEFF Research Database (Denmark)

    Porto da Silva, Edson; Zibar, Darko

    2016-01-01

    Simple analytical widely linear complex-valued models for IQ-imbalance and IQ-skew effects in multicarrier transmitters are presented. To compensate for such effects, a 4×4 MIMO widely linear adaptive equalizer is proposed and experimentally validated.......Simple analytical widely linear complex-valued models for IQ-imbalance and IQ-skew effects in multicarrier transmitters are presented. To compensate for such effects, a 4×4 MIMO widely linear adaptive equalizer is proposed and experimentally validated....

  5. Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis.

    Science.gov (United States)

    Kanno, Junko; Kure, Shigeo; Narisawa, Ayumi; Kamada, Fumiaki; Takayanagi, Masaru; Yamamoto, Katsuya; Hoshino, Hisao; Goto, Tomohide; Takahashi, Takao; Haginoya, Kazuhiro; Tsuchiya, Shigeru; Baumeister, Fritz A M; Hasegawa, Yuki; Aoki, Yoko; Yamaguchi, Seiji; Matsubara, Yoichi

    2007-08-01

    Pyridoxine dependent seizure (PDS) is a disorder of neonates or infants with autosomal recessive inheritance characterized by seizures, which responds to pharmacological dose of pyridoxine. Recently, mutations have been identified in the ALDH7A1 gene in Caucasian families with PDS. To elucidate further the genetic background of PDS, we screened for ALDH7A1 mutations in five PDS families (patients 1-5) that included four Orientals. Diagnosis as having PDS was confirmed by pyridoxine-withdrawal test. Exon sequencing analysis of patients 1-4 revealed eight ALDH7A1 mutations in compound heterozygous forms: five missense mutations, one nonsense mutation, one point mutation at the splicing donor site in intron 1, and a 1937-bp genomic deletion. The deletion included the entire exon 17, which was flanked by two Alu elements in introns 16 and 17. None of the mutations was found in 100 control chromosomes. In patient 5, no mutation was found by the exon sequencing analysis. Furthermore, expression level or nucleotide sequences of ALDH7A1 mRNA in lymphoblasts were normal. Plasma pipecolic acid concentration was not elevated in patient 5. These observations suggest that ALDH7A1 mutation is unlikely to be responsible for patient 5. Abnormal metabolism of GABA/glutamate in brain has long been suggested as the underlying pathophysiology of PDS. CSF glutamate concentration was elevated during the off-pyridoxine period in patient 3, but not in patient 2 or 5. These results suggest allelic and non-allelic heterogeneities of PDS, and that the CSF glutamate elevation does not directly correlate with the presence of ALDH7A1 mutations.

  6. Genomic Imprinting and the Expression of Affect in Angelman Syndrome: What's in the Smile?

    Science.gov (United States)

    Oliver, Chris; Horsler, Kate; Berg, Katy; Bellamy, Gail; Dick, Katie; Griffiths, Emily

    2007-01-01

    Background: Kinship theory (or the genomic conflict hypothesis) proposes that the phenotypic effects of genomic imprinting arise from conflict between paternally and maternally inherited alleles. A prediction arising for social behaviour from this theory is that imbalance in this conflict resulting from a deletion of a maternally imprinted gene,…

  7. Average-12.9 chromosome imbalances coupling with 15 differential expression genes possibly involved in the carcinogenesis, progression and metastasis of supraglottic laryngeal squamous cell cancer%声门上喉癌的染色体异常和重要相关基因的研究

    Institute of Scientific and Technical Information of China (English)

    富伟能; 尚超; 黄带发; 徐振明; 孙兴和; 孙开来

    2006-01-01

    Objective With the objective of discovering novel putative chromosomal regions and special genes involved in the carcinogenesis, progression and metastasis of laryngeal squamous cell cancer (LSCC). Methods DNA copy profile of LSCC were obtained and analyzed by comparative genomic hybridization (CGH) and a computerized digital image analysis system. cDNA microarray of LSCC was performed and the profile was analyzed by Hierarchical clustering. Results CGH analysis showed average-12.9 gains and losses of chromosomes in LSCC. Relatively high frequencies of gains were found at 3q15-21 (14/18), 5p12-13 (11/18), 8q22-24 (6/18), 11q12-13 (8/18), 15q21-23 (7/18) and 18p11 (8/18), while those of losses at 1p13-21 (8/18), 3p21-23 (14/18), 5q21-22 (14/18), 9p12-pter (11/18) and 13q21-31 (8/18). Hierarchical clustering analysis showed that the differentially expressed genes were segregated into three groups. Three genes differentially expressed in processⅠ( normal tissue to cancer) and processⅡ(cancer to lymph node metastasis), and the Cy5/Cy3 ratios of twelve genes were either higher than 5.0 or lower than 0.2 in processⅠor processⅡ. The fifteen special genes were first reported possibly to be the relationships with LSCC. In particular, 4 genes of them, which were cytochrome C oxidase Ⅴa, PPBP,EPHX2 andPON1, were first reported to correlate with tumorigenesis.SH3GL2, which was one of the 15 special genes, was located at one of the special chromosome regions, 9p12-pter. Conclusion The important genes and special chromosomal aberrances might provide us a clue for further investigation of carcinogenesis, progression and metastasis in LSCC.%目的筛查声门上喉癌发生、发展及转移相关的异常染色体和重要基因. 方法应用比较基因组杂交(comparative genomic hybridization, CGH)分析喉声门上鳞状细胞癌(laryngeal squamous cell cancer, LSCC)癌组织和癌旁组织DNA拷贝数的差异.应用cDNA芯片结合聚类分析研究喉声门上

  8. Cenozoic carbon cycle imbalances and a variable weathering feedback

    Science.gov (United States)

    Caves, Jeremy K.; Jost, Adam B.; Lau, Kimberly V.; Maher, Kate

    2016-09-01

    The long-term stability of Earth's climate and the recovery of the ocean-atmosphere system after carbon cycle perturbations are often attributed to a stabilizing negative feedback between silicate weathering and climate. However, evidence for the operation of this feedback over million-year timescales and in response to tectonic and long-term climatic change remains scarce. For example, the past 50 million years of the Cenozoic Era are characterized by long-term cooling and declining atmospheric CO2 (pCO2). During this interval, constant or decreasing carbon fluxes from the solid Earth to the atmosphere suggest that stable or decreasing weathering fluxes are needed to balance the carbon cycle. In contrast, marine isotopic proxies of weathering (i.e., 87Sr/86Sr, δ7 Li , and 187Os/188Os) are interpreted to reflect increasing weathering fluxes. Here, we evaluate the existence of a negative feedback by reconstructing the imbalance in the carbon cycle during the Cenozoic using the surface inventories of carbon and alkalinity. Only a sustained 0.25-0.5% increase in silicate weathering is necessary to explain the long-term decline in pCO2 over the Cenozoic. We propose that the long-term decrease in pCO2 is due to an increase in the strength of the silicate weathering feedback (i.e., the constant of proportionality between the silicate weathering flux and climate), rather than an increase in the weathering flux. This increase in the feedback strength, which mirrors the marine isotope proxies, occurs as transient, 1 million year timescales remains invariant to match the long-term inputs of carbon. Over the Cenozoic, this results in stable long-term weathering fluxes even as pCO2 decreases. We attribute increasing feedback strength to a change in the type and reactivity of rock in the weathering zone, which collectively has increased the reactivity of the surface of the Earth. Increasing feedback strength through the Cenozoic reconciles mass balance in the carbon cycle with

  9. Wide brick tunnel randomization - an unequal allocation procedure that limits the imbalance in treatment totals.

    Science.gov (United States)

    Kuznetsova, Olga M; Tymofyeyev, Yevgen

    2014-04-30

    In open-label studies, partial predictability of permuted block randomization provides potential for selection bias. To lessen the selection bias in two-arm studies with equal allocation, a number of allocation procedures that limit the imbalance in treatment totals at a pre-specified level but do not require the exact balance at the ends of the blocks were developed. In studies with unequal allocation, however, the task of designing a randomization procedure that sets a pre-specified limit on imbalance in group totals is not resolved. Existing allocation procedures either do not preserve the allocation ratio at every allocation or do not include all allocation sequences that comply with the pre-specified imbalance threshold. Kuznetsova and Tymofyeyev described the brick tunnel randomization for studies with unequal allocation that preserves the allocation ratio at every step and, in the two-arm case, includes all sequences that satisfy the smallest possible imbalance threshold. This article introduces wide brick tunnel randomization for studies with unequal allocation that allows all allocation sequences with imbalance not exceeding any pre-specified threshold while preserving the allocation ratio at every step. In open-label studies, allowing a larger imbalance in treatment totals lowers selection bias because of the predictability of treatment assignments. The applications of the technique in two-arm and multi-arm open-label studies with unequal allocation are described.

  10. Effects of specific muscle imbalance improvement training on the balance ability in elite fencers.

    Science.gov (United States)

    Kim, Taewhan; Kil, Sekee; Chung, Jinwook; Moon, Jeheon; Oh, Eunyoung

    2015-05-01

    [Purpose] The lunge Motion that occurs frequently in fencing training and matches results in imbalance of the upper and lower limbs muscles. This research focuses on the improvement of the imbalance that occurs in the national team fencers of the Republic of Korea through specific muscle imbalance improvement training. [Subjects] The subjects of this research were limited to right-handed male fencers. Nine male, right-handed national fencing athletes were selected for this study (4 epee, 5 sabre; age 28.2 ± 2.2 years; height 182.3 ± 4.0 cm; weight 76.5 ± 8.2 kg; experience 12.4 ± 3.0 years). [Methods] The specific muscle imbalance improvement training program was performed for 12 weeks and Pre-Post tests were to evaluate its effect on the experimental group. Measurements comprised anthropometry, test of balance, and movement analysis. [Results] After the training program, mediolateral sway of the nondominant lower limb and the balance scale showed statistically significant improvement. [Conclusion] The specific muscle imbalance improvement training program used in this research was proven to be effective for improving the muscle imbalance of elite fencers.

  11. A TALEN-based strategy for efficient bi-allelic miRNA ablation in human cells.

    Science.gov (United States)

    Uhde-Stone, Claudia; Sarkar, Nandita; Antes, Travis; Otoc, Nicole; Kim, Young; Jiang, Yan J; Lu, Biao

    2014-06-01

    Significant progress in the functional understanding of microRNAs (miRNAs) has been made in mice, but a need remains to develop efficient tools for bi-allelic knockouts of miRNA in the human genome. Transcription activator-like effector nucleases (TALENs) provide an exciting platform for targeted gene ablation in cultured human cells, but bi-allelic modifications induced by TALENs alone occur at low frequency, making screening for double knockouts a tedious task. Here, we present an approach that is highly efficient in bi-allelic miRNA ablation in the human genome by combining TALENs targeting to the miRNA seed region with a homologous recombination donor vector and a positive selection strategy. A pilot test of this approach demonstrates bi-allelic miR-21 gene disruption at high frequency (∼87%) in cultured HEK293 cells. Analysis of three independent clones showed a total loss of miR-21 expression. Phenotypical analysis revealed increased miR-21 target gene expression, reduced cell proliferation, and alterations of global miRNA expression profiles. Taken together, our study reveals a feasible and efficient approach for bi-allelic miRNA ablation in cultured human cells and demonstrates its usefulness in elucidating miRNA function in human cells.

  12. Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing.

    Science.gov (United States)

    Weber, H; Richter, J; Straube, B; Lueken, U; Domschke, K; Schartner, C; Klauke, B; Baumann, C; Pané-Farré, C; Jacob, C P; Scholz, C-J; Zwanzger, P; Lang, T; Fehm, L; Jansen, A; Konrad, C; Fydrich, T; Wittmann, A; Pfleiderer, B; Ströhle, A; Gerlach, A L; Alpers, G W; Arolt, V; Pauli, P; Wittchen, H-U; Kent, L; Hamm, A; Kircher, T; Deckert, J; Reif, A

    2016-06-01

    Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.

  13. Characterization of 12 silent alleles of the human butyrylcholinesterase (BCHE) gene

    Energy Technology Data Exchange (ETDEWEB)

    Primo-Parmo, S.L.; Wiersema, B.; Spek, A.F.L. van der [Univ. of Michigan Medical School, Ann Arbor, MI (United States)] [and others

    1996-01-01

    The silent phenotype of human butyrylcholinesterase (BChE), present in most human populations in frequencies of {approximately}1/100,000, is characterized by the complete absence of BChE activity or by activity < 10 % of the average levels of the usual phenotype. Heterogeneity in this phenotype has been well established at the phenotypic level, but only a few silent BCHE alleles have been characterized at the DNA level. Twelve silent alleles of the human butyrylcholinesterase gene (BCHE) have been identified in 17 apparently unrelated patients who were selected by their increased sensitivity to the muscle relaxant succinylcholine. All of these alleles are characterized by single nucleotide substitutions or deletions leading to distinct changes in the structure of the BChE enzyme molecule. Nine of the nucleotide substitutions result in the replacement of single amino acid residues. Three of these variants, BCHE*33C, BCHE*198G, and BCHE*201T, produce normal amounts of immunoreactive but enzymatically inactive BChE protein in the plasma. The other six amino acid substitutions, encoded by BCHE*37S, BCHE*125F, BCHE*170E, BCHE-471R, and BCHE*518L, seem to cause reduced expression of BChE protein, and their role in determining the silent phenotype was confirmed by expression in cell culture. The other four silent alleles, BCHE*271STOP, BCHE*500STOP, BCHE*FS6, and BCHE*I2E3-8G, encode BChEs truncated at their C-terminus because of premature stop codons caused by nucleotide substitutions, a frame shift, or altered splicing. The large number of different silent BCHE alleles found within a relatively small number of patients shows that the heterogeneity of the silent BChE phenotype is high. The characterization of silent BChE variants will be useful in the study of the structure/function relationship for this and other closely related enzymes. 83 refs., 3 figs., 4 tabs.

  14. Frequency of null allele of Human Leukocyte Antigen-G (HLA-G) locus in subjects to recurrent miscarriage

    Science.gov (United States)

    Alizadeh, Nazila; Mosaferi, Elnaz; Farzadi, Laya; Majidi, Jafar; Monfaredan, Amir; Yousefi, Bahman; Baradaran, Behzad

    2016-01-01

    Background: Human leukocyte antigen-G (HLA-G) is a non-classical class I molecule highly expressed by extravillous cytotrophoblast cells. Due to a single base pair deletion, its function can be compensated by other isoforms. Investigating the frequency of null allele in Recurrent Miscarriage (RM) subjects could be useful in understanding the relationship between frequency of this allele and RM in a given population. Objective: This study aimed to determine the frequency of HLA-G*0105N null allele and its potential association with down-regulation of HLA-G in subjects with RM. Materials and Methods: Western blotting was used to assess the level of HLA-G protein expression. For investigating the frequency of HLA-G*0105N null allele in RM subjects, PCR-RFLP method was used. Exon 3 of HLA-G gene was amplified by polymerase chain reaction (PCR). Subsequently, PpuM-1 enzyme was employed to digest the PCR products and fragments were analyzed using gel electrophoresis. Results: Digestion using restriction enzyme showed the presence of heterozygous HLA-G*0105N null allele in 10% of the test population. Western blotting results confirmed the decrease in expression of HLA-G in the placental tissue of subjects with RM compared to subjects who could give normal birth. Conclusion: The frequency of heterozygous HLA-G*0105N null allele was high to some extent in subjects with RM. The mutation rate in subjects suggested that there is a significant association between RM and frequency of mutations in this allele. PMID:27525330

  15. Genome-wide screen of genes imprinted in sorghum endosperm, and the roles of allelic differential cytosine methylation.

    Science.gov (United States)

    Zhang, Meishan; Li, Ning; He, Wenan; Zhang, Huakun; Yang, Wei; Liu, Bao

    2016-02-01

    Imprinting is an epigenetic phenomenon referring to allele-biased expression of certain genes depending on their parent of origin. Accumulated evidence suggests that, while imprinting is a conserved mechanism across kingdoms, the identities of the imprinted genes are largely species-specific. Using deep RNA sequencing of endosperm 14 days after pollination in sorghum, 5683 genes (29.27% of the total 19 418 expressed genes) were found to harbor diagnostic single nucleotide polymorphisms between two parental lines. The analysis of parent-of-origin expression patterns in the endosperm of a pair of reciprocal F1 hybrids between the two sorghum lines led to identification of 101 genes with ≥ fivefold allelic expression difference in both hybrids, including 85 maternal expressed genes (MEGs) and 16 paternal expressed genes (PEGs). Thirty of these genes were previously identified as imprinted in endosperm of maize (Zea mays), rice (Oryza sativa) or Arabidopsis, while the remaining 71 genes are sorghum-specific imprinted genes relative to these three plant species. Allele-biased expression of virtually all of the 14 tested imprinted genes (nine MEGs and five PEGs) was validated by pyrosequencing using independent sources of RNA from various developmental stages and dissected parts of endosperm. Forty-six imprinted genes (30 MEGs and 16 PEGs) were assayed by quantitative RT-PCR, and the majority of them showed endosperm-specific or preferential expression relative to embryo and other tissues. DNA methylation analysis of the 5' upstream region and gene body for seven imprinted genes indicated that, while three of the four PEGs were associated with hypomethylation of maternal alleles, no MEG was associated with allele-differential methylation.

  16. Identification of Multiple Alleles at the Wx Locus and Development of Single Segment Substitution Lines for the Alleles in Rice

    Institute of Scientific and Technical Information of China (English)

    ZENG Rui-zhen; ZHANG Ze-min; HE Feng-hua; XI Zhang-ying; Akshay TALUKDAR; SHI Jun-qiong; QIN Li-jun; HUANG Chao-feng; ZHANG Gui-quan

    2006-01-01

    The microsatellite markers 484/485 and 484/W2R were used to identify the multiple alleles at the Wx locus in rice germplasm. Fifteen alleles were identified in 278 accessions by using microsatellite class and G-T polymorphism. Among these alleles, (CT)12-G, (CT)15-G, (CT)16-G, (CT)17-G, (CT)18-G and (CT)21-G have not been reported. Seventy-two single-segment substitution lines (SSSLs) carrying different alleles at the Wx locus were developed by using Huajingxian 74 with the (CT)11-G allele as a recipient and 20 accessions containing 12 different alleles at the Wx locus as donors. The estimated length of the substituted segments ranged from 2.2 to 77.3 cM with an average of 17.4 cM.

  17. Multiple Alleles of Treponema pallidum Repeat Gene D in Treponema pallidum Isolates

    OpenAIRE

    Centurion-Lara, Arturo; Sun, Eileen S.; Barrett, Lynn K.; Castro, Christa; Lukehart, Sheila A.; Van Voorhis, Wesley C.

    2000-01-01

    Two new tprD alleles have been identified in Treponema pallidum: tprD2 is found in 7 of 12 T. pallidum subsp. pallidum isolates and 7 of 8 non-pallidum isolates, and tprD3 is found in one T. pallidum subsp. pertenue isolate. Antibodies against TprD2 are found in persons with syphilis, demonstrating that tprD2 is expressed during infection.

  18. The effect of Gata3-Targeting gene silence on dendritic cells phenotype and the effector T cell imbalance expression in pregnancy asthma of mice%靶向沉默Gata3对妊娠期哮喘小鼠树突状细胞表型及效应T细胞失衡表达的影响

    Institute of Scientific and Technical Information of China (English)

    马佳佳; 陈必良; Nick Lu

    2014-01-01

    ( MLR) ,T cell's proliferation a-bility was determined by MTT method. Results:The lentivirus vector was successfully restruc-tured and packaged,with the siRNA targeting to Gata3,and was infected to DC. The transcrip-tion and protein expression of Gata3 mRNA were down-regulated 87 . 30% and 81 . 33% respec-tively (P<0. 05),while the fluorescence intensity of CD86 on DCs membrane surface was re-duced (P<0. 05). In pSH1/siGata3 group,the secretion of IL-5,IL-17 in BALF was reduced and the level of IL-12 was increased ( P<0 . 05 ) . MLR results confirmed that the ability of the T cells,which were activated by co-culturing with infected DC, was obviously insufficient ( P<0 . 05 ) . Conclusions:siRNA can effectively inhibit the specific Gata3 pathway in the immune microenvironment of mice model,repress the differentiation of T cell and its subsets in order to induce the immune tolerance of DC. It lay a foundation for prevention and control of asthma dur-ing pregnancy,and provide new ideas and methods.

  19. Distribution of BoLA-DRB3 Allelic Frequencies and Identification of Two New Alleles in Iranian Buffalo Breed

    OpenAIRE

    Mosafer, J.; Heydarpour, M.; Manshad, E.; Russell, G.; Sulimova, G. E.

    2012-01-01

    The role of the major histocompatibility complex (MHC) in the immune response makes it an attractive candidate gene for associations with disease resistance and susceptibility. This study describes genetic variability in the BoLA-DRB3 in Iranian buffaloes. Heminested PCR-RFLP method was used to identify the frequency of BoLA-DRB3 alleles. The BoLA-DRB3 locus is highly polymorphic in the study herd (12 alleles). Almost 63.50% of the alleles were accounted for by four alleles (BoLA-DRB3.2 *48, ...

  20. Mono-allelic retrotransposon insertion addresses epigenetic transcriptional repression in human genome

    Directory of Open Access Journals (Sweden)

    Byun Hyang-Min

    2012-02-01

    Full Text Available Abstract Background Retrotransposons have been extensively studied in plants and animals and have been shown to have an impact on human genome dynamics and evolution. Their ability to move within genomes gives retrotransposons to affect genome instability. Methods we examined the polymorphic inserted AluYa5, evolutionary young Alu, in the progesterone receptor gene to determine the effects of Alu insertion on molecular environment. We used mono-allelic inserted cell lines which carry both Alu-present and Alu-absent alleles. To determine the epigenetic change and gene expression, we performed restriction enzyme digestion, Pyrosequencing, and Chromatin Immunoprecipitation. Results We observed that the polymorphic insertion of evolutionally young Alu causes increasing levels of DNA methylation in the surrounding genomic area and generates inactive histone tail modifications. Consequently the Alu insertion deleteriously inactivates the neighboring gene expression. Conclusion The mono-allelic Alu insertion cell line clearly showed that polymorphic inserted repetitive elements cause the inactivation of neighboring gene expression, bringing aberrant epigenetic changes.

  1. Generation of mice harbouring a conditional loss-of-function allele of Gata6

    Directory of Open Access Journals (Sweden)

    Duncan Stephen A

    2006-04-01

    Full Text Available Abstract The zinc finger transcription factor GATA6 is believed to have important roles in the development of several organs including the liver, gastrointestinal tract and heart. However, analyses of the contribution of GATA6 toward organogenesis have been hampered because Gata6-/- mice fail to develop beyond gastrulation due to defects in extraembryonic endoderm function. We have therefore generated a mouse line harbouring a conditional loss-of-function allele of Gata6 using Cre/loxP technology. LoxP elements were introduced into introns flanking exon 2 of the Gata6 gene by homologous recombination in ES cells. Mice containing this altered allele were bred to homozygosity and were found to be viable and fertile. To assess the functional integrity of the loxP sites and to confirm that we had generated a Gata6 loss-of-function allele, we bred Gata6 'floxed' mice to EIIa-Cre mice in which Cre is ubiquitously expressed, and to Villin-Cre mice that express Cre in the epithelial cells of the intestine. We conclude that we have generated a line of mice in which GATA6 activity can be ablated in a cell type specific manner by expression of Cre recombinase. This line of mice can be used to establish the role of GATA6 in regulating embryonic development and various aspects of mammalian physiology.

  2. The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins

    Energy Technology Data Exchange (ETDEWEB)

    Al-Saaidi, Rasha [Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus (Denmark); Rasmussen, Torsten B. [Department of Cardiology, Aarhus University Hospital, Aarhus (Denmark); Palmfeldt, Johan [Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus (Denmark); Nissen, Peter H. [Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus (Denmark); Beqqali, Abdelaziz [Heart Failure Research Center, Academic Medical Center, Amsterdam (Netherlands); Hansen, Jakob [Department of Forensic Medicine, Bioanalytical Unit, University of Aarhus (Denmark); Pinto, Yigal M. [Heart Failure Research Center, Academic Medical Center, Amsterdam (Netherlands); Boesen, Thomas [Department of Molecular Biology and Genetics, University of Aarhus (Denmark); Mogensen, Jens [Department of Cardiology, Odense University Hospital, Odense (Denmark); Bross, Peter, E-mail: peter.bross@ki.au.dk [Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus (Denmark)

    2013-11-15

    heterozygosity for the nonsense mutation causes NMD degradation of the mutant transcripts blocking expression of the truncated mutant protein and an additional trans effect on lamin A protein levels expressed from the wild type allele. We discuss the possibility that skewing of the lamin A to lamin C ratio may contribute to ensuing processes that destabilize cardiomyocytes and trigger cardiomyopathy - Highlights: • We study disease mechanisms in DCM patients carrying PTC mutations in the LMNA gene. • The mutant transcript is degraded by the nonsense mediated mRNA decay system. • Skewed lamin A to lamin C protein ratio expressed from the wild type allele. • We suggest a combined pathomechanism: haploinsuffiency plus lamin A/C imbalance.

  3. Low Penetrance Alleles in Colorectal Cancer: the arachidonic acid pathway

    NARCIS (Netherlands)

    C.L.E. Siezen

    2006-01-01

    textabstractIn summary, we can conclude that we have successfully identified low penetrance alleles in the PPAR., PLA2G2A and ALOX15 genes, conferring differential colorectal adenoma risk, and two such alleles in the PTGS2 gene, one of which is also involved in colorectal cancer risk. These resul

  4. Rescue of progeria in trichothiodystrophy by homozygous lethal Xpd alleles.

    Directory of Open Access Journals (Sweden)

    Jaan-Olle Andressoo

    2006-10-01

    Full Text Available Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of "null" alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals.

  5. Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations.

    Science.gov (United States)

    Fernandez Vina, Marcelo A; Hollenbach, Jill A; Lyke, Kirsten E; Sztein, Marcelo B; Maiers, Martin; Klitz, William; Cano, Pedro; Mack, Steven; Single, Richard; Brautbar, Chaim; Israel, Shosahna; Raimondi, Eduardo; Khoriaty, Evelyne; Inati, Adlette; Andreani, Marco; Testi, Manuela; Moraes, Maria Elisa; Thomson, Glenys; Stastny, Peter; Cao, Kai

    2012-03-19

    The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.

  6. Mechanisms for dominance: Adh heterodimer formation in heterozygotes between ENU or x-ray induced null alleles and normal alleles in drosophila melanogaster

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, J.C.; Lee, W.R.; Chang, S.H.; Silverman, H. (Louisiana State Univ., Baton Rouge (United States))

    1992-01-01

    To study mechanisms for dominance of phenotype, eight ENU- and four x-ray-induced mutations at the alcohol dehydrogenase (Adh) locus were analyzed for partial dominance in their interaction with normal alleles. All ENU and one of the x-ray mutations were single base substitutions; the other three x-ray mutations were 9-21 base deletions. All but one of the 12 mutant alleles were selected for this study because they produced detectable mutant polypeptides, but seven of the 11 producing a peptide could not form dimers with the normal peptide and the enzyme activity of heterozygotes was about half that of normal homozygotes. Four mutations formed dimers with a decreased catalytic efficiency and two of these were near the limit of detectability; these two also inhibited the formation of normal homodimers. The mutant alleles therefore show multiple mechanisms leading to partial enzyme expression in heterozygotes and a wide range of dominance ranging from almost complete recessive to nearly dominant. All amino acid changes in mutant peptides that form dimers are located between amino acids 182 and 194, so this region is not critical for dimerization. It may, however, be an important surface domain for catalyzation. 34 refs., 8 figs., 2 tabs.

  7. Estimating Relatedness in the Presence of Null Alleles.

    Science.gov (United States)

    Huang, Kang; Ritland, Kermit; Dunn, Derek W; Qi, Xiaoguang; Guo, Songtao; Li, Baoguo

    2016-01-01

    Studies of genetics and ecology often require estimates of relatedness coefficients based on genetic marker data. However, with the presence of null alleles, an observed genotype can represent one of several possible true genotypes. This results in biased estimates of relatedness. As the numbers of marker loci are often limited, loci with null alleles cannot be abandoned without substantial loss of statistical power. Here, we show how loci with null alleles can be incorporated into six estimators of relatedness (two novel). We evaluate the performance of various estimators before and after correction for null alleles. If the frequency of a null allele is 0.5, the potency of estimation is too low and such a locus should be excluded. We make available a software package entitled PolyRelatedness v1.6, which enables researchers to optimize these estimators to best fit a particular data set.

  8. Pistil-function breakdown in a new S-allele of European pear, S21*, confers self-compatibility.

    Science.gov (United States)

    Sanzol, Javier

    2009-03-01

    European pear exhibits RNase-based gametophytic self-incompatibility controlled by the polymorphic S-locus. S-allele diversity of cultivars has been extensively investigated; however, no mutant alleles conferring self-compatibility have been reported. In this study, two European pear cultivars, 'Abugo' and 'Ceremeño', were classified as self-compatible after fruit/seed setting and pollen tube growth examination. S-genotyping through S-PCR and sequencing identified a new S-RNase allele in the two cultivars, with identical deduced amino acid sequence as S(21), but differing at the nucleotide level. Test-pollinations and analysis of descendants suggested that the new allele is a self-compatible pistil-mutated variant of S(21), so it was named S(21)*. S-genotypes assigned to 'Abugo' and 'Ceremeño' were S(10)S(21)* and S(21)*S(25) respectively, of which S(25) is a new functional S-allele of European pear. Reciprocal crosses between cultivars bearing S(21) and S(21)* indicated that both alleles exhibit the same pollen function; however, cultivars bearing S(21)* had impaired pistil-S function as they failed to reject either S(21) or S (21)* pollen. RT-PCR analysis showed absence of S(21)* -RNase gene expression in styles of 'Abugo' and 'Ceremeño', suggesting a possible origin for S(21)* pistil dysfunction. Two polymorphisms found within the S-RNase genomic region (a retrotransposon insertion within the intron of S(21)* and indels at the 3'UTR) might explain the different pattern of expression between S(21) and S(21)*. Evaluation of cultivars with unknown S-genotype identified another cultivar 'Azucar Verde' bearing S(21)*, and pollen tube growth examination confirmed self-compatibility for this cultivar as well. This is the first report of a mutated S-allele conferring self-compatibility in European pear.

  9. Analysis of genomic imbalances and gene expression changes in transformed follicular lymphoma (FL)

    DEFF Research Database (Denmark)

    Obel, G.; Farinha, P.; Lam, W.;

    2005-01-01

    ) or down-regulated (11genes). Among upregulated genes were: AIM1L (1p36), SCN11A (3p22), CALM3/CPL (10p15), CPN1 (10q24), and ARF4L (17q21); among the down-regulated ones: DKFZp761B107 (4p15), LOC118812 (10q24), NAP1L4 (11p15), EB-1 (12q23), C14orf135 (14q23), SIRT2 (19q13), and CHD6 (20q12). Conclusions...

  10. Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays

    DEFF Research Database (Denmark)

    Smith, Frank Andrew; Howard, Philip; Shah, Sonia;

    2012-01-01

    identified an allele-specific regulatory polymorphism within NR1H3 (coding for LXR-α), rs7120118, coinciding with a previously GWAS-identified SNP for HDL-C levels. This finding was confirmed using FAIRE-gen with the 200,000 SNP Illumina Metabochip and verified with the established method of TaqMan allelic...... variants, we describe the technique of allele-specific FAIRE, utilising large-scale genotyping technology (FAIRE-gen) to determine allelic effects on chromatin accessibility and regulatory potential. FAIRE-gen was explored using lymphoblastoid cells and the 50,000 SNP Illumina CVD BeadChip. The technique...... discrimination. Examination of this SNP in two prospective Caucasian cohorts comprising 15,000 individuals confirmed the association with HDL-C levels (combined beta = 0.016; p = 0.0006), and analysis of gene expression identified an allelic association with LXR-α expression in heart tissue. Using increasingly...

  11. Efficient CRISPR-rAAV engineering of endogenous genes to study protein function by allele-specific RNAi.

    Science.gov (United States)

    Kaulich, Manuel; Lee, Yeon J; Lönn, Peter; Springer, Aaron D; Meade, Bryan R; Dowdy, Steven F

    2015-04-20

    Gene knockout strategies, RNAi and rescue experiments are all employed to study mammalian gene function. However, the disadvantages of these approaches include: loss of function adaptation, reduced viability and gene overexpression that rarely matches endogenous levels. Here, we developed an endogenous gene knockdown/rescue strategy that combines RNAi selectivity with a highly efficient CRISPR directed recombinant Adeno-Associated Virus (rAAV) mediated gene targeting approach to introduce allele-specific mutations plus an allele-selective siRNA Sensitive (siSN) site that allows for studying gene mutations while maintaining endogenous expression and regulation of the gene of interest. CRISPR/Cas9 plus rAAV targeted gene-replacement and introduction of allele-specific RNAi sensitivity mutations in the CDK2 and CDK1 genes resulted in a >85% site-specific recombination of Neo-resistant clones versus ∼8% for rAAV alone. RNAi knockdown of wild type (WT) Cdk2 with siWT in heterozygotic knockin cells resulted in the mutant Cdk2 phenotype cell cycle arrest, whereas allele specific knockdown of mutant CDK2 with siSN resulted in a wild type phenotype. Together, these observations demonstrate the ability of CRISPR plus rAAV to efficiently recombine a genomic locus and tag it with a selective siRNA sequence that allows for allele-selective phenotypic assays of the gene of interest while it remains expressed and regulated under endogenous control mechanisms.

  12. Salmonella Typhi shdA: pseudogene or allelic variant?

    Science.gov (United States)

    Urrutia, I M; Fuentes, J A; Valenzuela, L M; Ortega, A P; Hidalgo, A A; Mora, G C

    2014-08-01

    ShdA from Salmonella Typhimurium (ShdASTm) is a large outer membrane protein that specifically recognizes and binds to fibronectin. ShdASTm is involved in the colonization of the cecum and the Peyer's patches of terminal ileum in mice. On the other hand, shdA gene from Salmonella Typhi (shdASTy) has been considered a pseudogene (i.e. a nonfunctional sequence of genomic DNA) due to the presence of deletions and mutations that gave rise to premature stop codons. In this work we show that, despite the deletions and mutations, shdASTy is fully functional. S. Typhi ΔshdA mutants presented an impaired adherence and invasion of HEp-2 pre-treated with TGF-β1, an inducer of fibronectin production. Moreover, shdA from S. Typhi and S. Typhimurium seem to be equivalent since shdASTm restored the adherence and invasion of S. Typhi ΔshdA mutant to wild type levels. In addition, anti-FLAG mAbs interfered with the adherence and invasion of the S. Typhi shdA-3xFLAG strain. Finally, shdASTy encodes a detectable protein when heterologously expressed in Escherichia coli DH5α. The data presented here show that shdASTy is not a pseudogene, but a different functional allele compared with shdASTm.

  13. Biosemiotic Entropy of the Genome: Mutations and Epigenetic Imbalances Resulting in Cancer

    Directory of Open Access Journals (Sweden)

    Samuel S. Shepard

    2013-01-01

    Full Text Available Biosemiotic entropy involves the deterioration of biological sign systems. The genome is a coded sign system that is connected to phenotypic outputs through the interpretive functions of the tRNA/ribosome machinery. This symbolic sign system (semiosis at the core of all biology has been termed “biosemiosis”. Layers of biosemiosis and cellular information management are analogous in varying degrees to the semiotics of computer programming, spoken, and written human languages. Biosemiotic entropy — an error or deviation from a healthy state — results from errors in copying functional information (mutations and errors in the appropriate context or quantity of gene expression (epigenetic imbalance. The concept of biosemiotic entropy is a deeply imbedded assumption in the study of cancer biology. Cells have a homeostatic, preprogrammed, ideal or healthy state that is rooted in genomics, strictly orchestrated by epigenetic regulation, and maintained by DNA repair mechanisms. Cancer is an eminent illustration of biosemiotic entropy, in which the corrosion of genetic information via substitutions, deletions, insertions, fusions, and aberrant regulation results in malignant phenotypes. However, little attention has been given to explicitly outlining the paradigm of biosemiotic entropy in the context of cancer. Herein we distill semiotic theory (from the familiar and well understood spheres of human language and computer code to draw analogies useful for understanding the operation of biological semiosis at the genetic level. We propose that the myriad checkpoints, error correcting mechanisms, and immunities are all systems whose primary role is to defend against the constant pressure of biosemiotic entropy, which malignancy must shut down in order to achieve advanced stages. In lieu of the narrower tumor suppressor/oncogene model, characterization of oncogenesis into the biosemiotic framework of sign, index, or object entropy may allow for more

  14. Ethical guideposts for allelic variation databases.

    Science.gov (United States)

    Knoppers, B M; Laberge, C M

    2000-01-01

    Basically, a mutation database (MDB) is a repository where allelic variations are described and assigned within a specific gene locus. The purposes of an MDB may vary greatly and have different content and structure. The curator of an electronic and computer-based MDB will provide expert feedback (clinical and research). This requires ethical guideposts. Going to direct on-line public access for the content of an MDB or to interactive communication also raises other considerations. Currently, HUGO's MDI (Mutation Database Initiative) is the only integrated effort supporting and guiding the coordinated deployment of MDBs devoted to genetic diversity. Thus, HUGO's ethical "Statements" are applicable. Among the ethical principles, the obligation of preserving the confidentiality of information transferred by a collaborator to the curator is particularly important. Thus, anonymization of such data prior to transmission is essential. The 1997 Universal Declaration on the Human Genome and Human Rights of UNESCO addresses the participation of vulnerable persons. Researchers in charge of MDBs should ensure that information received on the testing of children or incompetent adults is subject to ethical review and approval in the country of origin. Caution should be taken against the involuntary consequences of public disclosure of results without complete explanation. Clear and enforceable regulations must be developed to protect the public against misuse of genetic databanks. Interaction with a databank could be seen as creating a "virtual" physician-patient relationship. However, interactive public MDBs should not give medical advice. We have identified new social ethical principles to govern different levels of complexity of genetic information. They are: reciprocity, mutuality, solidarity, and universality. Finally, precaution and prudence at this early stage of the MDI may not only avoid ethically inextricable conundrums but also provide for the respect for the rights

  15. Carrier Frequency Offset Estimation and I/Q Imbalance Compensation for OFDM Systems

    Directory of Open Access Journals (Sweden)

    M. Omair Ahmad

    2007-01-01

    Full Text Available Two types of radio-frequency front-end imperfections, that is, carrier frequency offset and the inphase/quadrature (I/Q imbalance are considered for orthogonal frequency division multiplexing (OFDM communication systems. A preamble-assisted carrier frequency estimator is proposed along with an I/Q imbalance compensation scheme. The new frequency estimator reveals the relationship between the inphase and the quadrature components of the received preamble and extracts the frequency offset from the phase shift caused by the frequency offset and the cross-talk interference due to the I/Q imbalance. The proposed frequency estimation algorithm is fast, efficient, and robust to I/Q imbalance. An I/Q imbalance estimation/compensation algorithm is also presented by solving a least-square problem formulated using the same preamble as employed for the frequency offset estimation. The computational complexity of the I/Q estimation scheme is further reduced by using part of the short symbols with a little sacrifice in the estimation accuracy. Computer simulation and comparison with some of the existing algorithms are conducted, showing the effectiveness of the proposed method.

  16. Allelic barley MLA immune receptors recognize sequence-unrelated avirulence effectors of the powdery mildew pathogen.

    Science.gov (United States)

    Lu, Xunli; Kracher, Barbara; Saur, Isabel M L; Bauer, Saskia; Ellwood, Simon R; Wise, Roger; Yaeno, Takashi; Maekawa, Takaki; Schulze-Lefert, Paul

    2016-10-18

    Disease-resistance genes encoding intracellular nucleotide-binding domain and leucine-rich repeat proteins (NLRs) are key components of the plant innate immune system and typically detect the presence of isolate-specific avirulence (AVR) effectors from pathogens. NLR genes define the fastest-evolving gene family of flowering plants and are often arranged in gene clusters containing multiple paralogs, contributing to copy number and allele-specific NLR variation within a host species. Barley mildew resistance locus a (Mla) has been subject to extensive functional diversification, resulting in allelic resistance specificities each recognizing a cognate, but largely unidentified, AVRa gene of the powdery mildew fungus, Blumeria graminis f. sp. hordei (Bgh). We applied a transcriptome-wide association study among 17 Bgh isolates containing different AVRa genes and identified AVRa1 and AVRa13, encoding candidate-secreted effectors recognized by Mla1 and Mla13 alleles, respectively. Transient expression of the effector genes in barley leaves or protoplasts was sufficient to trigger Mla1 or Mla13 allele-specific cell death, a hallmark of NLR receptor-mediated immunity. AVRa1 and AVRa13 are phylogenetically unrelated, demonstrating that certain allelic MLA receptors evolved to recognize sequence-unrelated effectors. They are ancient effectors because corresponding loci are present in wheat powdery mildew. AVRA1 recognition by barley MLA1 is retained in transgenic Arabidopsis, indicating that AVRA1 directly binds MLA1 or that its recognition involves an evolutionarily conserved host target of AVRA1 Furthermore, analysis of transcriptome-wide sequence variation among the Bgh isolates provides evidence for Bgh population structure that is partially linked to geographic isolation.

  17. Frequency of alleles conferring resistance to the Bt toxins Cry1Ac and Cry2Ab in Australian populations of Helicoverpa armigera (Lepidoptera: Noctuidae).

    Science.gov (United States)

    Mahon, R J; Olsen, K M; Downes, S; Addison, S

    2007-12-01

    Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) is an important lepidopteran pest of cotton (Gossypium spp.) in Australia and the Old World. From 2002, F2 screens were used to examine the frequency of resistance alleles in Australian populations of H. armigera to Bacillus thuringiensis (Bt) CrylAc and Cry2Ab, the two insecticidal proteins present in the transgenic cotton Bollgard II. At that time, Ingard (expressing Cry1Ac) cotton had been grown in Australia for seven seasons, and Bollgard II was about to be commercially released. The principal objective of our study was to determine whether sustained exposure caused an elevated frequency of alleles conferring resistance to Cry1Ac in a species with a track record of evolving resistance to conventional insecticides. No major alleles conferring resistance to Cry1Ac were found. The frequency of resistance alleles for Cry1Ac was <0.0003, with a 95% credibility interval between 0 and 0.0009. In contrast, alleles conferring resistance to Cry2Ab were found at a frequency of 0.0033 (0.0017, 0.0055). The first isolation of this allele was found before the widespread deployment of Bollgard II. For both toxins the experiment-wise detection probability was 94.4%. Our results suggest that alleles conferring resistance to Cry1Ac are rare and that a relatively high baseline frequency of alleles conferring resistance to Cry2Ab existed before the introduction of Bt cotton containing this toxin.

  18. Allele-Selective Transcriptome Recruitment to Polysomes Primed for Translation: Protein-Coding and Noncoding RNAs, and RNA Isoforms.

    Directory of Open Access Journals (Sweden)

    Roshan Mascarenhas

    Full Text Available mRNA translation into proteins is highly regulated, but the role of mRNA isoforms, noncoding RNAs (ncRNAs, and genetic variants remains poorly understood. mRNA levels on polysomes have been shown to correlate well with expressed protein levels, pointing to polysomal loading as a critical factor. To study regulation and genetic factors of protein translation we measured levels and allelic ratios of mRNAs and ncRNAs (including microRNAs in lymphoblast cell lines (LCL and in polysomal fractions. We first used targeted assays to measure polysomal loading of mRNA alleles, confirming reported genetic effects on translation of OPRM1 and NAT1, and detecting no effect of rs1045642 (3435C>T in ABCB1 (MDR1 on polysomal loading while supporting previous results showing increased mRNA turnover of the 3435T allele. Use of high-throughput sequencing of complete transcript profiles (RNA-Seq in three LCLs revealed significant differences in polysomal loading of individual RNA classes and isoforms. Correlated polysomal distribution between protein-coding and non-coding RNAs suggests interactions between them. Allele-selective polysome recruitment revealed strong genetic influence for multiple RNAs, attributable either to differential expression of RNA isoforms or to differential loading onto polysomes, the latter defining a direct genetic effect on translation. Genes identified by different allelic RNA ratios between cytosol and polysomes were enriched with published expression quantitative trait loci (eQTLs affecting RNA functions, and associations with clinical phenotypes. Polysomal RNA-Seq combined with allelic ratio analysis provides a powerful approach to study polysomal RNA recruitment and regulatory variants affecting protein translation.

  19. New Fuzzy Support Vector Machine for the Class Imbalance Problem in Medical Datasets Classification

    Directory of Open Access Journals (Sweden)

    Xiaoqing Gu

    2014-01-01

    Full Text Available In medical datasets classification, support vector machine (SVM is considered to be one of the most successful methods. However, most of the real-world medical datasets usually contain some outliers/noise and data often have class imbalance problems. In this paper, a fuzzy support machine (FSVM for the class imbalance problem (called FSVM-CIP is presented, which can be seen as a modified class of FSVM by extending manifold regularization and assigning two misclassification costs for two classes. The proposed FSVM-CIP can be used to handle the class imbalance problem in the presence of outliers/noise, and enhance the locality maximum margin. Five real-world medical datasets, breast, heart, hepatitis, BUPA liver, and pima diabetes, from the UCI medical database are employed to illustrate the method presented in this paper. Experimental results on these datasets show the outperformed or comparable effectiveness of FSVM-CIP.

  20. Outage Analysis of PLNC Based Bidirectional Relay Network in the presence of I/Q Imbalance

    Directory of Open Access Journals (Sweden)

    V.N.Senthil Kumaran

    2014-08-01

    Full Text Available Bidirectional relay network consists of two sources and a relay, where each node has a single antenna and operates in half duplex mode. The PLNC based OFDM system transmits numerous high data streams through narrow band flat fading subchannels to achieve high spectral efficiency over wide band channels. However in practice, I/Q imbalance is introduced at the radio frequency sections of the nodes affects the orthogonality among the subcarriers. In this paper, the bidirectional relay network is modelled with I/Q imbalance and the outage performance of Orthogonal Frequency Division Multiplexing (OFDM based bidirectional relay network which employs physical layer network coding (PLNC is analyzed in the presence of In-phase and Quadrature (I/Q imbalance at both the time slots.

  1. Genome-wide survey of allele-specific splicing in humans

    Directory of Open Access Journals (Sweden)

    Scheffler Konrad

    2008-06-01

    Full Text Available Abstract Background Accurate mRNA splicing depends on multiple regulatory signals encoded in the transcribed RNA sequence. Many examples of mutations within human splice regulatory regions that alter splicing qualitatively or quantitatively have been reported and allelic differences in mRNA splicing are likely to be a common and important source of phenotypic diversity at the molecular level, in addition to their contribution to genetic disease susceptibility. However, because the effect of a mutation on the efficiency of mRNA splicing is often difficult to predict, many mutations that cause disease through an effect on splicing are likely to remain undiscovered. Results We have combined a genome-wide scan for sequence polymorphisms likely to affect mRNA splicing with analysis of publicly available Expressed Sequence Tag (EST and exon array data. The genome-wide scan uses published tools and identified 30,977 SNPs located within donor and acceptor splice sites, branch points and exonic splicing enhancer elements. For 1,185 candidate splicing polymorphisms the difference in splicing between alternative alleles was corroborated by publicly available exon array data from 166 lymphoblastoid cell lines. We developed a novel probabilistic method to infer allele-specific splicing from EST data. The method uses SNPs and alternative mRNA isoforms mapped to EST sequences and models both regulated alternative splicing as well as allele-specific splicing. We have also estimated heritability of splicing and report that a greater proportion of genes show evidence of splicing heritability than show heritability of overall gene expression level. Our results provide an extensive resource that can be used to assess the possible effect on splicing of human polymorphisms in putative splice-regulatory sites. Conclusion We report a set of genes showing evidence of allele-specific splicing from an integrated analysis of genomic polymorphisms, EST data and exon array

  2. Influence of Motor Program on Correct Posture and Muscular Imbalance Correction in Pupils of Primary Schools (1-4 Grades

    Directory of Open Access Journals (Sweden)

    Pavol Bartík

    2013-01-01

    Full Text Available The paper presents the results of the research, focused on evaluation and development of correct posture and muscular imbalance correction in pupils of primary schools. The research involved 58 pupils of the fourth grade of primary school. The main method was educational experiment and tests for the evaluation of muscular imbalance and posture. We used the motor program, involving yoga exercises and fitball exercises in the experimental group. After the educational experiment, the posture and muscular imbalance in the experimental group improved if compared to the initial measurements. The research showed the positive effect of motor program on the posture and muscular imbalance.

  3. Multi-hop amplify-and-forward relaying cooperation in the presence of I/Q imbalance

    KAUST Repository

    Qi, Jian

    2013-06-01

    In this paper, multi-hop cooperative networks implementing channel state information (CSI)-assisted amplify-and-forward (AF) relaying in the presence of in-phase and quadrature-phase (I/Q) imbalance are investigated. We propose a compensation algorithm for the I/Q imbalance. The performance of the multi-hop CSI-assisted AF cooperative networks with and without compensation for I/Q imbalance in Nakagami-m fading environment is evaluated in terms of average symbol error probability. Numerical results are provided and show that the proposed compensation method can effectively mitigate the impact of I/Q imbalance. © 2013 IEEE.

  4. Chromosomal imbalances in successive moments of human bladder urothelial carcinoma

    DEFF Research Database (Denmark)

    Nascimento e Pontes, Merielen Garcia; da Silveira, Sara Martorelli; Trindade Filho, José Carlos de Souza;

    2013-01-01

    in 16p12, in line with suggestions that these chromosome regions contain genes critical for urinary bladder carcinogenesis. Within a same patient, tumors and their respective recurrences showed common genomic losses and gains, which implies that the genomic profile acquired by primary tumors...... cells expressing the p53 protein, suggesting that the apparently normal urothelium was genomically unstable. No numerical alterations of the chromosomes 7, 17, and 9p21 region were found by FISH during the periods "free-of-neoplasia." Our data are informative for further studies to better understand...

  5. Probing nuclear effects using single-transverse kinematic imbalance with MINERvA

    CERN Document Server

    Lu, X -G

    2016-01-01

    Kinematic imbalance of the final-state particles in the plane transverse to the neutrino direction provides a sensitive probe of nuclear effects. In this contribution, we report the MINERvA measurement of the single-transverse kinematic imbalance in neutrino charged-current quasielastic-like events on CH targets. To improve the momentum measurements of the final-state particles, we develop a method to select elastically scattering contained (ESC) protons and a general procedure to correct the transverse momentum scales.

  6. Probing nuclear effects using single-transverse kinematic imbalance with MINERvA

    Energy Technology Data Exchange (ETDEWEB)

    Lu, X. -G. [Oxford U.; Betancourt, M. [Fermilab

    2016-08-15

    Kinematic imbalance of the final-state particles in the plane transverse to the neutrino direction provides a sensitive probe of nuclear effects. In this contribution, we report the MINERvA measurement of the single-transverse kinematic imbalance in neutrino charged-current quasielastic-like events on CH targets. To improve the momentum measurements of the final-state particles, we develop a method to select elastically scattering contained (ESC) protons and a general procedure to correct the transverse momentum scales.

  7. Imbalance in resting state functional connectivity is associated with eating behaviors and adiposity in children

    Directory of Open Access Journals (Sweden)

    BettyAnn A. Chodkowski

    2016-01-01

    Conclusions: In the absence of any explicit eating-related stimuli, the developing brain is primed toward food approach and away from food avoidance behavior with increasing adiposity. Imbalance in resting state functional connectivity that is associated with non-homeostatic eating develops during childhood, as early as 8–13 years of age. Our results indicate the importance of identifying children at risk for obesity for earlier intervention. In addition to changing eating habits and physical activity, strategies that normalize neural functional connectivity imbalance are needed to maintain healthy weight. Mindfulness may be one such approach as it is associated with increased response inhibition and decreased impulsivity.

  8. In Operation Detection and Correction of Rotor Imbalance in Jet Engines Using Active Vibration Control

    Science.gov (United States)

    Manchala, Daniel W.; Palazzolo, Alan B.; Kascak, Albert F.; Montague, Gerald T.; Brown, Gerald V.; Lawrence, Charles; Klusman, Steve

    1994-01-01

    Jet Engines may experience severe vibration due to the sudden imbalance caused by blade failure. This research investigates employment of on board magnetic bearings or piezoelectric actuators to cancel these forces in flight. This operation requires identification of the source of the vibrations via an expert system, determination of the required phase angles and amplitudes for the correction forces, and application of the desired control signals to the magnetic bearings or piezo electric actuators. This paper will show the architecture of the software system, details of the control algorithm used for the sudden imbalance correction project described above, and the laboratory test results.

  9. Gene Deletion by Fluorescence-Reported Allelic Exchange Mutagenesis in Chlamydia trachomatis

    Directory of Open Access Journals (Sweden)

    Konrad E. Mueller

    2016-01-01

    Full Text Available Although progress in Chlamydia genetics has been rapid, genomic modification has previously been limited to point mutations and group II intron insertions which truncate protein products. The bacterium has thus far been intractable to gene deletion or more-complex genomic integrations such as allelic exchange. Herein, we present a novel suicide vector dependent on inducible expression of a chlamydial gene that renders Chlamydia trachomatis fully genetically tractable and permits rapid reverse genetics by fluorescence-reported allelic exchange mutagenesis (FRAEM. We describe the first available system of targeting chlamydial genes for deletion or allelic exchange as well as curing plasmids from C. trachomatis serovar L2. Furthermore, this approach permits the monitoring of mutagenesis by fluorescence microscopy without disturbing bacterial growth, a significant asset when manipulating obligate intracellular organisms. As proof of principle, trpA was successfully deleted and replaced with a sequence encoding both green fluorescent protein (GFP and β-lactamase. The trpA-deficient strain was unable to grow in indole-containing medium, and this phenotype was reversed by complementation with trpA expressed in trans. To assess reproducibility at alternate sites, FRAEM was repeated for genes encoding type III secretion effectors CTL0063, CTL0064, and CTL0065. In all four cases, stable mutants were recovered one passage after the observation of transformants, and allelic exchange was limited to the specific target gene, as confirmed by whole-genome sequencing. Deleted sequences were not detected by quantitative real-time PCR (qPCR from isogenic mutant populations. We demonstrate that utilization of the chlamydial suicide vector with FRAEM renders C. trachomatis highly amenable to versatile and efficient genetic manipulation.

  10. HPV16 Oncoproteins Induce MMPs/RECK-TIMP-2 Imbalance in Primary Keratinocytes: Possible Implications in Cervical Carcinogenesis

    Science.gov (United States)

    Cardeal, Laura Beatriz da Silva; Boccardo, Enrique; Termini, Lara; Rabachini, Tatiana; Andreoli, Maria Antonieta; di Loreto, Celso; Filho, Adhemar Longatto; Villa, Luisa Lina; Maria-Engler, Silvya Stuchi

    2012-01-01

    Cervical cancer is the third most common cancer in women worldwide. Persistent infection with high-risk HPV types, principally HPV16 and 18 is the main risk factor for the development of this malignancy. However, the onset of invasive tumor occurs many years after initial exposure in a minority of infected women. This suggests that other factors beyond viral infection are necessary for tumor establishment and progression. Tumor progression is characterized by an increase in secretion and activation of matrix metalloproteinases (MMPs) produced by either the tumor cells themselves or tumor-associated fibroblasts or macrophages. Increased MMPs expression, including MMP-2, MMP-9 and MT1-MMP, has been observed during cervical carcinoma progression. These proteins have been associated with degradation of ECM components, tumor invasion, metastasis and recurrence. However, few studies have evaluated the interplay between HPV infection and the expression and activity of MMPs and their regulators in cervical cancer. We analyzed the effect of HPV16 oncoproteins on the expression and activity of MMP-2, MMP-9, MT1-MMP, and their inhibitors TIMP-2 and RECK in cultures of human keratinocytes. We observed that E7 expression is associated with increased pro-MMP-9 activity in the epithelial component of organotypic cultures, while E6 and E7 oncoproteins co-expression down-regulates RECK and TIMP-2 levels in organotypic and monolayers cultures. Finally, a study conducted in human cervical tissues showed a decrease in RECK expression levels in precancer and cancer lesions. Our results indicate that HPV oncoproteins promote MMPs/RECK-TIMP-2 imbalance which may be involved in HPV-associated lesions outcome. PMID:22438955

  11. HPV16 oncoproteins induce MMPs/RECK-TIMP-2 imbalance in primary keratinocytes: possible implications in cervical carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Laura Beatriz da Silva Cardeal

    Full Text Available Cervical cancer is the third most common cancer in women worldwide. Persistent infection with high-risk HPV types, principally HPV16 and 18 is the main risk factor for the development of this malignancy. However, the onset of invasive tumor occurs many years after initial exposure in a minority of infected women. This suggests that other factors beyond viral infection are necessary for tumor establishment and progression. Tumor progression is characterized by an increase in secretion and activation of matrix metalloproteinases (MMPs produced by either the tumor cells themselves or tumor-associated fibroblasts or macrophages. Increased MMPs expression, including MMP-2, MMP-9 and MT1-MMP, has been observed during cervical carcinoma progression. These proteins have been associated with degradation of ECM components, tumor invasion, metastasis and recurrence. However, few studies have evaluated the interplay between HPV infection and the expression and activity of MMPs and their regulators in cervical cancer. We analyzed the effect of HPV16 oncoproteins on the expression and activity of MMP-2, MMP-9, MT1-MMP, and their inhibitors TIMP-2 and RECK in cultures of human keratinocytes. We observed that E7 expression is associated with increased pro-MMP-9 activity in the epithelial component of organotypic cultures, while E6 and E7 oncoproteins co-expression down-regulates RECK and TIMP-2 levels in organotypic and monolayers cultures. Finally, a study conducted in human cervical tissues showed a decrease in RECK expression levels in precancer and cancer lesions. Our results indicate that HPV oncoproteins promote MMPs/RECK-TIMP-2 imbalance which may be involved in HPV-associated lesions outcome.

  12. HPV16 oncoproteins induce MMPs/RECK-TIMP-2 imbalance in primary keratinocytes: possible implications in cervical carcinogenesis.

    Science.gov (United States)

    Cardeal, Laura Beatriz da Silva; Boccardo, Enrique; Termini, Lara; Rabachini, Tatiana; Andreoli, Maria Antonieta; di Loreto, Celso; Longatto Filho, Adhemar; Villa, Luisa Lina; Maria-Engler, Silvya Stuchi

    2012-01-01

    Cervical cancer is the third most common cancer in women worldwide. Persistent infection with high-risk HPV types, principally HPV16 and 18 is the main risk factor for the development of this malignancy. However, the onset of invasive tumor occurs many years after initial exposure in a minority of infected women. This suggests that other factors beyond viral infection are necessary for tumor establishment and progression. Tumor progression is characterized by an increase in secretion and activation of matrix metalloproteinases (MMPs) produced by either the tumor cells themselves or tumor-associated fibroblasts or macrophages. Increased MMPs expression, including MMP-2, MMP-9 and MT1-MMP, has been observed during cervical carcinoma progression. These proteins have been associated with degradation of ECM components, tumor invasion, metastasis and recurrence. However, few studies have evaluated the interplay between HPV infection and the expression and activity of MMPs and their regulators in cervical cancer. We analyzed the effect of HPV16 oncoproteins on the expression and activity of MMP-2, MMP-9, MT1-MMP, and their inhibitors TIMP-2 and RECK in cultures of human keratinocytes. We observed that E7 expression is associated with increased pro-MMP-9 activity in the epithelial component of organotypic cultures, while E6 and E7 oncoproteins co-expression down-regulates RECK and TIMP-2 levels in organotypic and monolayers cultures. Finally, a study conducted in human cervical tissues showed a decrease in RECK expression levels in precancer and cancer lesions. Our results indicate that HPV oncoproteins promote MMPs/RECK-TIMP-2 imbalance which may be involved in HPV-associated lesions outcome.

  13. Plasma neutrophil elastase and elafin imbalance is associated with acute respiratory distress syndrome (ARDS development.

    Directory of Open Access Journals (Sweden)

    Zhaoxi Wang

    Full Text Available BACKGROUND: We conducted an exploratory study of genome-wide gene expression in whole blood and found that the expression of neutrophil elastase inhibitor (PI3, elafin was down-regulated during the early phase of ARDS. Further analyses of plasma PI3 levels revealed a rapid decrease during early ARDS development. PI3 and secretory leukocyte proteinase inhibitor (SLPI are important low-molecular-weight proteinase inhibitors produced locally at neutrophil infiltration site in the lung. In this study, we tested the hypothesis that an imbalance between neutrophil elastase (HNE and its inhibitors in blood is related to the development of ARDS. METHODOLOGY/PRINCIPAL FINDINGS: PI3, SLPI, and HNE were measured in plasma samples collected from 148 ARDS patients and 63 critical ill patients at risk for ARDS (controls. Compared with the controls, the ARDS patients had higher HNE, but lower PI3, at the onset of ARDS, resulting in increased HNE/PI3 ratio (mean = 14.5; 95% CI, 10.9-19.4, P<0.0001, whereas plasma SLPI was not associated with the risk of ARDS development. Although the controls had elevated plasma PI3 and HNE, their HNE/PI3 ratio (mean = 6.5; 95% CI, 4.9-8.8 was not significantly different from the healthy individuals (mean = 3.9; 95% CI, 2.7-5.9. Before the onset (7-days period prior to ARDS diagnosis, we only observed significantly elevated HNE, but the HNE-PI3 balance remained normal. With the progress from prior to the onset of ARDS, the plasma level of PI3 declined, whereas HNE was maintained at a higher level, tilting the balance toward more HNE in the circulation as characterized by an increased HNE/PI3 ratio. In contrast, three days after ICU admission, there was a significant drop of HNE/PI3 ratio in the at-risk controls. CONCLUSIONS/SIGNIFICANCE: Plasma profiles of PI3, HNE, and HNE/PI3 may be useful clinical biomarkers in monitoring the development of ARDS.

  14. Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection - A prospective cross-sectional study

    Institute of Scientific and Technical Information of China (English)

    Golo Ahlenstiel; Tilman Sauerbruch; Ulrich Spengler; Rainer P Woitas; Agathe Iwan; Jacob Nattermann; Karin Bueren; Jürgen K Rockstroh; Hans H Brackmann; Bernd Kupfer; Oifert Landt; Amnon Peled

    2005-01-01

    AIM: Chemokines and their receptors are crucial for immune responses in HCV and HIV infection. RANTES gene polymorphisms lead to altered gene expression and influence the natural course of HIV infection. Therefore,these mutations may also affect the course of HIV/HCV coinfection.METHODS: We determined allele frequencies of RANTES-403 (G→A), RANTES-28 (C→G) and RANTESIN1.1 (T→C) polymorphisms using real-time PCR and hybridization probes in patients with HIV (n = 85), HCV (n= 112), HIV/HCV coinfection (n = 121), and 109 healthy controls. Furthermore, HIV and HCV loads as well as CD4+ and CD8+ cell counts were compared between different RANTES genotypes.RESULTS: Frequencies of RANTES-403 A, RANTES-28 G and RANTES-IN1.1 C alleles were higher in HIV infected patients than in healthy controls (-403: 28.2% vs 15.1%,P = 0.002; -28: 5.4% vs 2.8%, not significant; IN1.1:19.0% vs 11.0%, P = 0.038). In HIV/HCV coinfected patients, these RANTES alleles were less frequent than in patients with HIV infection alone (15.4% P = 0.002;1.7%; P = 0.048; 12.0%; not significant). Frequencies of these alleles were not significantly different between HIV/HCV positive patients, HCV positive patients and healthy controls.CONCLUSION: All three RANTES polymorphisms showed increased frequencies of the variant allele exclusively in patients with HIV monoinfection. The finding that the frequencies of these alleles remained unaltered in HIV/HCV coinfected patients suggests that HCV coinfection interferes with selection processes associated with these alleles in HIV infection.

  15. Heterozygous alleles restore male fertility to cytoplasmic male-sterile radish (Raphanus sativus L.): a case of overdominance.

    Science.gov (United States)

    Wang, Zhi Wei; De Wang, Chuan; Wang, Chuan; Gao, Lei; Mei, Shi Yong; Zhou, Yuan; Xiang, Chang Ping; Wang, Ting

    2013-04-01

    The practice of hybridization has greatly contributed to the increase in crop productivity. A major component that exploits heterosis in crops is the cytoplasmic male sterility (CMS)/nucleus-controlled fertility restoration (Rf) system. Through positional cloning, it is shown that heterozygous alleles (RsRf3-1/RsRf3-2) encoding pentatricopeptide repeat (PPR) proteins are responsible for restoring fertility to cytoplasmic male-sterile radish (Raphanus sativus L.). Furthermore, it was found that heterozygous alleles (RsRf3-1/RsRf3-2) show higher expression and RNA polymerase II occupancy in the CMS cytoplasmic background compared with their homozygous alleles (RsRf3-1/RsRf3-1 or RsRf3-2/RsRf3-2). These data provide new insights into the molecular mechanism of fertility restoration to cytoplasmic male-sterile plants and illustrate a case of overdominance.

  16. HLA Class I & II Alleles in Multiple Sclerosis patients from Puerto Rico

    Science.gov (United States)

    Miranda, María T.; Suárez, Erick; Abbas, Muneer; Chinea, Ángel; Tosado, Rafael; Mejías, Ida A; Boukli, Nawal; Dunston, Georgia M

    2015-01-01

    Multiple Sclerosis (MS) is a complex disease where genetic and environmental factors have been implicated. The onset of symptoms occurs in individuals from twenty to fifty years of age, producing a progressive impairment of motor, sensory and cognitive functions. MS is more frequent in females than in males with a ratio of 4:1. The prevalence of the MS varies among ethnics groups such as Europeans, Africans and Caucasians. The estimated prevalence of MS in Puerto Rico is 42 for each 100,000 habitants, which is more than the prevalence reported for Central America and the Caribbean. In spite of this prevalence, the genetic component of MS has not been explored in order to know the alleles’ expression of Puerto Rican MS patients and compare it with the allele expression in other ethnic groups. Thirty-five patients and 31 control subjects were genotyped. The allele frequencies expressed in this sample were similar to those expressed for Puerto Ricans in the National Marrow Donor Program Registry (n=3,149). The most prevalent alleles for MS patients were HLA-DRB1*01 and *03. HLA-DQB1*04 was the most frequent in the control group and HLA-A*30, in MS patients. These findings are in agreement with published data. HLA-DQB1*04 was a marginal protector in this sample and this role has not been described before. The accuracy of the results is limited due to the sample size. After performing a statistical power analysis it showed that by increasing the sample the values would be significant. PMID:23767380

  17. Sequencing of 15 new BoLA-DRB3 alleles.

    Science.gov (United States)

    Wang, K; Sun, D; Zhang, Y

    2008-08-01

    The class II DR of bovine major histocompatibility complex of cattle (BoLA) plays a central role in the regulation of the immune response through their ability to present those peptides to T-cell receptors. In this work, we sequenced the exon2 of DRB3 to identify new alleles in Chinese yellow cattle, a total of 15 new BoLA-DRB3 alleles were found.

  18. Robust identification of local adaptation from allele frequencies.

    Science.gov (United States)

    Günther, Torsten; Coop, Graham

    2013-09-01

    Comparing allele frequencies among populations that differ in environment has long been a tool for detecting loci involved in local adaptation. However, such analyses are complicated by an imperfect knowledge of population allele frequencies and neutral correlations of allele frequencies among populations due to shared population history and gene flow. Here we develop a set of methods to robustly test for unusual allele frequency patterns and correlations between environmental variables and allele frequencies while accounting for these complications based on a Bayesian model previously implemented in the software Bayenv. Using this model, we calculate a set of "standardized allele frequencies" that allows investigators to apply tests of their choice to multiple populations while accounting for sampling and covariance due to population history. We illustrate this first by showing that these standardized frequencies can be used to detect nonparametric correlations with environmental variables; these correlations are also less prone to spurious results due to outlier populations. We then demonstrate how these standardized allele frequencies can be used to construct a test to detect SNPs that deviate strongly from neutral population structure. This test is conceptually related to FST and is shown to be more powerful, as we account for population history. We also extend the model to next-generation sequencing of population pools-a cost-efficient way to estimate population allele frequencies, but one that introduces an additional level of sampling noise. The utility of these methods is demonstrated in simulations and by reanalyzing human SNP data from the Human Genome Diversity Panel populations and pooled next-generation sequencing data from Atlantic herring. An implementation of our method is available from http://gcbias.org.

  19. Paternal-specific S-allele transmission in sweet cherry (Prunus avium L.): the potential for sexual selection.

    Science.gov (United States)

    Hedhly, A; Wünsch, A; Kartal, Ö; Herrero, M; Hormaza, J I

    2016-03-01

    Homomorphic self-incompatibility is a well-studied example of a physiological process that is thought to increase population diversity and reduce the expression of inbreeding depression. Whereas theoretical models predict the presence of a large number of S-haplotypes with equal frequencies at equilibrium, unequal allele frequencies have been repeatedly reported and attributed to sampling effects, population structure, demographic perturbation, sheltered deleterious mutations or selection pressure on linked genes. However, it is unclear to what extent unequal segregations are the results of gametophytic or sexual selection. Although these two forces are difficult to disentangle, testing S-alleles in the offspring of controlled crosses provides an opportunity to separate these two phenomena. In this work, segregation and transmission of S-alleles have been characterized in progenies of mixed donors and fully compatible pollinations under field conditions in Prunus avium. Seed set patterns and pollen performance have also been characterized. The results reveal paternal-specific distorted transmission of S-alleles in most of the crosses. Interestingly, S-allele segregation within any given paternal or maternal S-locus was random. Observations on pollen germination, pollen tube growth rate, pollen tube cohort size, seed set dynamics and transmission patterns strongly suggest post-pollination, prezygotic sexual selection, with male-male competition as the most likely mechanism. According to these results, post-pollination sexual selection takes precedence over frequency-dependent selection in explaining unequal S-haplotype frequencies.

  20. Absence of germline mono-allelic promoter hypermethylation of the CDH1 gene in gastric cancer patients

    Directory of Open Access Journals (Sweden)

    Ozawa Takachika

    2009-08-01

    Full Text Available Abstract Background Germline mono-allelic promoter hypermethylation of the MLH1 or MSH2 gene in families with hereditary nonpolyposis colorectal cancer has recently been reported. The purpose of this study was to evaluate if germline promoter hypermethylation of the tumor suppressor gene CDH1 (E-cadherin might cause predisposition to gastric cancer. Methods We prepared two groups of samples, a group of blood samples from 22 patients with familial gastric cancer or early-onset gastric cancer selected from among 39 patients, and a group of non-cancerous gastric tissue samples from 18 patients with sporadic gastric cancer showing loss of CDH1 expression selected from among 159 patients. We then investigated the allele-specific methylation status of the CDH1 promoter by bisulfite sequencing of multiple clones. Results Although there was a difference between the methylation level of the two alleles in some samples, there was no mono-allelic promoter hypermethylation in any of the samples. Conclusion These results suggest that germline mono-allelic hypermethylation of the CDH1 promoter is not a major predisposing factor for gastric cancer.

  1. SNPsplit: Allele-specific splitting of alignments between genomes with known SNP genotypes [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Felix Krueger

    2016-06-01

    Full Text Available Sequencing reads overlapping polymorphic sites in diploid mammalian genomes may be assigned to one allele or the other. This holds the potential to detect gene expression, chromatin modifications, DNA methylation or nuclear interactions in an allele-specific fashion. SNPsplit is an allele-specific alignment sorter designed to read files in SAM/BAM format and determine the allelic origin of reads or read-pairs that cover known single nucleotide polymorphic (SNP positions. For this to work libraries must have been aligned to a genome in which all known SNP positions were masked with the ambiguity base ’N’ and aligned using a suitable mapping program such as Bowtie2, TopHat, STAR, HISAT2, HiCUP or Bismark. SNPsplit also provides an automated solution to generate N-masked reference genomes for hybrid mouse strains based on the variant call information provided by the Mouse Genomes Project. The unique ability of SNPsplit to work with various different kinds of sequencing data including RNA-Seq, ChIP-Seq, Bisulfite-Seq or Hi-C opens new avenues for the integrative exploration of allele-specific data.

  2. SNPsplit: Allele-specific splitting of alignments between genomes with known SNP genotypes [version 2; referees: 3 approved

    Directory of Open Access Journals (Sweden)

    Felix Krueger

    2016-07-01

    Full Text Available Sequencing reads overlapping polymorphic sites in diploid mammalian genomes may be assigned to one allele or the other. This holds the potential to detect gene expression, chromatin modifications, DNA methylation or nuclear interactions in an allele-specific fashion. SNPsplit is an allele-specific alignment sorter designed to read files in SAM/BAM format and determine the allelic origin of reads or read-pairs that cover known single nucleotide polymorphic (SNP positions. For this to work libraries must have been aligned to a genome in which all known SNP positions were masked with the ambiguity base 'N' and aligned using a suitable mapping program such as Bowtie2, TopHat, STAR, HISAT2, HiCUP or Bismark. SNPsplit also provides an automated solution to generate N-masked reference genomes for hybrid mouse strains based on the variant call information provided by the Mouse Genomes Project. The unique ability of SNPsplit to work with various different kinds of sequencing data including RNA-Seq, ChIP-Seq, Bisulfite-Seq or Hi-C opens new avenues for the integrative exploration of allele-specific data.

  3. Socio-Cultural Imbalances in AIED Research: Investigations, Implications and Opportunities

    Science.gov (United States)

    Blanchard, Emmanuel G.

    2015-01-01

    This paper investigates international representations in the Artificial Intelligence in Education (AIED) research field. Its methodological and theoretical groundings are inspired by Arnett (2008) and Henrich et al. (2010a) who addressed the same issue in psychology, and respectively a) discovered massive imbalances in representation in top-tier…

  4. The impact of effort-reward imbalance and learning motivation on teachers' sickness absence.

    Science.gov (United States)

    Derycke, Hanne; Vlerick, Peter; Van de Ven, Bart; Rots, Isabel; Clays, Els

    2013-02-01

    The aim of this study was to analyse the impact of the effort-reward imbalance and learning motivation on sickness absence duration and sickness absence frequency among beginning teachers in Flanders (Belgium). A total of 603 teachers, who recently graduated, participated in this study. Effort-reward imbalance and learning motivation were assessed by means of self-administered questionnaires. Prospective data of registered sickness absence during 12 months follow-up were collected. Multivariate logistic regression analyses were performed. An imbalance between high efforts and low rewards (extrinsic hypothesis) was associated with longer sickness absence duration and more frequent absences. A low level of learning motivation (intrinsic hypothesis) was not associated with longer sickness absence duration but was significantly positively associated with sickness absence frequency. No significant results were obtained for the interaction hypothesis between imbalance and learning motivation. Further research is needed to deepen our understanding of the impact of psychosocial work conditions and personal resources on both sickness absence duration and frequency. Specifically, attention could be given to optimizing or reducing efforts spent at work, increasing rewards and stimulating learning motivation to influence sickness absence.

  5. Effort-Reward Imbalance for Learning Is Associated with Fatigue in School Children

    Science.gov (United States)

    Fukuda, Sanae; Yamano, Emi; Joudoi, Takako; Mizuno, Kei; Tanaka, Masaaki; Kawatani, Junko; Takano, Miyuki; Tomoda, Akemi; Imai-Matsumura, Kyoko; Miike, Teruhisa; Watanabe, Yasuyoshi

    2010-01-01

    We examined relationships among fatigue, sleep quality, and effort-reward imbalance for learning in school children. We developed an effort-reward for learning scale in school students and examined its reliability and validity. Self-administered surveys, including the effort reward for leaning scale and fatigue scale, were completed by 1,023…

  6. Structural imbalance promotes behavior analogous to aesthetic preference in domestic chicks.

    Directory of Open Access Journals (Sweden)

    Mark A Elliott

    Full Text Available BACKGROUND: Visual images may be judged 'aesthetic' when their positioning appears imbalanced. An apparent imbalance may signify an as yet incomplete action or event requiring more detailed processing. As such it may refer to phylogenetically ancient stimulus-response mechanisms such as those mediating attentional deployment. METHODOLOGY/PRINCIPAL FINDINGS: We studied preferences for structural balance or imbalance in week-old domestic chicks (Gallus gallus, using a conditioning procedure to reinforce pecking at either "aligned" (balanced or "misaligned" (imbalanced training stimuli. A testing phase with novel balanced and imbalanced stimuli established whether chicks would retain their conditioned behavior or revert to chance responding. Whereas those trained on aligned stimuli were equally likely to choose aligned or misaligned stimuli, chicks trained on misaligned stimuli maintained the trained preference. CONCLUSIONS/SIGNIFICANCE: Our results are consistent with the idea that the coding of structural imbalance is primary and even overrides classical conditioning. Generalized to the humans, these results suggest aesthetic judgments based upon structural imbalance may be based on evolutionarily ancient mechanisms, which are shared by different vertebrate species.

  7. Analysis of the impact of imbalance settlement design on market behaviour in electricity balancing markets

    NARCIS (Netherlands)

    Van der Veen, R.A.C.; Abbasy, A.; Hakvoort, R.A.

    2010-01-01

    The imbalance settlement design is the part of an electricity balancing market design that stimulates so-called Balance Responsible Parties (BRPs) to balance their electricity production and consumption portfolio and to stick to their energy schedules by penalizing any deviations from these schedule

  8. Reverse knowledge and technology transfer: imbalances caused by cognitive barriers in asymmetric relationships

    NARCIS (Netherlands)

    Millar, Carla C.J.M.; Choi, Chong Ju

    2009-01-01

    An imbalance exists in almost any type of knowledge and technology transfer due to the information asymmetry of the relationship. However, this is especially the case for reverse technology and knowledge transfer which is epitomised for us by "transfers from an MNC's subsidiary to its headquarters".

  9. Is Visuospatial Hemineglect Longitudinally Associated With Postural Imbalance in the Postacute Phase of Stroke?

    NARCIS (Netherlands)

    van Nes, Ilse J. W.; van Kessel, Marlies E.; Schils, Fanny; Fasotti, Luciano; Geurts, Alexander C. H.; Kwakkel, Gert

    2009-01-01

    Introduction. The purpose of this study was to determine the longitudinal association of visuospatial hemineglect with postural imbalance in postacute stroke patients and to establish whether this relationship is confounded by other determinants. Methods. A prospective cohort study of 53 postacute s

  10. Effort reward imbalance is associated with vagal withdrawal in Danish public sector employees

    DEFF Research Database (Denmark)

    Eller, Nanna Hurwitz; Blønd, Morten; Nielsen, Martin

    2011-01-01

    The current study analyzed the relationship between psychosocial work environment assessed by the Effort Reward Imbalance Model (ERI-model) and heart rate variability (HRV) measured at baseline and again, two years later, as this relationship is scarcely covered by the literature....

  11. ICI mitigation in concurrent multi-band receiver due to the phase noise and IQ imbalance

    Science.gov (United States)

    Lee, Hui-Kyu; Ryu, Heung-Gyoon

    2012-06-01

    For the next generation long-term evolution (LTE) advanced mobile communication system, 100 MHz bandwidth and 1 Gbit/s data speed are needed. However, there is not enough and wide vacant frequency band. Therefore, spectrum aggregation method has been studied to extend available frequency bands. Frequency synthesiser and power amplifier of transceiver should cover this wide bandwidth. The phase noise and In-phase and quadrature (IQ) imbalance would increase, which would be a serious problem in this transceiver. Also, signal-to-noise ratio becomes degraded because of nonlinearity and the quantisation noises of the Analog-to-digital conversion (ADC) in the receiver. Uplink of LTE-advanced uses Aggregated DFT-spread (NxDFT-S) orthogonal frequency division multiplexing (OFDM) signals. Since the effect of the phase noise and IQ imbalance are more serious in the multi-band Discrete Fourier transform (DFT)-spreading OFDM system, we like to analyse the effect of inter-carrier interference in frequency domain of receiver and the degradation of bit error rate (BER) performance. Also, by the channel response in frequency domain of the uplink system, we separate phase noise and IQ imbalance effect. Finally, we like to propose a compensation method that estimates the channel exactly and removes IQ imbalance and phase noise. Simulation result shows that the proposed method achieves the 2 dB performance gain of BER = 10-4.

  12. An accurate autonomous islanding microgrid reactive power, imbalance power and harmonic power sharing scheme

    DEFF Research Database (Denmark)

    He, Jinwei; Li, Yun Wei; Blaabjerg, Frede

    2013-01-01

    To address inaccurate power sharing problems in autonomous islanding microgrids, an enhanced droop control method through adaptive virtual impedance adjustment is proposed. First, a term associated with DG reactive power, imbalance power or harmonic power is added to the conventional real power...

  13. Cognitive vulnerability and implicit emotional processing : imbalance in frontolimbic brain areas?

    NARCIS (Netherlands)

    Groenewold, Nynke A.; Roest, Annelieke M.; Renken, Remco J.; Opmeer, Esther M.; Veltman, Dick J.; van der Wee, Nic J. A.; de Jonge, Peter; Aleman, Andre; Harmer, Catherine J.

    2015-01-01

    It has been proposed that the neural basis for cognitive vulnerability to depression involves an imbalance in frontolimbic activity during the processing of cues with a negative affective value. Although the question is central to cognitive theory, whether this association is amplified by diagnosis

  14. The Mental Effort-Reward Imbalances Model and Its Implications for Behaviour Management

    Science.gov (United States)

    Poulton, Alison; Whale, Samina; Robinson, Joanne

    2016-01-01

    Attention deficit hyperactivity disorder (ADHD) is frequently associated with oppositional defiant disorder (ODD). The Mental Effort Reward Imbalances Model (MERIM) explains this observational association as follows: in ADHD a disproportionate level of mental effort is required for sustaining concentration for achievement; in ODD the subjective…

  15. Mannose-binding lectin variant alleles and HLA-DR4 alleles are associated with giant cell arteritis

    DEFF Research Database (Denmark)

    Jacobsen, Soren; Baslund, Bo; Madsen, Hans O.

    2002-01-01

    OBJECTIVE: To determine whether variant alleles of the mannose-binding lectin (MBL) gene causing low serum concentrations of MBL and/or polymorphisms of HLA-DRB1 are associated with increased susceptibility to polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) or particular clinical...... phenotypes of PMR/GCA. METHODS: MBL and HLA-DRB1 alleles were determined by polymerase chain reaction in 102 Danish patients with PMR (n = 37) or GCA (n = 65). Two hundred fifty and 193 healthy individuals served as controls for MBL and HLA genotyping, respectively. RESULTS: The prevalence of MBL variant...... alleles in controls, patients with PMR only, and patients with GCA was 37, 32, and 53% (p = 0.01), respectively. HLA-DRB1*04 was found in 47% of patients with PMR only and in 54% of patients with GCA, which differed significantly from the 35% found in controls (p = 0.01). HLA-DR4 alleles were...

  16. Impaired Uptake and/or Utilization of Leucine by Saccharomyces cerevisiae Is Suppressed by the SPT15-300 Allele of the TATA-Binding Protein Gene

    DEFF Research Database (Denmark)

    Baerends, RJ; Qiu, Jin-Long; Rasmussen, Simon;

    2009-01-01

    us to examine the effect of expression of the SPT15-300 allele in various yeast species of industrial importance. Expression of SPT15-300 in leucine-prototrophic strains of S. cerevisiae, Saccharomyces bayanus, or Saccharomyces pastorianus (lager brewing yeast), however, did not improve tolerance...

  17. Molecular chaperones and proteostasis regulation during redox imbalance

    Directory of Open Access Journals (Sweden)

    Katerina Niforou

    2014-01-01

    Full Text Available Free radicals originate from both exogenous environmental sources and as by-products of the respiratory chain and cellular oxygen metabolism. Sustained accumulation of free radicals, beyond a physiological level, induces oxidative stress that is harmful for the cellular homeodynamics as it promotes the oxidative damage and stochastic modification of all cellular biomolecules including proteins. In relation to proteome stability and maintenance, the increased concentration of oxidants disrupts the functionality of cellular protein machines resulting eventually in proteotoxic stress and the deregulation of the proteostasis (homeostasis of the proteome network (PN. PN curates the proteome in the various cellular compartments and the extracellular milieu by modulating protein synthesis and protein machines assembly, protein recycling and stress responses, as well as refolding or degradation of damaged proteins. Molecular chaperones are key players of the PN since they facilitate folding of nascent polypeptides, as well as holding, folding, and/or degradation of unfolded, misfolded, or non-native proteins. Therefore, the expression and the activity of the molecular chaperones are tightly regulated at both the transcriptional and post-translational level at organismal states of increased oxidative and, consequently, proteotoxic stress, including ageing and various age-related diseases (e.g. degenerative diseases and cancer. In the current review we present a synopsis of the various classes of intra- and extracellular chaperones, the effects of oxidants on cellular homeodynamics and diseases and the redox regulation of chaperones.

  18. [Polymorphism of human HLA-DRB1 leukocyte antigen alleles and its association to juvenile rheumatoid arthritis in a sample of Colombian mestizo children].

    Science.gov (United States)

    Garavito, Gloria; Malagón, Clara; Ramírez, Luis A; De La Cruz, Oscar F; Uribe, Oscar; Navarro, Edgar; Iglesias, Antonio; Martínez, Paz; Jaraquemada, Dolores; Egea, Eduardo

    2003-09-01

    Oligotypes of the human leukocyte antigen HLA Class II, DRB1 alleles were characterized at the molecular level in a group of Colombian children suffering juvenile rheumatoid arthritis (JRA). The distribution of these alleles was examined in a group of Colombian mestizo children (genetic admixture of Amerindians, Europeans and Africans) suffering from clinically distinct JRA subsets in order to detect HLA allele frequency differences in patients with different JRA subsets. A group of 65 patients with JRA and 65 controls were characterized for the subtypes of the HLA-DRB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide probes (PCR-SSOP). The oligotyping protocol recommended by the 12th International Histocompatibility Workshop held in St. Malo, Paris, in 1996, was used. Subtype HLA-DRB1*1104 was the allele most strongly associated with susceptibility to JRA (Fisher's p = 0.013, odds ratio (OR) = 16.79, etiologic fraction (EF) = 0.93). HLA-DRB1*1602 was also associated with susceptibility to a lesser degree (Fisher's p = 0.016, OR = 8.98, EF = 0.88). HLA-DRB1 alleles participating in JRA protection were HLA-DRB1*1501 (preventive fraction (PF) = 0.466, p = 0.005) and HLA DRB1*1402 (PF = 0.49, p = 0.009). The relationship between some HLA-DRB1 alleles and clinical features was also compared. The presence of rheumatic factor was associated with the alleles HLA-DRB1*0407 (p = 0.05, OR = 11.2, EF = 0.45) and HLA-DRB1*1302 (p = 0.02, OR = 22.8, EF = 0.63). There was also an association between HLA-DRB1*0701 (p = 0.001, OR = 58, EF = 0.73) with expressing ANA +. We found that in the oligoarticular subset, the allele HLA-DRB1*1104 (p = 0.0034, OR = 41.53, EF = 0.97) was the one expressed most commonly. In the poliarticular group, the alleles most frequently expressed were HLA-DRB1*0404 (Fisher's p = 0.012, OR = 8.75, EF = 0.88). In patients with systemic JRA, the HLA-DRB1*1602 allele (p = 0.005, OR = 21.33, EF = 0.95) was most frequent. These

  19. HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity.

    Directory of Open Access Journals (Sweden)

    Camilla Stephens

    Full Text Available BACKGROUND AND AIM: The genotype-phenotype interaction in drug-induced liver injury (DILI is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. METHODS: High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS: The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7 and B*1801 (P/Pc = 0.008/0.22, OR 2.9 were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0 was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019 and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2 and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15 were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07. CONCLUSIONS: HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

  20. Distribution of BoLA-DRB3 allelic frequencies and identification of two new alleles in Iranian buffalo breed.

    Science.gov (United States)

    Mosafer, J; Heydarpour, M; Manshad, E; Russell, G; Sulimova, G E

    2012-01-01

    The role of the major histocompatibility complex (MHC) in the immune response makes it an attractive candidate gene for associations with disease resistance and susceptibility. This study describes genetic variability in the BoLA-DRB3 in Iranian buffaloes. Heminested PCR-RFLP method was used to identify the frequency of BoLA-DRB3 alleles. The BoLA-DRB3 locus is highly polymorphic in the study herd (12 alleles). Almost 63.50% of the alleles were accounted for by four alleles (BoLA-DRB3.2 ∗48, ∗20, ∗21, and obe) in Iranian buffalo. The DRB3.2 ∗48 allele frequency (24.20%) was higher than the others. The frequencies of the DRB3.2 ∗20 and DRB3.2 ∗21 are 14.52 and 14.00, respectively, and obe and gbb have a new pattern. Significant distinctions have been found between Iranian buffalo and other cattle breed studied. In the Iranian buffaloes studied alleles associated with resistance to various diseases are found.

  1. Distribution of BoLA-DRB3 Allelic Frequencies and Identification of Two New Alleles in Iranian Buffalo Breed

    Directory of Open Access Journals (Sweden)

    J. Mosafer

    2012-01-01

    Full Text Available The role of the major histocompatibility complex (MHC in the immune response makes it an attractive candidate gene for associations with disease resistance and susceptibility. This study describes genetic variability in the BoLA-DRB3 in Iranian buffaloes. Heminested PCR-RFLP method was used to identify the frequency of BoLA-DRB3 alleles. The BoLA-DRB3 locus is highly polymorphic in the study herd (12 alleles. Almost 63.50% of the alleles were accounted for by four alleles (BoLA-DRB3.2 *48, *20, *21, and obe in Iranian buffalo. The DRB3.2 *48 allele frequency (24.20% was higher than the others. The frequencies of the DRB3.2 *20 and DRB3.2 *21 are 14.52 and 14.00, respectively, and obe and gbb have a new pattern. Significant distinctions have been found between Iranian buffalo and other cattle breed studied. In the Iranian buffaloes studied alleles associated with resistance to various diseases are found.

  2. Differential anti-influenza activity among allelic variants at the Sus scrofa Mx1 locus.

    Science.gov (United States)

    Palm, M; Leroy, M; Thomas, A; Linden, A; Desmecht, D

    2007-02-01

    A promising way to oppose infectious challenges would be to improve the resistance of the target species through genetic selection. Theoretically, a candidate gene is available against influenza viruses since a resistance trait was fortuitously discovered in the A2G mouse strain. This trait was demonstrated to be correlated with the expression of a specific isoform of the type I interferon (IFN)-dependent protein MX, an isoform coded by a specific allele at the mouse Mx1 locus. Two allelic polymorphisms were described recently in the Sus scrofa homologous gene. In this study, the frequencies and distribution of both alleles were evaluated among European domestic pig and wild boar populations by PCR-RFLP, and the anti-influenza activity conferred by both MX1 isoforms was evaluated in vitro using transfection of Vero cells followed by flow cytometric determination of the fraction of influenza virus-infected cells among MX-producing and MX-nonproducing cell populations. A significant difference in the anti-influenza activity brought by the two MX1 isoforms was demonstrated, which suggests that a significant improvement of innate resistance of pigs by genetic selection might be feasible provided the differences found here in vitro are epidemiologically relevant in vivo.

  3. Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder

    Science.gov (United States)

    2017-01-01

    The human brain is the outcome of innumerable evolutionary processes; the systems genetics of psychiatric disorders could bear their signatures. On this basis, we analyzed five psychiatric disorders, attention deficit hyperactivity disorder, autism spectrum disorder (ASD), bipolar disorder, major depressive disorder, and schizophrenia (SCZ), using GWAS summary statistics from the Psychiatric Genomics Consortium. Machine learning-derived scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele reached fixation) and incomplete selection (loci where a selected allele has not yet reached fixation). ASD GWAS results positively correlated with incomplete-selection (p = 3.53*10−4). Variants with ASD GWAS pgene-expression enrichments for brain and pituitary tissues (p = 2.3*10−5 and p = 3*10−5, respectively) and 53 gene ontology (GO) enrichments, such as nervous system development (GO:0007399, p = 7.57*10−12), synapse organization (GO:0050808, p = 8.29*10−7), and axon guidance (GO:0007411, p = 1.81*10−7). Previous genetic studies demonstrated that ASD positively correlates with childhood intelligence, college completion, and years of schooling. Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability. PMID:28187187

  4. Analyzing surface EMG signals to determine relationship between jaw imbalance and arm strength loss

    Directory of Open Access Journals (Sweden)

    Truong Quang Dang Khoa

    2012-08-01

    Full Text Available Abstract Background This study investigated the relationship between dental occlusion and arm strength; in particular, the imbalance in the jaw can cause loss in arm strength phenomenon. One of the goals of this study was to record the maximum forces that the subjects can resist against the pull-down force on their hands while biting a spacer of adjustable height on the right or left side of the jaw. Then EMG measurement was used to determine the EMG-Force relationship of the jaw, neck and arms muscles. This gave us useful insights on the arms strength loss due to the biomechanical effects of the imbalance in the jaw mechanism. Methods In this study to determine the effects of the imbalance in the jaw to the strength of the arms, we conducted experiments with a pool of 20 healthy subjects of both genders. The subjects were asked to resist a pull down force applied on the contralateral arm while biting on a firm spacer using one side of the jaw. Four different muscles – masseter muscles, deltoid muscles, bicep muscles and trapezoid muscles – were involved. Integrated EMG (iEMG and Higuchi fractal dimension (HFD were used to analyze the EMG signals. Results The results showed that (1 Imbalance in the jaw causes loss of arm strength contra-laterally; (2 The loss is approximately a linear function of the height of the spacers. Moreover, the iEMG showed the intensity of muscle activities decreased when the degrees of jaw imbalance increased (spacer thickness increased. In addition, the tendency of Higuchi fractal dimension decreased for all muscles. Conclusions This finding indicates that muscle fatigue and the decrease in muscle contraction level leads to the loss of arm strength.

  5. A nine-base pair deletion distinguishes two En/Spm transposon alleles in maize: Their genetic activity and molecular description

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    Menssen Adriane

    2008-01-01

    Full Text Available Two En/Spm-transposable element alleles of the A1 locus in maize (Zea mays are described. One of the alleles is al-m (papu, (PETERSON, 1961. The distinctive phenotype of this allele is characterized with pale and purple sectoring amidst large areas of no sectoring. The other allele, al-m (Au, appears full colored but is heavily mutating and expresses large colorless areas. These two alleles differ in the frequency of derivative products [al-m( papu-colorless and pale exceptions vs al- m(Au-mostly colorless exceptions]. A molecular description is provided in an attempt to explain these differences in phenotypes and derivative products. A nine-base-pair deficiency in Exon 2 of the A1 locus of the a1- m (papu allele originated following the origin of this allele and this deficiency is likely responsible for the differential phenotypes. The possible origin of this nine-base-pair deletion is discussed. .

  6. Bcl-2/caspase 3 mucosal imbalance favors T cell resistance to apoptosis in dogs with inflammatory bowel disease.

    Science.gov (United States)

    Jergens, A; Young, J; Moore, D; Wang, C; Hostetter, J; Augustine, L; Allenspach, K; Schmitz, S; Mosher, C

    2014-04-15

    Canine idiopathic inflammatory bowel disease (IBD) is believed to result from complex interplay between genetic, microbial, and immunologic factors. Abnormal cell death by apoptosis may result in the persistence of activated intestinal T cells that contribute to mucosal inflammation and clinical severity. To test this hypothesis, we investigated the mucosal expression of pro- and anti-apoptotic proteins in different intestinal compartments and their association with inflammatory indices in dogs with IBD. Apoptosis of lamina propria (LP) T cells in duodenal, ileal, and colonic tissues in control and IBD dogs was analyzed by caspase 3/Bcl-2 immunohistochemistry and TUNEL assays. Densities and distributions of LP caspase 3 and Bcl-2 cells were correlated to histopathologic lesions and the clinical activity index (CIBDAI). Compared to control tissues, IBD dogs had significantly (Pdogs, there were significantly greater numbers of Bcl-2 cells at the apical and basilar villus in the duodenum as compared to the colon and to the apical and basilar villus in the ileum (Pdogs compared with controls (Pdogs and the CIBDAI (Pdogs with IBD. Mucosal imbalance of Bcl-2/caspase 3 expression favors T cell resistance to apoptosis which may contribute to T cell accumulation and chronic intestinal inflammation, similar to human IBD.

  7. Treg/Th17 Cell Imbalance and IL-6 Profile in Patients With Unexplained Recurrent Spontaneous Abortion.

    Science.gov (United States)

    Zhu, Liqiong; Chen, Hui; Liu, Meilan; Yuan, Yu; Wang, Zhaohua; Chen, Ying; Wei, Jing; Su, Fang; Zhang, Jianping

    2016-10-02

    Regulatory T cells (Treg) and T helper 17 cells (Th17) are 2 distinct subsets of CD4(+) T cells, which are mutually antagonistic in the immune response. Recently, dysregulation of these 2 cell subsets have been described in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). The purpose of this study was to investigate whether the Treg/Th17 balance was perturbed in URSA patients and to explore contributing factors. We found that the proportion of Treg cells and expression of forkhead box P3 (Foxp3) messenger RNA (mRNA) were significantly lower in URSA patients than in healthy controls. However, the proportion of Th17 cells and expression of retinoid-related orphan nuclear receptor-γt (ROR-γt) mRNA were higher in URSA patients than in controls, revealing inverse correlation with Treg. The ratio of Treg/Th17 and Foxp3/ROR-γt decreased in patients with URSA compared to healthy controls. The serum levels of interleukin (IL)-6 and IL-17A were significantly higher, whereas IL-10 was lower in URSA patients compared with controls, and the level of IL-6 showed a positive correlation with Th17, ROR-γt and inverse correlation with Treg, Foxp3. The present study indicated that an imbalance between Treg and Th17 cells might be implicated in the pathogenesis of URSA and this seems to relate to elevation in serum IL-6 level.

  8. Novel SLA-DQ alleles and their recombinant molecules in xenogeneic stimulation of human T cells.

    Science.gov (United States)

    Chen, Fuxiang; Xie, Jin; Li, Ningli; Zhou, Yun; Xin, Lijun; Chou, Kuang-Yen

    2005-06-01

    MHC class II antigens DR and DQ are essential for graft rejection both in allo- and xeno-transplantation. The antigens, especially the DQA and DQB gene-coencoded DQ molecules, are also involved in transplantation tolerance induced by activation of regulatory T cells. Here we report six novel DQ alleles from three properly inbred Chinese pig strains Gz, Bm and Yn. In our study, cDNA of swine leukocyte antigen (SLA)-DQA and -DQB were amplified by RT-PCR and sequenced for each strain. The ORF-containing SLA-DQA and -DQB genes are composed of 768 (or 765) and 786 nucleotides, encoding antigen molecules of 255 (or 254) and 261 amino acid residues, respectively. Sequences of both SLA-DQA and -DQB alleles showed disparities when compared either among the three pig strains or with available SLA data, which allows our novel alleles receiving their accession numbers from GenBank. The sequence analysis further revealed a phylogenic connection of our SLA-DQ alleles with SLA-DQ(c) haplotype. In addition, the homologies of MHC DQ or DQ-like molecules between Chinese pigs (SLA) and human (HLA) are higher than those between pigs and mice (H-2). By co-transfection of Bm pig DQA and DQB genes into L929 cells, the Bm-DQ heterodimer-expressed cells could effectively stimulate the human lymphoproliferation in presence of human APCs with a mean stimulation index (SI) 9.9+/-1.4. This functional assay indicated that our recombinant DQ antigens are capable of initiating human lymphoproliferation in a xeno-MLR.

  9. Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects

    Science.gov (United States)

    Redig, Jennifer K.; Fouad, Gameil T.; Babcock, Darcie; Reshey, Benjamin; Feingold, Eleanor; Reeves, Roger H.; Maslen, Cheryl L.

    2014-01-01

    Atrioventricular septal defects (AVSD) are highly heritable, clinically significant congenital heart malformations. Genetic and environmental modifiers of risk are thought to work in unknown combinations to cause AVSD. Approximately 5–10% of simplex AVSD cases carry a missense mutation in CRELD1. However, CRELD1 mutations are not fully penetrant and require interactions with other risk factors to result in AVSD. Vascular endothelial growth factor-A (VEGFA) is a well-characterized modulator of heart valve development. A functional VEGFA polymorphism, VEGFA c.–634C, which causes constitutively increased VEGFA expression, has been associated with cardiac septal defects suggesting it may be a genetic risk factor. To determine if there is an allelic association with AVSD we genotyped the VEGFA c.–634 SNP in a simplex AVSD study cohort. Over-representation of the c.–634C allele in the AVSD group suggested that this genotype may increase risk. Correlation of CRELD1 and VEGFA genotypes revealed that potentially pathogenic missense mutations in CRELD1 were always accompanied by the VEGFA c.–634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used a Creld1 knockout mouse model to determine the effect of deficiency of Creld1 combined with increased VEGFA on atrioventricular canal development. Morphogenic response to VEGFA was abnormal in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis. This supports our hypothesis that an additive effect between missense mutations in CRELD1 and a functional SNP in VEGFA contributes to the pathogenesis of AVSD. PMID:25328912

  10. Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects

    Directory of Open Access Journals (Sweden)

    Jennifer K. Redig

    2014-03-01

    Full Text Available Atrioventricular septal defects (AVSD are highly heritable, clinically significant congenital heart malformations. Genetic and environmental modifiers of risk are thought to work in unknown combinations to cause AVSD. Approximately 5–10% of simplex AVSD cases carry a missense mutation in CRELD1. However, CRELD1 mutations are not fully penetrant and require interactions with other risk factors to result in AVSD. Vascular endothelial growth factor-A (VEGFA is a well-characterized modulator of heart valve development. A functional VEGFA polymorphism, VEGFA c.-634C, which causes constitutively increased VEGFA expression, has been associated with cardiac septal defects suggesting it may be a genetic risk factor. To determine if there is an allelic association with AVSD we genotyped the VEGFA c.-634 SNP in a simplex AVSD study cohort. Over-representation of the c.-634C allele in the AVSD group suggested that this genotype may increase risk. Correlation of CRELD1 and VEGFA genotypes revealed that potentially pathogenic missense mutations in CRELD1 were always accompanied by the VEGFA c.-634C allele in individuals with AVSD suggesting a potentially pathogenic allelic interaction. We used a Creld1 knockout mouse model to determine the effect of deficiency of Creld1 combined with increased VEGFA on atrioventricular canal development. Morphogenic response to VEGFA was abnormal in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis. This supports our hypothesis that an additive effect between missense mutations in CRELD1 and a functional SNP in VEGFA contributes to the pathogenesis of AVSD.

  11. The retarded hair growth (rhg mutation in mice is an allele of ornithine aminotransferase (Oat

    Directory of Open Access Journals (Sweden)

    Jason J. Bisaillon

    2014-01-01

    Full Text Available Because of the similar phenotypes they generate and their proximate reported locations on Chromosome 7, we tested the recessive retarded hair growth (rhg and frizzy (fr mouse mutations for allelism, but found instead that these defects complement. To discover the molecular basis of rhg, we analyzed a large intraspecific backcross panel that segregated for rhg and restricted this locus to a 0.9 Mb region that includes fewer than ten genes, only five of which have been reported to be expressed in skin. Complementation testing between rhg and a recessive null allele of fibroblast growth factor receptor 2 eliminated Fgfr2 as the possible basis of the retarded hair growth phenotype, but DNA sequencing of another of these candidates, ornithine aminotransferase (Oat, revealed a G to C transversion specifically associated with the rhg allele that would result in a glycine to alanine substitution at residue 353 of the gene product. To test whether this missense mutation might cause the mutant phenotype, we crossed rhg/rhg mice with mice that carried a recessive, perinatal-lethal, null mutation in Oat (designated OatΔ herein. Hybrid offspring that inherited both rhg and OatΔ displayed markedly delayed postnatal growth and hair development, indicating that these two mutations are allelic, and suggesting strongly that the G to C mutation in Oat is responsible for the retarded hair growth phenotype. Comparisons among +/+, +/rhg, rhg/rhg and rhg/OatΔ mice showed plasma ornithine levels and ornithine aminotransferase activities (in liver lysates consistent with this assignment. Because histology of 7- and 12-month-old rhg/rhg and rhg/OatΔ retinas revealed chorioretinal degeneration similar to that described previously for OatΔ/OatΔ mice, we suggest that the rhg mutant may offer an ideal model for gyrate atrophy of the choroid and retina (GACR in humans, which is also caused by the substitution of glycine 353 in some families.

  12. Sexual selection by female immunity against paternal antigens can fix loss of function alleles.

    Science.gov (United States)

    Ghaderi, Darius; Springer, Stevan A; Ma, Fang; Cohen, Miriam; Secrest, Patrick; Taylor, Rachel E; Varki, Ajit; Gagneux, Pascal

    2011-10-25

    Humans lack the common mammalian cell surface molecule N-glycolylneuraminic acid (Neu5Gc) due to a CMAH gene inactivation, which occurred approximately three million years ago. Modern humans produce antibodies specific for Neu5Gc. We hypothesized that anti-Neu5Gc antibodies could enter the female reproductive tract and target Neu5Gc-positive sperm or fetal tissues, reducing reproductive compatibility. Indeed, female mice with a human-like Cmah(-/-) mutation and immunized to express anti-Neu5Gc antibodies show lower fertility with Neu5Gc-positive males, due to prezygotic incompatibilities. Human anti-Neu5Gc antibodies are also capable of targeting paternally derived antigens and mediate cytotoxicity against Neu5Gc-bearing chimpanzee sperm in vitro. Models of populations polymorphic for such antigens show that reproductive incompatibility by female immunity can drive loss-of-function alleles to fixation from moderate initial frequencies. Initially, the loss of a cell-surface antigen can occur due to drift in isolated populations or when natural selection favors the loss of a receptor exploited by pathogens, subsequently the same loss-of-function allele can come under sexual selection because it avoids being targeted by the female immune system. Thus, we provide evidence of a link between sexual selection and immune function: Antigenicity in females can select against foreign paternal antigens on sperm and rapidly fix loss-of-function alleles. Similar circumstances existed when the CMAH null allele was polymorphic in ancestral hominins, just before the divergence of Homo from australopithecines.

  13. Splicing imbalances in basal-like breast cancer underpin perturbation of cell surface and oncogenic pathways and are associated with patients’ survival

    Science.gov (United States)

    Gracio, Filipe; Burford, Brian; Gazinska, Patrycja; Mera, Anca; Mohd Noor, Aisyah; Marra, Pierfrancesco; Gillett, Cheryl; Grigoriadis, Anita; Pinder, Sarah; Tutt, Andrew; de Rinaldis, Emanuele

    2017-01-01

    Despite advancements in the use of transcriptional information to understand and classify breast cancers, the contribution of splicing to the establishment and progression of these tumours has only recently starting to emerge. Our work explores this lesser known landscape, with special focus on the basal-like breast cancer subtype where limited therapeutic opportunities and no prognostic biomarkers are currently available. Using ExonArray analysis of 176 breast cancers and 9 normal breast tissues we demonstrate that splicing levels significantly contribute to the diversity of breast cancer molecular subtypes and explain much of the differences compared with normal tissues. We identified pathways specifically affected by splicing imbalances whose perturbation would be hidden from a conventional gene-centric analysis of gene expression. We found that a large fraction of them involve cell-to-cell communication, extracellular matrix and transport, as well as oncogenic and immune-related pathways transduced by plasma membrane receptors. We identified 247 genes in which splicing imbalances are associated with clinical patients’ outcome, whilst no association was detectable at the gene expression level. These include the signaling gene TGFBR1, the proto-oncogene MYB as well as many immune-related genes such as CCR7 and FCRL3, reinforcing evidence for a role of immune components in influencing breast cancer patients’ prognosis. PMID:28059167

  14. Natural variation in the Pto pathogen resistance gene within species of wild tomato (Lycopersicon). I. Functional analysis of Pto alleles.

    Science.gov (United States)

    Rose, Laura E; Langley, Charles H; Bernal, Adriana J; Michelmore, Richard W

    2005-09-01

    Disease resistance to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) in the cultivated tomato, Lycopersicon esculentum, and the closely related L. pimpinellifolium is triggered by the physical interaction between plant disease resistance protein, Pto, and the pathogen avirulence protein, AvrPto. To investigate the extent to which variation in the Pto gene is responsible for naturally occurring variation in resistance to Pst, we determined the resistance phenotype of 51 accessions from seven species of Lycopersicon to isogenic strains of Pst differing in the presence of avrPto. One-third of the plants displayed resistance specifically when the pathogen expressed AvrPto, consistent with a gene-for-gene interaction. To test whether this resistance in these species was conferred specifically by the Pto gene, alleles of Pto were amplified and sequenced from 49 individuals and a subset (16) of these alleles was tested in planta using Agrobacterium-mediated transient assays. Eleven alleles conferred a hypersensitive resistance response (HR) in the presence of AvrPto, while 5 did not. Ten amino acid substitutions associated with the absence of AvrPto recognition and HR were identified, none of which had been identified in previous structure-function studies. Additionally, 3 alleles encoding putative pseudogenes of Pto were isolated from two species of Lycopersicon. Therefore, a large proportion, but not all, of the natural variation in the reaction to strains of Pst expressing AvrPto can be attributed to sequence variation in the Pto gene.

  15. A microRNA allele that emerged prior to apple domestication may underlie fruit size evolution.

    Science.gov (United States)

    Yao, Jia-Long; Xu, Juan; Cornille, Amandine; Tomes, Sumathi; Karunairetnam, Sakuntala; Luo, Zhiwei; Bassett, Heather; Whitworth, Claire; Rees-George, Jonathan; Ranatunga, Chandra; Snirc, Alodie; Crowhurst, Ross; de Silva, Nihal; Warren, Ben; Deng, Cecilia; Kumar, Satish; Chagné, David; Bus, Vincent G M; Volz, Richard K; Rikkerink, Erik H A; Gardiner, Susan E; Giraud, Tatiana; MacDiarmid, Robin; Gleave, Andrew P

    2015-10-01

    The molecular genetic mechanisms underlying fruit size remain poorly understood in perennial crops, despite size being an important agronomic trait. Here we show that the expression level of a microRNA gene (miRNA172) influences fruit size in apple. A transposon insertional allele of miRNA172 showing reduced expression associates with large fruit in an apple breeding population, whereas over-expression of miRNA172 in transgenic apple significantly reduces fruit size. The transposon insertional allele was found to be co-located with a major fruit size quantitative trait locus, fixed in cultivated apples and their wild progenitor species with relatively large fruit. This finding supports the view that the selection for large size in apple fruit was initiated prior to apple domestication, likely by large mammals, before being subsequently strengthened by humans, and also helps to explain why signatures of genetic bottlenecks and selective sweeps are normally weaker in perennial crops than in annual crops.

  16. Functional characteristics of the Staphylococcus aureus δ-toxin allelic variant G10S.

    Science.gov (United States)

    Cheung, Gordon Y C; Yeh, Anthony J; Kretschmer, Dorothee; Duong, Anthony C; Tuffuor, Kwame; Fu, Chih-Lung; Joo, Hwang-Soo; Diep, Binh A; Li, Min; Nakamura, Yuumi; Nunez, Gabriel; Peschel, Andreas; Otto, Michael

    2015-12-10

    Staphylococcus aureus δ-toxin is a member of the phenol-soluble modulin (PSM) peptide family. PSMs have multiple functions in staphylococcal pathogenesis; for example, they lyse red and white blood cells and trigger inflammatory responses. Compared to other PSMs, δ-toxin is usually more strongly expressed but has only moderate cytolytic capacities. The amino acid sequences of S. aureus PSMs are well conserved with two exceptions, one of which is the δ-toxin allelic variant G10S. This variant is a characteristic of the subspecies S. argenteus and S. aureus sequence types ST1 and ST59, the latter representing the most frequent cause of community-associated infections in Asia. δ-toxin G10S and strains expressing that variant from plasmids or the genome had significantly reduced cytolytic and pro-inflammatory capacities, including in a strain background with pronounced production of other PSMs. However, in murine infection models, isogenic strains expressing the two δ-toxin variants did not cause measurable differences in disease severity. Our findings indicate that the widespread G10S allelic variation of the δ-toxin locus has a significant impact on key pathogenesis mechanisms, but more potent members of the PSM peptide family may overshadow that impact in vivo.

  17. Comparative analysis of conditional reporter alleles in the developing embryo and embryonic nervous system.

    Science.gov (United States)

    Ellisor, Debra; Koveal, Dorothy; Hagan, Nellwyn; Brown, Ashly; Zervas, Mark

    2009-10-01

    A long-standing problem in development is understanding how progenitor cells transiently expressing genes contribute to complex anatomical and functional structures. In the developing nervous system an additional level of complexity arises when considering how cells of distinct lineages relate to newly established neural circuits. To address these problems, we used both cumulative marking with Cre/loxP and Genetic Inducible Fate Mapping (GIFM), which permanently and heritably marks small populations of progenitors and their descendants with fine temporal control using CreER/loxP. A key component used in both approaches is a conditional phenotyping allele that has the potential to be expressed in all cell types, but is quiescent because of a loxP flanked Stop sequence, which precedes a reporter allele. Upon recombination, the resulting phenotyping allele is 'turned on' and then constitutively expressed. Thus, the reporter functions as a high fidelity genetic lineage tracer in vivo. Currently there is an array of reporter alleles that can be used in marking strategies, but their recombination efficiency and applicability to a wide array of tissues has not been thoroughly described. To assess the recombination/marking potential of the reporters, we utilized CreER(T) under the control of a Wnt1 transgene (Wnt1-CreER(T)) as well as a cumulative, non-inducible En1(Cre) knock-in line in combination with three different reporters: R26R (LacZ reporter), Z/EG (EGFP reporter), and Tau-Lox-STOP-Lox-mGFP-IRES-NLS-LacZ (membrane-targeted GFP/nuclear LacZ reporter). We marked the Wnt1 lineage using each of the three reporters at embryonic day (E) 8.5 followed by analysis at E10.0, E12.5, and in the adult. We also compared cumulative marking of cells with a history of En1 expression at the same stages. We evaluated the reporters by whole-mount and section analysis and ascertained the strengths and weaknesses of each of the reporters. Comparative analysis with the reporters

  18. Engineered zinc-finger proteins can compensate genetic haploinsufficiency by transcriptional activation of the wild-type allele: application to Willams-Beuren syndrome and supravalvular aortic stenosis.

    Science.gov (United States)

    Zhang, Pei; Huang, Angela; Morales-Ruiz, Manuel; Starcher, Barry C; Huang, Yan; Sessa, William C; Niklason, Laura E; Giordano, Frank J

    2012-11-01

    Williams-Beuren syndrome (WBS) and supravalvular aortic stenosis (SVAS) are genetic syndromes marked by the propensity to develop severe vascular stenoses. Vascular lesions in both syndromes are caused by haploinsufficiency of the elastin gene. We used these distinct genetic syndromes as models to evaluate the feasibility of using engineered zinc-finger protein transcription factors (ZFPs) to achieve compensatory expression of haploinsufficient genes by inducing augmented expression from the remaining wild-type allele. For complex genes with multiple splice variants, this approach could have distinct advantages over cDNA-based gene replacement strategies. Targeting the elastin gene, we show that transcriptional activation by engineered ZFPs can induce compensatory expression from the wild-type allele in the setting of classic WBS and SVAS genetic mutations, increase elastin expression in wild-type cells, induce expression of the major elastin splice variants, and recapitulate their natural stoichiometry. Further, we establish that transcriptional activation of the mutant allele in SVAS does not overcome nonsense-mediated decay, and thus ZFP-mediated transcriptional activation is not likely to induce production of a mutant protein, a crucial consideration. Finally, we show in bioengineered blood vessels that ZFP-mediated induction of elastin expression is capable of stimulating functional elastogenesis. Haploinsufficiency is a common mechanism of genetic disease. These findings have significant implications for WBS and SVAS, and establish that haploinsufficiency can be overcome by targeted transcriptional activation without inducing protein expression from the mutant allele.

  19. Vitamin D Responsive Elements within the HLA-DRB1 Promoter Region in Sardinian Multiple Sclerosis Associated Alleles

    Science.gov (United States)

    Murru, Maria Rita; Corongiu, Daniela; Tranquilli, Stefania; Fadda, Elisabetta; Murru, Raffaele; Schirru, Lucia; Secci, Maria Antonietta; Costa, Gianna; Asunis, Isadora; Cuccu, Stefania; Fenu, Giuseppe; Lorefice, Lorena; Carboni, Nicola; Mura, Gioia; Rosatelli, Maria Cristina; Marrosu, Maria Giovanna

    2012-01-01

    Vitamin D response elements (VDREs) have been found in the promoter region of the MS-associated allele HLA-DRB1*15∶01, suggesting that with low vitamin D availability VDREs are incapable of inducing *15∶01 expression allowing in early life autoreactive T-cells to escape central thymic deletion. The Italian island of Sardinia exhibits a very high frequency of MS and high solar radiation exposure. We test the contribution of VDREs analysing the promoter region of the MS-associated DRB1 *04∶05, *03∶01, *13∶01 and *15∶01 and non-MS-associated *16∶01, *01, *11, *07∶01 alleles in a cohort of Sardinians (44 MS patients and 112 healthy subjects). Sequencing of the DRB1 promoter region revealed a homozygous canonical VDRE in all *15∶01, *16∶01, *11 and in 45/73 *03∶01 and in heterozygous state in 28/73 *03∶01 and all *01 alleles. A new mutated homozygous VDRE was found in all *13∶03, *04∶05 and *07∶01 alleles. Functionality of mutated and canonical VDREs was assessed for its potential to modulate levels of DRB1 gene expression using an in vitro transactivation assay after stimulation with active vitamin D metabolite. Vitamin D failed to increase promoter activity of the *04∶05 and *03∶01 alleles carrying the new mutated VDRE, while the *16∶01 and *03∶01 alleles carrying the canonical VDRE sequence showed significantly increased transcriptional activity. The ability of VDR to bind the mutant VDRE in the DRB1 promoter was evaluated by EMSA. Efficient binding of VDR to the VDRE sequence found in the *16∶01 and in the *15∶01 allele reduced electrophoretic mobility when either an anti-VDR or an anti-RXR monoclonal antibody was added. Conversely, the Sardinian mutated VDRE sample showed very low affinity for the RXR/VDR heterodimer. These data seem to exclude a role of VDREs in the promoter region of the DRB1 gene in susceptibility to MS carried by DRB1* alleles in Sardinian patients. PMID:22848563

  20. Dietary lysine imbalance affects muscle proteome in zebrafish (Danio rerio): a comparative 2D-DIGE study.

    Science.gov (United States)

    de Vareilles, Mahaut; Conceição, Luis E C; Gómez-Requeni, Pedro; Kousoulaki, Katerina; Richard, Nadège; Rodrigues, Pedro M; Fladmark, Kari E; Rønnestad, Ivar

    2012-10-01

    Lysine (Lys) is an indispensable amino acid (AA) and generally the first limiting AA in vegetable protein sources in fish feeds. Inadequate dietary Lys availability may limit protein synthesis, accretion and growth of fish. This experiment aimed to further elucidate the role of Lys imbalance on growth by examining the myotomal muscle proteome of juvenile zebrafish (Danio rerio). Quadruplicate groups of 8 fish were fed either a low-Lys [Lys(-), 1.34 g kg(-1)], medium/control (Lys, 2.47 g kg(-1)) or high-Lys [Lys(+), 4.63 g kg(-1)] diet. Fish growth was monitored from 33 to 49 days post-fertilization (dpf) and trunk myotomal muscle proteome of Lys(-) and Lys(+) treatments were screened by 2D-DIGE and MALDI ToF tandem mass spectrometry. Growth rate was negatively affected by diet Lys(-). Out of 527 ± 11 (mean ± S.E.M.) protein spots detected (∼10-150 kDa and 4-7 pI value), 30 were over-expressed and 22 under-expressed in Lys(-) fish (|fold-change| >1.2, p value muscle protein accretion. The Lys deficiency also possibly induced a higher feeding activity, reflected in the over-expression of beta enolase and mitochondrial ATP synthase. Contrarily, in the faster growing fish [Lys(+)], over-expression of apolipoprotein A-I, F-actin capping protein and Pdlim7 point to increased energy storage as fat and enhanced muscle growth, particularly by mosaic hyperplasia. Thus using an exploratory approach, this study pinpoints interesting candidates for further elucidating the role of dietary Lys on growth of juvenile fish.

  1. Identification and characterization of variant alleles at CODIS STR loci.

    Science.gov (United States)

    Allor, Catherine; Einum, David D; Scarpetta, Marco

    2005-09-01

    Short tandem repeat (STR) profiles from 32,671 individuals generated by the ABI Profiler Plus and Cofiler systems were screened for variant alleles not represented within manufacturer-provided allelic ladders. A total of 85 distinct variants were identified at 12 of the 13 CODIS loci, most of which involve a truncated tetranucleotide repeat unit. Twelve novel alleles, identified at D3S1358, FGA, D18S51, D5S818, D7S820 and TPOX, were confirmed by nucleotide sequence analysis and include both insertions and deletions involving the repeat units themselves as well as DNA flanking the repeat regions. Population genetic data were collected for all variants and frequencies range from 0.0003 (many single observations) to 0.0042 (D7S820 '10.3' in North American Hispanics). In total, the variant alleles identified in this study are carried by 1.6% of the estimated 1 million individuals tested annually in the U.S. for the purposes of parentage resolution. A paternity case involving a recombination event of paternal origin is presented and demonstrates how variant alleles can significantly strengthen the genetic evidence in troublesome cases. In such instances, increased costs and turnaround time associated with additional testing may be eliminated.

  2. STR allele sequence variation: Current knowledge and future issues.

    Science.gov (United States)

    Gettings, Katherine Butler; Aponte, Rachel A; Vallone, Peter M; Butler, John M

    2015-09-01

    This article reviews what is currently known about short tandem repeat (STR) allelic sequence variation in and around the twenty-four loci most commonly used throughout the world to perform forensic DNA investigations. These STR loci include D1S1656, TPOX, D2S441, D2S1338, D3S1358, FGA, CSF1PO, D5S818, SE33, D6S1043, D7S820, D8S1179, D10S1248, TH01, vWA, D12S391, D13S317, Penta E, D16S539, D18S51, D19S433, D21S11, Penta D, and D22S1045. All known reported variant alleles are compiled along with genomic information available from GenBank, dbSNP, and the 1000 Genomes Project. Supplementary files are included which provide annotated reference sequences for each STR locus, characterize genomic variation around the STR repeat region, and compare alleles present in currently available STR kit allelic ladders. Looking to the future, STR allele nomenclature options are discussed as they relate to next generation sequencing efforts underway.

  3. A platform for interrogating cancer-associated p53 alleles.

    Science.gov (United States)

    D'Brot, A; Kurtz, P; Regan, E; Jakubowski, B; Abrams, J M

    2017-01-12

    p53 is the most frequently mutated gene in human cancer. Compelling evidence argues that full transformation involves loss of growth suppression encoded by wild-type p53 together with poorly understood oncogenic activity encoded by missense mutations. Furthermore, distinguishing disease alleles from natural polymorphisms is an important clinical challenge. To interrogate the genetic activity of human p53 variants, we leveraged the Drosophila model as an in vivo platform. We engineered strains that replace the fly p53 gene with human alleles, producing a collection of stocks that are, in effect, 'humanized' for p53 variants. Like the fly counterpart, human p53 transcriptionally activated a biosensor and induced apoptosis after DNA damage. However, all humanized strains representing common alleles found in cancer patients failed to complement in these assays. Surprisingly, stimulus-dependent activation of hp53 occurred without stabilization, demonstrating that these two processes can be uncoupled. Like its fly counterpart, hp53 formed prominent nuclear foci in germline cells but cancer-associated p53 variants did not. Moreover, these same mutant alleles disrupted hp53 foci and inhibited biosensor activity, suggesting that these properties are functionally linked. Together these findings establish a functional platform for interrogating human p53 alleles and suggest that simple phenotypes could be used to stratify disease variants.

  4. Swine Leukocyte Antigen (SLA) class I allele typing of Danish swine herds and identification of commonly occurring haplotypes using sequence specific low and high resolution primers.

    Science.gov (United States)

    Pedersen, Lasse Eggers; Jungersen, Gregers; Sorensen, Maria Rathmann; Ho, Chak-Sum; Vadekær, Dorte Fink

    2014-12-15

    The swine major histocompatibility complex (MHC) genomic region (SLA) is extremely polymorphic comprising high numbers of different alleles, many encoding a distinct MHC class I molecule, which binds and presents endogenous peptides to circulating T cells of the immune system. Upon recognition of such peptide-MHC complexes (pMHC) naïve T cells can become activated and respond to a given pathogen leading to its elimination and the generation of memory cells. Hence SLA plays a crucial role in maintaining overall adaptive immunologic resistance to pathogens. Knowing which SLA alleles that are commonly occurring can be of great importance in regard to future vaccine development and the establishment of immune protection in swine through broad coverage, highly specific, subunit based vaccination against viruses such as swine influenza, porcine reproductive and respiratory syndrome virus, vesicular stomatitis virus, foot-and-mouth-disease virus and others. Here we present the use of low- and high-resolution PCR-based typing methods to identify individual and commonly occurring SLA class I alleles in Danish swine. A total of 101 animals from seven different herds were tested, and by low resolution typing the top four most frequent SLA class I alleles were those of the allele groups SLA-3*04XX, SLA-1*08XX, SLA-2*02XX, and SLA-1*07XX, respectively. Customised high resolution primers were used to identify specific alleles within the above mentioned allele groups as well as within the